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Obesity-Related Changes in High-Density Lipoprotein Metabolism and Function

Julia T. Stadler, Gunther Marsche

International Journal of Molecular Sciences · 2020 · Review · CC BY

doi:10.3390/ijms21238985

Abstract

In obese individuals, atherogenic dyslipidemia is a very common and important factor in the increased risk of cardiovascular disease. Adiposity-associated dyslipidemia is characterized by low high-density lipoprotein cholesterol (HDL-C) levels and an increase in triglyceride-rich lipoproteins. Several factors and mechanisms are involved in lowering HDL-C levels in the obese state and HDL quantity and quality is closely related to adiponectin levels and the bioactive lipid sphingosine-1-phosphate. Recent studies have shown that obesity profoundly alters HDL metabolism, resulting in altered HDL subclass distribution, composition, and function. Importantly, weight loss through gastric bypass surgery and Mediterranean diet, especially when enriched with virgin olive oil, is associated with increased HDL-C levels and significantly improved metrics of HDL function. A thorough understanding of the underlying mechanisms is crucial for a better understanding of the impact of obesity on lipoprotein metabolism and for the development of appropriate therapeutic approaches. The objective of this review article was to summarize the newly identified changes in the metabolism, composition, and function of HDL in obesity and to discuss possible pathophysiological consequences.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

The increasing prevalence of obesity in the last decades has become a major health problem worldwide. In Northern America and Europe, in particular, the number of overweight and obese people is ever increasing and is becoming more common in children and adolescents. The causes of obesity are multifactorial, with the most important factors being excess calorie intake and lack of physical activity. Excessive body weight increases the risk of disease development, such as coronary artery disease, hypertension, type-2 diabetes mellitus, and dyslipidemia. High levels of triglyceride-rich lipoproteins and low levels of high-density lipoprotein cholesterol (HDL-C) commonly characterize dyslipidemia in obesity. In obesity, not only HDL levels are altered, but an altered HDL distribution pattern and abnormal HDL metabolism have also been observed, which often leads to dysfunction of the HDL particles. Consequently, the focus has shifted from studying the quantity of HDL to studying the quality of HDL. The current review will focus on HDL metabolism and the pathophysiological changes seen in obesity. Further, we will focus on obesity-induced changes in HDL composition and the concomitant changes of HDL functionality. Another aspect will be the relationship of HDL with the adipokine adiponectin as well as with the bioactive lipid sphingosine-1-phosphate (S1P), whose levels are altered in the state of obesity. We also summarize the effects of weight loss induced by bariatric surgery, Mediterranean diet and pharmacological approaches, which effectively increase HDL-C levels and improve HDL function.

2.1. HDL Metabolism

The biogenesis of HDL starts in the liver and the intestine, where apolipoprotein (apo) A-I is synthesized (Figure 1). After secretion, lipid-poor apoA-I interacts with the integral cell membrane protein ATP-binding cassette transporter A1 (ABCA1), which is abundantly expressed by hepatocytes and enterocytes. Through interaction, apoA-I acquires lipids from the cellular lipid pool, generating nascent HDL particles. Additional lipids and apolipoproteins are acquired, which are derived from hydrolysis of triglyceride-rich lipoproteins. This process partly explains the strong inverse relationship of HDL-C and triglyceride levels, often observed in obese subjects. The acquired cholesterol of HDL is further esterified by lecithin-cholesterol-acyl transferase (LCAT), forming mature HDL particles. The reaction takes place at the surface of HDL and requires apoA-I as an activator for LCAT. The generated HDL-associated cholesteryl-esters are partially transferred to apoB-containing lipoproteins by cholesteryl-ester transfer protein (CETP), usually in exchange for triglycerides. Another pathway for clearance of cholesteryl-ester in HDL is the direct uptake by the liver via scavenger receptor class B type 1 (SR-BI). After interaction of SR-BI with large cholesterol-rich HDL, cholesteryl-esters and free cholesterol are internalized and cholesterol is removed through the bile, while apoA-I dissociates.

HDL is enriched in triglycerides through the activity of CETP, generating HDL particles that are more susceptible to lipolysis by endothelial lipase (EL) or hepatic lipase (HL). Substrates for lipolysis are mainly phospholipids (EL) or phospholipids and triglycerides (HL), but with different specificity for phospholipids. The lipolysis of triglycerides leads to the formation of smaller HDL particles, which are susceptible to faster catabolism. Another important key player of HDL metabolism is the phospholipid transfer protein (PLTP), which transfers phospholipids between HDL particles and lipids between triglyceride-rich lipoproteins and HDL. Many apolipoproteins, lipid transfer proteins, enzymes, cell surface receptors, and cellular lipid transporters are involved in the regulation of HDL metabolism and partly determine levels of plasma HDL-C. This complex metabolism produces HDL particles of varying size, density, and composition. Therefore, plasma HDL-C concentrations are not a good parameter to reflect functional properties of HDL, such as HDL-mediated reverse cholesterol transport or anti-oxidative or anti-inflammatory properties.

2.2. HDL Structure and Composition

Plasma levels of HDL-C have been associated with cardiovascular diseases for decades. However, it is becoming widely accepted that it is not the quantity but the quality of HDL that is important, as HDL performs different functions depending on the protein and lipid composition. ApoA-I is the most prevalent protein component of HDL, accounting for approximately 70% of the total protein. ApoA-I has a variety of functions, such as activation of LCAT, interaction with cellular receptors, and anti-atherogenic activities. ApoA-II is the second major apolipoprotein in HDL and presents about 15–20% of the total protein component. The remaining 10–15% of HDL protein mass comprises minor proteins, including apoA-IV, ApoCs, which are important enzyme regulators, apoD, apoE, apoF, apoH, apoJ, ApoL-I, and apoM, and several enzymes. Paraoxonase 1 (PON1) is almost exclusively associated with HDL and has been shown to exert anti-inflammatory and anti-oxidative properties. Other enzymes associated with HDL are LCAT and the platelet-activating factor acetyl hydrolase. The phospholipid transfer protein and CETP have a lipid transfer activity and are important in lipoprotein metabolism. Remarkably, it is not cholesterol that predominates the HDL lipidome, but phospholipids. Taken together, phospholipids and sphingolipids account for 40–60% of total lipids, while cholesteryl-ester (30–40%), triglycerides (5–12%), and free cholesterol (5–10%) are less abundant. Similar to functions of HDL-associated proteins, HDL lipids also accomplish distinct structural functions. The lipid surface monolayer is constituted of phospholipids, while cholesteryl-ester and triglycerides form the hydrophobic core. In total, more than 200 lipids and 80 proteins are carried by different HDL subclasses, with individual HDL particles carrying only a few other proteins besides apoA-I.

2.3. HDL Subclasses

Multiple subclasses of HDL exist, depending on its stage of maturation, site of origin, and its protein and lipid composition. Thus, HDL particles are highly heterogeneous in their size, shape, structure, and density (Table 1). Pre-β HDL is structurally the simplest form of HDL. These particles consist of one or two apoA-I molecules with a phospholipid layer and a trace amount of cholesterol. These particles are discoidal shaped with a diameter of approximately 9.6 nm and a thickness of 4.7 nm. Pre-β HDL particles rapidly take up cholesterol and phospholipids, which convert them into larger HDL subclasses. Therefore, pre-β HDL only accounts for about 5% of HDL in the circulation. Because of their function to avidly absorb cholesterol and phospholipids, pre-β HDL particles are thought to be a major factor in preventing atherosclerotic plaque formation. Importantly, higher serum cholesterol efflux capacity is related to plasma concentrations of pre-β HDL. HDL3 particles have a smaller diameter (7.5 nm) and are enriched with proteins, while HDL2 particles are larger (10 nm) and lipid rich. Most abundant apolipoproteins are apoA-I and apoA-II in both subclasses; however, apoA-II is more present in HDL3. Interestingly, the HDL-associated enzyme PON1, which has anti-oxidative and anti-inflammatory properties, has been shown to be more frequently associated with HDL3. This higher abundance of PON1 on HDL3 could partly explain the higher anti-oxidative capacity of the smaller HDL particles. HDL2 and HDL3 further show differences in lipid composition. Sphingolipids are, in general, less abundant in the HDL3 subclass, affecting surface lipid fluidity, whereas the bioactive lipid sphingosine-1-phosphate (S1P) is predominantly associated with HDL3. In line, the abundance of apoM, which specifically anchors S1P to HDL particle, shows higher abundance in HDL3. S1P maintains vascular integrity and mediates multiple effects of HDL on endothelial cells. The functions of HDL to induce vasorelaxation as well as promoting barrier function have been attributed to signaling of S1P. Taken together, it seems that smaller subclasses of HDL have a greater protective potential than larger particles.

2.4. Important Functions of HDL

One of the main functions of HDL is its ability to promote reverse cholesterol transport, the uptake of excess cholesterol from peripheral cells, and the transport to the liver for excretion. This process is considered as the major antiatherogenic effect of HDL.

The reverse cholesterol transport starts with the secretion of lipid-poor apoA-I, which is released from liver or intestine into the plasma to circulate to peripheral cells from which excess cholesterol is removed, forming nascent HDL. A key role in the reverse cholesterol transport is the interaction of apoA-I with ABCA1. Studies have shown that ABCA1 preferentially lipidates small HDL, specifically apoA-I, to form nascent HDL, while ATP-binding cassette subfamily G member 1 (ABCG1) stimulates cholesterol efflux to mature HDL and not to lipid-poor apoA-I. Cholesterol efflux includes the passive diffusion of cholesterol from cells as well as the active cellular cholesterol transfer by ABCA1, ABCG1, and SR-BI. The absorbed cholesterol is esterified by LCAT and mature HDL is formed. HDL-associated cholesteryl-ester is partially transferred to triglyceride-rich lipoproteins by CETP and further cleared by hepatic clearance through the low-density lipoprotein (LDL) receptor or taken up together with free cholesterol by the hepatic receptor SR-BI. Therefore, the transfer of cholesterol from peripheral cells to the liver involves two routes: (1) the direct uptake via SR-BI and (2) indirect by HDL-LDL/very low-density lipoprotein (VLDL) interaction. In the liver, the cholesteryl-esters are hydrolyzed, and free cholesterol is either transported by ABCG5 and ABCG8 into the bile for excretion into feces or converted into bile acids or reused for VLDL production.

This process of HDL-mediated cholesterol efflux has been of expanded research interest in recent years. A number of different cell-based assays have been developed, to measure the ability of HDL to promote cholesterol efflux, the first step of reverse cholesterol transport. In the most established assay, a mouse macrophage cell line (J774) was employed. Cells are enriched with radioactively or fluorescently labeled cholesterol and cyclic adenosine monophosphate to upregulate expression of ABCA1. For these assays, isolated HDL or apoB-depleted serum from patients is added to cell medium and the proportion between labeled cholesterol in the supernatant and in the cells is calculated.

Besides the ability of HDL to promote cholesterol efflux, there is increasing evidence that HDL-mediated antiatherogenic actions toward the endothelium have physiological relevance.

The beneficial properties of HDL on the endothelium include vasodilatory activity, primarily through stimulation of nitric oxide (NO) release from endothelial cells, and also the production of prostacyclin. The initial step for the activation of NO production involves binding of HDL to SR-BI on the endothelium. Subsequent intracellular events are mediated by endothelial protein kinase B and intracellular Ca2+ mobilization, increase in intracellular ceramide levels, and the phosphorylation of the endothelial NO-synthase, leading to NO release. HDL reduces the activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the endothelium, which reduces the cellular production of superoxide, an inactivator of NO, thereby increasing NO bioavailability. Vasodilatory actions of HDL further include cholesterol efflux of cholesterol and 7-oxysterols, mediated by ABCG1, which improves formation of active endothelial NO-synthase dimers, resulting in decreased production of reactive oxygen species.

Another anti-atherogenic function of HDL is its ant-oxidative activity by protecting LDL from oxidative damage induced by free radicals, thus reducing its atherogenicity. ApoA-I, the major protein component of HDL may play a central role in HDL-mediated anti-oxidative activity, by reduction of lipid hydroperoxides through methionine residues. In addition, HDL-associated PON1 was shown to decrease lipid peroxidation of LDL and HDL through a specific cysteine residue. Other apolipoprotein components and HDL-associated enzymes, such as apoA-II, apoE, apoJ, lipoprotein-associated phospholipase A2, and LCAT, may further contribute to the anti-oxidative properties. HDL-associated lipophilic antioxidants such as tocopherols seem to make a small contribution to the antioxidant properties of HDL.

Additionally, to the number of anti-oxidative effects, HDL further possesses anti-inflammatory properties. In vitro experiments have shown that HDL inhibits transmigration of monocytes and inhibits cytokine-induced expression of vascular cell adhesion molecule, intercellular cell adhesion molecule, and E-selectin expression. By modulation of the nuclear factor κB and the peroxisome proliferator-activated receptor gamma, HDL further inhibits the production of pro-inflammatory cytokines. Due to these capabilities, HDL reduces the recruitment of lymphocytes, monocytes, and basophils to the vascular endothelium, thereby decelerating downstream events of inflammatory response.

3. HDL-C-Raising Therapies and Cardiovascular Outcome

The cholesterol component of HDL has been shown to be inversely associated with the risk of coronary heart disease (CHD) and is a key component of predicting cardiovascular risk in the general population. The Framingham Heart Study was the first study to observe the strong association between HDL-C and CHD and, therefore, served as the basis for the hypothesis that HDL, as the “good” cholesterol, might hold protective properties against CHD. However, more recent data clearly indicate that the association between HDL-C concentration and all-cause mortality is U-shaped, and both extremely high and low HDL-C concentrations are associated with an increase in mortality. This leads to considerable uncertainty about the potential benefit of increasing HDL-C and may reflect or explain the disappointing results of recent clinical studies on a number of therapeutic interventions aimed at increasing HDL-C levels, such as CETP inhibitors. Given the heterogeneity of HDL particles in terms of structure, size, lipidomic/proteomic composition, and metabolism, HDL-C values are only a snapshot of the steady-state cholesterol pool. HDL-C values provide no direct information on the rate of cholesterol efflux from vascular macrophages in liver, which is influenced by many factors beyond the mass of HDL-C alone. Furthermore, the circulating HDL-C concentrations do not provide information about the anti-inflammatory, anti-oxidant, anti-thrombotic, and endothelial function-promoting activities of HDL. Therefore, considerable interest has recently focused on approaches to influence the biological functions of HDL in the search for new cardioprotective therapies. This is based on new findings that underline the importance of HDL functionality, which has led to ongoing efforts to develop new risk markers and therapeutics that focus on HDL quality rather than quantity.

4. Obesity Alters HDL-C Levels

Obesity is commonly accompanied by low HDL-C levels and an increase in triglyceride-rich lipoproteins, which is often termed as atherogenic dyslipidemia. Characteristic for this dyslipidemia is a decreased clearance of triglyceride-rich lipoproteins, which is caused by a relative lack of insulin-sensitive lipoprotein lipase. Lipoprotein lipase hydrolyzes triglycerides of chylomicrons and VLDL, leading to shrinkage of the particles and transfer of surface phospholipids and apolipoproteins to HDL, thus increasing HDL size. During obesity, the response of lipoprotein lipase activity to glucose stimulation has been shown to be reduced, representing one potential factor contributing to the decrease of HDL-C in obesity.

The increase of triglyceride-rich lipoproteins is a causal factor for low HDL-C levels in obesity. The increase in the release of free fatty acids from the adipocytes caused by obesity increases their uptake by the liver, resulting in liver accumulation and enhanced production of VLDL and its release into the bloodstream (Figure 2). This increase of acceptor lipoproteins further stimulates the transfer of triglycerides on HDL in exchange for cholesteryl-esters mediated by CETP. During this process, HDL is enriched in triglycerides and represents a better substrate for hepatic lipase and is hydrolyzed more rapidly. In obese insulin-resistant subjects, HDL is enriched in triglycerides and the activity of hepatic lipase is increased. Hydrolysis of triglyceride-rich HDL further leads to the formation of smaller HDL3 particles, which are susceptible to faster catabolism. Interestingly, even when fasting plasma triglyceride levels are at a normal level, obese patients often display low HDL-C levels, suggesting further mechanisms leading to HDL-C lowering in obesity.

Another characteristic of obesity is an imbalance of adipokines, including leptin. Leptin is mainly produced by adipocytes and is elevated in overweight and obese individuals. Interestingly, a study in children showed that plasma leptin levels correlated with HDL-C. Further, a correlation between leptin and HDL-associated triglycerides and with HDL particle size has been reported in adults. In vivo experiments in leptin-deficient (ob/ob) mice suggest that leptin upregulates hepatic SR-BI and thereby influences levels of HDL-C.

In the state of obesity, increased CETP levels are correlated with leptin levels, in line with the fact that adipose tissue is one of the major sources of CETP expression. Therefore, the obesity-associated increase in CETP production is thought to affect HDL-C levels.

Another molecule, secreted from adipose tissue, which may have a direct impact on HDL metabolism, is the adipokine adiponectin. Studies have shown that levels of adiponectin, which are reduced in the state of obesity, are directly correlated with plasma HDL-C levels. Furthermore, an intervention study showed that levels of adiponectin as well as of HDL-C are increasing after weight loss and that this improvement was independent of changes in insulin sensitivity and fat mass. The relationship of HDL with adiponectin will be discussed in Section 5.3 in more detail.

As mentioned above, the activity of hepatic lipase is increased in obesity and insulin resistance, leading to faster clearance of triglyceride-rich HDL, which is produced by CETP-mediated transfer. The triglyceride-enriched HDL is a more susceptible substrate for hepatic lipase and, therefore, undergoes rapid hydrolysis. The mechanisms underlying the increase in hepatic lipase activity in obese states are not yet understood, but it appears that hepatic insulin resistance plays an important role. However, further studies are needed to clarify the link between HDL metabolism and hepatic lipase expression in obesity and insulin resistance.

Another lipase, which may affect HDL-C levels in obesity or insulin resistance is endothelial lipase. Experiments with rodents already revealed the impact of endothelial lipase on HDL metabolism: Inhibition or genetic deletion of endothelial lipase resulted in elevated levels of HDL-C by reduction of catabolism rate, while overexpression of endothelial lipase caused a reduction of HDL-C by increased catabolism rate. Human studies further have shown that some rare genetic variants in the endothelial lipase gene are linked with high HDL-C levels and that they are correlated to levels of plasma endothelial lipase mass. In obesity, levels of endothelial lipase have been shown to be significantly elevated, proposing an upregulation of endothelial lipase during obese states, which may contribute to the reduced HDL-C levels. Obesity is characterized by low-grade inflammation, leading to infiltration of immune cells into adipose tissue. The obesity-induced inflammation may decrease HDL-C levels by upregulation of endothelial lipase. However, the significance of endothelial lipase on low levels of HDL-C in the obese state further needs to be investigated.

Another factor affecting HDL-C is cholesterol released by adipocytes. In humans, adipose tissue is a major site for cholesterol storage and contains up to 25% of total body cholesterol in normal-weight subjects and approximately half of it in obese states. In adipose tissue, nearly all of the cholesterol is stored in the unesterified form, as free cholesterol, which makes adipocytes unique among cells. It is well reported that adipocytes express the major cholesterol transporters ABCA1 and SR-BI as well as ABCG1, but in a much lesser extent. Adipocytes are promoting cholesterol transfer to HDL via ABCA1 and SR-BI, representing a direct factor for modulation of HDL-C levels. Importantly, Zhang et al. demonstrated that lack of adipose ABCA1 resulted in reduced levels of HDL-C and caused a backlog of cholesterol within adipose tissue. Further, they showed that adipocyte inflammation, which is a hallmark of central obesity, downregulates ABCA1 and SR-BI expression and impairs cholesterol efflux from adipocytes to HDL. Therefore, their results suggest a direct impact of adipose tissue on modulation of HDL-C and that obesity-induced inflammation of adipocytes may result in impaired cholesterol efflux to HDL, contributing to reduced HDL-C levels.

Concluding, several factors and mechanisms are involved in the reduction of HDL-C levels in the obese state, but further research on these mechanisms is of importance to find novel treatment strategies improving HDL quality and quantity.

5. Obesity, HDL, and Cardiovascular Risk

Obesity is one of the major risk factors for cardiovascular disease, which is associated with atherogenic dyslipidemia. These alterations in plasma lipid and lipoprotein levels contribute to the manifestation of such a severe morbidity.

5.1. Obesity Leads to a Shift in HDL Subclass Distribution

As described above, plasma HDL-C levels do not adequately reflect protective functions of HDL and greater protective potential is attributed to the smaller, more dense HDL particles. Recent studies of Woudberg et al. assessed HDL subclass distribution in normal-weight and obese white and black South African women. In obese study participants, a shift from large HDL toward increased levels of intermediate and small HDL subclasses was seen, whereby the effect was more pronounced in white women. In a 5.5-year follow-up study they showed that the shifts in HDL subclass distribution were related to increasing central adiposity, suggesting a link between body fat distribution and lipid metabolism. Based on the observed changes in HDL subclass distribution in obese individuals, Woudberg et al. explored the effect of exercise training on HDL subfractions. Interestingly, 12 weeks of exercise intervention altered the distribution of small HDL in obese women.

In adolescents suffering from type 2 diabetes mellitus, Davidson et al. determined the risk factors associated with the depletion of large HDL particles and simultaneous accumulation of small particles. The authors investigated the distribution of HDL subclasses of individuals who differed in body mass index and insulin sensitivity and found that obesity is the major risk factor linked to the altered HDL subclasses. An increased CETP-mediated transfer of triglycerides on HDL and the subsequent hydrolysis of triglyceride-enriched HDL by hepatic lipase appeared to be the mechanism underlying the shift of large HDL to small and dense HDL particles.

5.2. Obesity Affects HDL Function

It is known that HDL functionality is severely impaired in certain diseases and HDL may even have inflammatory or pro-atherogenic properties. This was clearly demonstrated in HDL from patients suffering from chronic kidney disease, diabetes, cardiovascular disease, liver disease, psoriasis, or even atopic dermatitis and allergic rhinitis. Obesity-associated complications, such as inflammation or diabetes, have been shown to render HDL dysfunctional. HDL isolated from type 2 diabetes patients did not reduce endothelial oxidant stress and did not improve endothelium-dependent vasodilatation when compared to HDL isolated from healthy subjects. Vasodilatory activity of HDL has been shown to be inversely correlated with triglyceride content of HDL, which is elevated in obesity. A reduction of the overall capacity of HDL to promote cholesterol efflux from fibroblasts in obese, compared to lean, normal-weight, subjects was reported. Of particular interest, cholesterol efflux capacity appears to be significantly inversely correlated with the body mass index. Since cholesterol efflux capacity is the main metric of HDL function and has strong inverse association with coronary artery disease, the reduction of efflux capacity in obesity may have a crucial impact on the development of cardiovascular disease.

5.3. Adiponectin and HDL

It has been well reported that plasma HDL-C concentrations show a strong correlation with levels of adiponectin, independent of body mass index, distribution of body fat, and insulin sensitivity. Adiponectin is mainly secreted by adipocytes, shows anti-atherogenic properties, and modulates glucose metabolism. Studies with mice overexpressing or lacking adiponectin as well as in vitro studies suggest a causal relationship with HDL-C levels.

Adiponectin increases the production of apoA-I as well as hepatic ABCA1, which increases HDL-C levels (Figure 3). The enhanced expression of ABCA1 has been suggested by activation of liver X receptor alpha and peroxisome proliferator-activated receptor gamma. Plasma levels of adiponectin show a negative correlation with fractional catabolic rate of apoA-I in individuals with metabolic syndrome and control subjects. Besides ABCA1, adiponectin upregulates ABCG1 expression, increases cholesterol efflux capacity, and efficiently promotes lipidation of apoA-I, leading to formation of nascent HDL.

Adiponectin has been consistently reported to be associated with cholesterol efflux capacity of HDL. Other studies have shown an inverse association of hepatic lipase with serum adiponectin levels. Adiponectin might inhibit the hepatic lipase-mediated hydrolysis of triglycerides and phospholipids of HDL2 particles. This is in line with studies showing an association of adiponectin with HDL particle size and HDL2. However, further studies are needed to prove causality. Another further mechanism suggested that adiponectin increases lipoprotein lipase activity, thereby accelerating clearance of triglyceride-rich particles. This, in turn, would lead to less exchange of triglycerides and cholesteryl-ester by CETP and, thus, to cholesteryl-ester-enriched HDL2 particles. A positive correlation between circulating adiponectin and post-heparin lipoprotein lipase activity has been reported, but causality has to be proven to draw firm conclusions. Low-grade inflammation and fat accumulation cause a dysregulated adipokine production and markedly reduce adiponectin levels. Therefore, low adiponectin observed in obesity levels may explain, at least in part, the shift of large HDL to small HDL particles.

5.4. Obesity and HDL-Associated Sphingosine-1-Phosphate (S1P)

Of particular importance, the complete sphingolipid metabolism is altered in obesity. In obese individuals the levels of ceramides, sphingosine, sphinganine, and S1P are increased in adipocytes when compared to lean controls. The bioactive lipid S1P is mainly carried via apoM anchored to HDL (about 65%) and to a lesser extent via albumin (about 25%) or LDL/VLDL (about 10%). The half-life of S1P is prolonged when it is associated with HDL, when compared with albumin-associated S1P. S1P is a member of the sphingolipid family, a large group of molecules with a wide range of physiological functions. S1P in the circulation is mainly derived from erythrocytes, vascular endothelial cells, and platelets. S1P activates five different G protein-coupled receptors, termed S1P receptors 1–5 (S1PR1–5), in an autocrine or paracrine manner.

Kowalski et al. observed that levels of S1P are elevated in plasma of obese humans and rodents and that the levels correlate with metabolic abnormalities such as adiposity and markers of insulin resistance. However, this increase of S1P could not be confirmed in a study comparing levels between overweight and lean adolescents. More recently, the group of Green et al. analyzed the liver metabolome of mice after caloric restriction and revealed that caloric restriction had an impact on S1P signaling. The authors observed that as a response to caloric restriction, liver expression of S1P was significantly increased. S1P levels were negatively associated with decreasing body mass, leptin, and insulin-like growth factor-1. Another study investigated the role of S1P/S1PR1 signaling in the regulation of energy homeostasis in rodents. The authors showed that S1PR is highly expressed in the hypothalamus and that a fasting period of 12 h could reduce S1PR level, whereas refeeding restored the protein levels of the receptor in the hypothalamus. Altogether, their results indicated that the S1P/S1PR1 axis plays a critical role in energy balance and represents a potential target for treatment of obesity. The potential role of S1P signaling in energy metabolism was strengthened by Christoffersen et al., showing that lack of apoM in mice increases the amount of brown adipose tissue and that the turnover of fat is increased, resulting in low white adipose tissue mass and low body weight. These effects of apoM knockout suggest that pharmacological modulation of S1PRs may be a promising approach for the treatment of obesity and associated diseases in the future.

Noteworthily, only a small number of studies investigated plasma levels of S1P in obese or overweight human subjects. While obesity is associated with a shift from large HDL to small and dense HDL, S1P has to be increasingly transported with alternative chaperones, reducing the effectiveness of S1P. In line with this hypothesis, Frej et al. showed that a shift in apoM/S1P between HDL particles in women was associated with impaired anti-inflammatory effects of the apoM/S1P complex.

6. Bariatric Surgery Improves HDL Levels and Function

Bariatric surgery has been demonstrated as the most effective intervention for patients with severe obesity, which induces sustained long-term weight reduction associated with decreased obesity-associated comorbidities and cardiovascular mortality. The standard bariatric surgeries are Roux-en-Y gastric bypass (RYGB), where most of the stomach is bypassed, creating a small gastric pouch; whereas sleeve gastrectomy resects the gastric fundus and most of the gastric body. RYGB surgeries resulted in significant improvements of plasma lipid levels, decreased risk of cardiovascular disease, and overall mortality. Further, after RYGB, levels of circulating adiponectin increased, insulin sensitivity improved, and blood pressure levels were reduced.

Of particular interest is that the plasma levels of HDL-C after bariatric surgery were remarkably improved compared to the preoperative values and compared to people who only received medical therapy for weight loss. In the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) clinical trial, obese patients with type 2 diabetes mellitus were randomly assigned to receive intensive medical therapy alone or in combination with RYGB or sleeve gastrectomy. Five years after surgical procedures, the levels of HDL-C were increased by 32%, 30%, and 7% in the RYGB, sleeve gastrectomy, and medical therapy alone groups, respectively. In a substudy, Lorkowski et al. investigated serum HDL function, by determining the apoA-I exchange rate and cholesterol efflux capacity in the STAMPEDE study. The apoA-I exchange rate is determined by adding labeled apoA-I to serum samples and recording labeled apoA-I incorporation into serum HDL. This apoA-I exchange rate has been linked with risk of major adverse cardiovascular events. HDL in both RYGB and sleeve gastrectomy groups showed improved functionality, by increased apoA-I exchange rate after one and five years compared to baseline. Moreover, also cholesterol efflux capacity after five years was improved when compared to pre-operative samples (Figure 4). Improvement of cholesterol efflux capacity appears to depend on the procedure, with an improvement only with sleeve gastrectomy, but not with RYGB at six months after surgery. However, after 12 months both operations resulted in improved cholesterol efflux capacity.

In addition, other metrics of HDL function were assessed in morbidly obese patients after bariatric procedure. Six months after surgery, the antioxidant potential of HDL was increased, accompanied by an increase in PON1 protein levels. Further, alterations in the distribution of HDL subpopulations with a shift toward more mature HDL as well as an increase in apoA-I/apoE ratio was found.

Laparoscopic adjustable gastric banding is another type of weight-loss surgery, which is minimally invasive and associated with low rates of associated complications and mortality rates. Recently, the impact of laparoscopic adjustable gastric banding on HDL subclass distribution was studied. The authors observed an increase in large HDL and intermediate HDL subclasses and a decrease of the small HDL subfraction. Similar to this, another study observed an increase in the large HDL subfractions after laparoscopic adjustable gastric banding and a reduction of HDL-associated pro-inflammatory serum amyloid A.

Another study evaluated whether RYGB restores protective properties of HDL and reverses the obesity-induced endothelial dysfunction. In a rat model of RYGB as well as in human samples, endothelium protective activities of HDL were improved and associated with increased plasma levels of the gut hormone glucagon-like peptide-1 and bile acids. HDL isolated from patients after RYGB led to restored endothelial nitric oxide synthase, increased nitric oxide release and, in parallel, a reduction of endothelial nicotinamide adenine dinucleotide phosphate oxidase, and decrease in endothelial apoptosis and vascular adhesion molecule expression. Moreover, the ability of HDL to induce cholesterol efflux from macrophages as well as PON1 activity was enhanced. Interestingly, 12 weeks after RYGB, the properties of HDL were improved to levels of healthy subjects, although the patients were still obese. A recently published study confirmed the improvement of cholesterol efflux capacity and PON1 activity 12 months after RYGB and observed an association of miR-222 and miR-223, both reported to play an important role in the pathophysiology of obesity, with markers of HDL function.

Altogether, the current state of research suggests that the marked increase in HDL quality and quantity observed after bariatric surgery is likely linked to reduction of obesity-related comorbidities and cardiovascular mortality.

7. Effects of Pharmacological Anti-Obesity Interventions on HDL Levels and Function

Changes in dietary and physical lifestyle have been shown to result in a limited reduction in bodyweight (3–10%) and that most people regained weight again. Therefore, besides bariatric surgery, complementary treatments with anti-obesity drugs are a strategy to achieve permanent weight loss in pathologically obese individuals. In 1959, the first anti-obesity drug, termed phentermine was approved by the United States Food and Drug Administration Nowadays, a number of pharmacotherapies have become available to treat obesity.

Phentermine belongs to the group of sympathomimetics and is the most commonly prescribed anti-obesity drug in the USA. Twelve weeks of administration of phentermine reduced body weight and decreased levels of total cholesterol in Korean obese subjects.

A combination therapy of phentermine with topiramate has been shown to induce greater weight loss than either drug alone and showed fewer occurrence of side effects. Administration of phentermine and topiramate in overweight and obese patients with dyslipidemia showed improvements in HDL-C levels and non-HDL-C levels vs. the placebo group at week 56. Another study designed to evaluate the long-term efficacy of phentermine/topiramate treatment found that the HDL-C levels of study participants increased more than in the placebo group.

Orlistat is an intestinal lipase inhibitor that prevents breakdown of triglycerides and has an excellent long-term safety record. Interestingly, orlistat causes a 25% reduction in cholesterol absorption. Regarding orlistat-induced changes in HDL-C levels, studies are inconsistent. Some studies reported a significant increase of HDL-C in patients receiving orlistat, while others observed no significant changes.

Noteworthily, food intake only minimally affects HDL-C, which might explain the inconsistent effects of orlistat on HDL-C levels.

Lorcaserin is a serotonin 2c receptor agonist available in the USA that increases central serotonin release and has been shown to be effective for long-term weight management. A recent study showed that lorcaserin treatment for six months resulted in decrease of LDL-C, while plasma levels of HDL-C were increased. Lipid subfraction analysis further revealed an increase in HDL particle size.

Liraglutide is a glucagon-like peptide-1 receptor agonist widely used to treat type 2 diabetes. This drug further increases satiety, slows gastric emptying, and also decreases body weight, besides reducing glucose concentration. Long-term treatments with liraglutide have been shown to reduce body weight and waist circumference, but also to improve plasma lipid levels, including an increase in HDL-C levels.

Overall, most pharmacological approaches for obesity treatment increase HDL-C. Further studies examining potential effects of anti-obesity treatment on metrics of HDL function are warranted.

8. Effects of Dietary Approaches on HDL Levels and Function

Other strategies to treat obesity, besides pharmacological treatments and surgical procedures, are hypocaloric diets, such as intermittent fasting and caloric restriction. Furthermore, dietary patterns including Mediterranean diet are commonly used to induce weight loss and improve cardiovascular health in obese individuals.

Caloric restriction is the most common form of dietary restriction, in which subjects strive to decrease their daily energy intake by 15–40% of baseline needs each day. In a 16-week intervention trial in which obese diabetic participants were given a very low calorie diet (450 kcal/day), caloric restriction was shown to reduce CETP activity and increase ApoA-I levels, but did not affect HDL-C levels or HDL cholesterol efflux capacity. Another recently published study compared the effect of an 8-week intermittent caloric restriction regimen to continuous caloric restriction in overweight and obese subjects. They observed that these interventions similarly reduced body weight and fat mass and improved plasma triglycerides but had no effect on levels of HDL-C. Interestingly, Liang et al. observed that a 3-month intervention of caloric restriction, together with moderate physical activity, resulted in weight reduction in obese subjects with metabolic syndrome but decreased PON1 levels. In line with this, another study with obese participants observed that a low-calorie diet reduced PON1 enzyme activity. Furthermore, weight loss through caloric restriction has been shown to decrease LCAT activity in obese as well as in normal-weight subjects.

Alternate-day fasting (ADF) regimens consist of a “feeding day”, with ad libitum feeding and a “fasting day”, with complete abstinence of food and drink intake, except for water for 24 h. These regimens are less common than caloric restriction but were created to facilitate compliance with dietary restriction protocol, as these regimens require energy restriction only every-other day. In a modified ADF study, in which obese participants were allowed to consume 25% of their regular energy needs on the fasting day, body weight and body fat decreased and also levels of triglycerides, total cholesterol, and LDL-C decreased, whereas levels of HDL-C remained unchanged. Varady et al. demonstrated that the same ADF regimen was effective in both weight reduction and cardioprotection in normal-weight and overweight subjects. After 12 weeks of ADF, the study participants showed decreased body weight and fat mass, but no changes in the levels of HDL-C were observed. Similar results were observed in another ADF intervention study in normal-weight participants.

Mediterranean diet is a dietary approach to induce weight loss and to prevent cardiovascular events. This diet pattern is generally characterized by high consumption of vegetables, fruits, nuts, legumes, wheat-based cereals, olive oil, and fish; moderate consumption of dairy products and poultry; and low consumption of red and processed meats. In the Prevention with Mediterranean Diet study (PREDIMED), individuals with high cardiovascular risk were assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts and had lower incidence of cardiovascular events than the control group, assigned to a reduced-fat diet. A substudy, including volunteers of the PREDIMED trial, concentrated on examining the effect of this anti-oxidant-rich dietary pattern on HDL function. Of particular interest, they observed that a 1-year Mediterranean diet, enriched with olive oil or nuts, increased the HDL cholesterol efflux capacity, PON1 activity, and HDL vasodilatory activity. Similarly, another study showed that 12 weeks of Mediterranean diet and exercise improved HDL cholesterol efflux capacity and improved HDL function by inhibiting myeloperoxidase-mediated oxidative stress in subjects with metabolic syndrome.

9. Conclusions

Obesity leads to a depletion of HDL-C, due to a marked shift from large cholesteryl-ester-rich HDL to small and dense triglyceride-rich particles. The mechanisms underlying this shift are multifactorial, including elevated CETP activity linked to increased levels of triglyceride-rich lipoproteins, lower adiponectin levels, and increased clearance of large HDL particles. These changes in HDL subspecies are accompanied by changes in composition and functionality. S1P will potentially be attached to alternative chaperones, resulting in attenuated multiple beneficial effects of S1P. Bariatric surgery is currently the most effective treatment for raising HDL-C levels and, more importantly, it also significantly improves HDL functionality and may be related, at least in part, to the reduction in mortality observed in observational studies. In addition, there is accumulating evidence that Mediterranean diet, especially when enriched with virgin olive oil, significantly enhances parameters of HDL atheroprotective functions. Further studies are warranted to identify specific components in olive oil or other nutrients that improve HDL function. Most pharmacological approaches for obesity treatment increase HDL-C but further studies examining potential effects of anti-obesity treatment on metrics of HDL function are needed. The data of caloric restriction strategies are inconsistent and even show negative effects on some metrics of HDL functionality.

Considerable interest has recently focused on approaches to influence the biological functions of HDL in the search for new cardioprotective therapies and might establish novel treatment strategies in obese individuals.

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    Not in our library10.1056/nejmoa070635

  76. 76.

    Kastelein J.J.P., van Leuven S.I., Burgess L., Evans G.W., Kuivenhoven J.A., Barter P.J., Revkin J.H., Grobbee D.E., Riley W.A., Shear C.L., et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N. Engl. J. Med. 2007;356:1620-1630.

    Not in our library10.1056/nejmoa071359

  77. 77.

    Marsche G., Saemann M.D., Heinemann A., Holzer M. Inflammation alters HDL composition and function: Implications for HDL-raising therapies. Pharmacol. Ther. 2013;137:341-351.

    Not in our library10.1016/j.pharmthera.2012.12.001

  78. 78.

    Rayner K.J., Esau C.C., Hussain F.N., McDaniel A.L., Marshall S.M., van Gils J.M., Ray T.D., Sheedy F.J., Goedeke L., Liu X., et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and reduces VLDL triglycerides. Nature. 2011;478:404-407.

    Not in our library10.1038/nature10486

  79. 79.

    Sacks F.M., Rudel L.L., Conner A., Akeefe H., Kostner G., Baki T., Rothblat G., de la Llera-Moya M., Asztalos B., Perlman T., et al. Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo. J. Lipid Res. 2009;50:894-907.

    Not in our library10.1194/jlr.m800622-jlr200

  80. 80.

    Hovingh G.K., Smits L.P., Stefanutti C., Soran H., Kwok S., de Graaf J., Gaudet D., Keyserling C.H., Klepp H., Frick J., et al. The effect of an apolipoprotein A-I–containing high-density lipoprotein–mimetic particle (CER-001) on carotid artery wall thickness in patients with homozygous familial hypercholesterolemia: The Modifying Orphan Disease Evaluation (MODE) study. Am. Heart J. 2015;169:736-742.e1.

    Not in our library10.1016/j.ahj.2015.01.008

  81. 81.

    Parolini C., Marchesi M., Lorenzon P., Castano M., Balconi E., Miragoli L., Chaabane L., Morisetti A., Lorusso V., Martin B.J., et al. Dose-Related Effects of Repeated ETC-216 (Recombinant Apolipoprotein A-IMilano/1-Palmitoyl-2-Oleoyl Phosphatidylcholine Complexes) Administrations on Rabbit Lipid-Rich Soft Plaques: In Vivo Assessment by Intravascular Ultrasound and Magnetic Resonance Imaging. J. Am. Coll. Cardiol. 2008;51:1098-1103.

    Not in our library10.1016/j.jacc.2007.12.010

  82. 82.

    Tardif J.-C., Grégoire J., L’Allier P.L., Ibrahim R., Lespérance J., Heinonen T.M., Kouz S., Berry C., Basser R., Lavoie M.-A., et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: A randomized controlled trial. JAMA. 2007;297:1675-1682.

    Not in our library10.1001/jama.297.15.jpc70004

  83. 83.

    Waksman R., Torguson R., Kent K.M., Pichard A.D., Suddath W.O., Satler L.F., Martin B.D., Perlman T.J., Maltais J.-A.B., Weissman N.J., et al. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J. Am. Coll. Cardiol. 2010;55:2727-2735.

    Not in our library10.1016/j.jacc.2009.12.067

  84. 84.

    Nissen S.E., Tsunoda T., Tuzcu E.M., Schoenhagen P., Cooper C.J., Yasin M., Eaton G.M., Lauer M.A., Sheldon W.S., Grines C.L., et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: A randomized controlled trial. JAMA. 2003;290:2292-2300.

    Not in our library10.1001/jama.290.17.2292

  85. 85.

    Rohatgi A., Khera A., Berry J.D., Givens E.G., Ayers C.R., Wedin K.E., Neeland I.J., Yuhanna I.S., Rader D.R., de Lemos J.A., et al. HDL Cholesterol Efflux Capacity and Incident Cardiovascular Events. N. Engl. J. Med. 2014;371:2383-2393.

    Not in our library10.1056/nejmoa1409065

  86. 86.

    Kosmas C.E., Martinez I., Sourlas A., Bouza K.V., Campos F.N., Torres V., Montan P.D., Guzman E. High-density lipoprotein (HDL) functionality and its relevance to atherosclerotic cardiovascular disease. Drugs Context. 2018;7:212525.

    Not in our library10.7573/dic.212525

  87. 87.

    Kosmas C.E., Christodoulidis G., Cheng J., Lerakis S., Vittorio T.J. High-Density Lipoprotein Functionality in Coronary Artery Disease. Am. J. Med. Sci. 2014;347:504-508.

    Not in our library10.1097/maj.0000000000000231

  88. 88.

    Ashen M.D., Blumenthal R.S. Clinical practice. Low HDL cholesterol levels. N. Engl. J. Med. 2005;353:1252-1260.

    Not in our library10.1056/nejmcp044370

  89. 89.

    Clemente-Postigo M., Queipo-Ortuño M.I., Fernandez-Garcia D., Gomez-Huelgas R., Tinahones F.J., Cardona F. Adipose Tissue Gene Expression of Factors Related to Lipid Processing in Obesity. PLoS ONE. 2011;6:e24783.

    Not in our library10.1371/journal.pone.0024783

  90. 90.

    Walton R.G., Zhu B., Unal R., Spencer M., Sunkara M., Morris A.J., Charnigo R., Katz W.S., Daugherty A., Howatt D.A., et al. Increasing Adipocyte Lipoprotein Lipase Improves Glucose Metabolism in High Fat Diet-induced Obesity. J. Biol. Chem. 2015;290:11547-11556.

    Not in our library10.1074/jbc.m114.628487

  91. 91.
    Dyslipidemia in Obesity: Mechanisms and Potential Targets · 2013
    No notice
  92. 92.

    Taskinen M.-R., Nikkilä E.A. Lipoprotein lipase of adipose tissue and skeletal muscle in human obesity: Response to glucose and to semistarvation. Metabolism. 1981;30:810-817.

    Not in our library10.1016/0026-0495(81)90028-7

  93. 93.

    Feng R., Luo C., Li C., Du S., Okekunle A.P., Li Y., Chen Y., Zi T., Niu Y. Free fatty acids profile among lean, overweight and obese non-alcoholic fatty liver disease patients: A case—Control study. Lipids Health Dis. 2017;16:165.

    Not in our library10.1186/s12944-017-0551-1

  94. 94.

    Ginsberg H.N. Insulin resistance and cardiovascular disease. J. Clin. Investig. 2000;106:453-458.

    Not in our library10.1172/jci10762

  95. 95.

    Rashid S., Uffelman K.D., Lewis G.F. The mechanism of HDL lowering in hypertriglyceridemic, insulin-resistant states. J. Diabetes Complicat. 2002;16:24-28.

    Not in our library10.1016/s1056-8727(01)00191-x

  96. 96.

    Carr M.C., Hokanson J.E., Zambon A., Deeb S.S., Barrett P.H., Purnell J.Q., Brunzell J.D. The contribution of intraabdominal fat to gender differences in hepatic lipase activity and low/high density lipoprotein heterogeneity. J. Clin. Endocrinol. Metab. 2001;86:2831-2837.

    Not in our library10.1210/jc.86.6.2831

  97. 97.

    Chatterjee C., Sparks D.L. Hepatic Lipase, High Density Lipoproteins, and Hypertriglyceridemia. Am. J. Pathol. 2011;178:1429-1433.

    Not in our library10.1016/j.ajpath.2010.12.050

  98. 98.

    Blades B., Vega G.L., Grundy S.M. Activities of lipoprotein lipase and hepatic triglyceride lipase in postheparin plasma of patients with low concentrations of HDL cholesterol. Arterioscler. Thromb. J. Vasc. Biol. 1993;13:1227-1235.

    Not in our library10.1161/01.atv.13.8.1227

  99. 99.

    Rashid S., Barrett P.H.R., Uffelman K.D., Watanabe T., Adeli K., Lewis G.F. Lipolytically Modified Triglyceride-Enriched HDLs Are Rapidly Cleared from the Circulation. Arterioscler. Thromb. Vasc. Biol. 2002;22:483-487.

    Not in our library10.1161/hq0302.105374

  100. 100.

    Lönnqvist F., Nordfors L., Jansson M., Thörne A., Schalling M., Arner P. Leptin secretion from adipose tissue in women. Relationship to plasma levels and gene expression. J. Clin. Investig. 1997;99:2398-2404.

    Not in our library10.1172/jci119422

  101. 101.

    Singh P., Peterson T.E., Sert-Kuniyoshi F.H., Glenn J.A., Davison D.E., Romero-Corral A., Pusalavidyasagar S., Jensen M.D., Somers V.K. Leptin signaling in adipose tissue: Role in lipid accumulation and weight gain. Circ. Res. 2012;111:599-603.

    Not in our library10.1161/circresaha.112.273656

  102. 102.

    Wu D.M., Shen M.H., Chu N.F. Relationship between plasma leptin levels and lipid profiles among school children in Taiwan--the Taipei Children Heart Study. Eur. J. Epidemiol. 2001;17:911-916.

    Not in our library10.1023/a:1016280427032

  103. 103.

    Rainwater D.L., Comuzzie A.G., VandeBerg J.L., Mahaney M.C., Blangero J. Serum leptin levels are independently correlated with two measures of HDL. Atherosclerosis. 1997;132:237-243.

    Not in our library10.1016/s0021-9150(97)00104-4

  104. 104.

    Lundåsen T., Liao W., Angelin B., Rudling M. Leptin induces the hepatic high density lipoprotein receptor scavenger receptor B type I (SR-BI) but not cholesterol 7alpha-hydroxylase (Cyp7a1) in leptin-deficient (ob/ob) mice. J. Biol. Chem. 2003;278:43224-43228.

    Not in our library10.1074/jbc.m302645200

  105. 105.

    Dullaart R.P.F., de Vries R., Dallinga-Thie G.M., van Tol A., Sluiter W.J. Plasma cholesteryl ester transfer protein mass and phospholipid transfer protein activity are associated with leptin in type 2 diabetes mellitus. Biochim. Biophys. Acta. 2007;1771:113-118.

    Not in our library10.1016/j.bbalip.2006.11.003

  106. 106.

    Radeau T., Lau P., Robb M., McDonnell M., Ailhaud G., McPherson R. Cholesteryl ester transfer protein (CETP) mRNA abundance in human adipose tissue: Relationship to cell size and membrane cholesterol content. J. Lipid Res. 1995;36:2552-2561.

    Not in our library

  107. 107.

    Bamba V., Rader D.J. Obesity and Atherogenic Dyslipidemia. Gastroenterology. 2007;132:2181-2190.

    Not in our library10.1053/j.gastro.2007.03.056

  108. 108.

    Yamamoto Y., Hirose H., Saito I., Tomita M., Taniyama M., Matsubara K., Okazaki Y., Ishii T., Nishikai K., Saruta T. Correlation of the adipocyte-derived protein adiponectin with insulin resistance index and serum high-density lipoprotein-cholesterol, independent of body mass index, in the Japanese population. Clin. Sci. Lond. Engl. 2002;103:137-142.

    Not in our library10.1042/cs1030137

  109. 109.

    Ryo M., Nakamura T., Kihara S., Kumada M., Shibazaki S., Takahashi M., Nagai M., Matsuzawa Y., Funahashi T. Adiponectin as a biomarker of the metabolic syndrome. Circ. J. Off. J. Jpn. Circ. Soc. 2004;68:975-981.

    Not in our library10.1253/circj.68.975

  110. 110.

    Sattar N., Wannamethee G., Sarwar N., Tchernova J., Cherry L., Wallace A., Danesh J., Whincup P. Adiponectin and Coronary Heart Disease. Circulation. 2006;114:623-629.

    Not in our library10.1161/circulationaha.106.618918

  111. 111.

    Cnop M., Havel P.J., Utzschneider K.M., Carr D.B., Sinha M.K., Boyko E.J., Retzlaff B.M., Knopp R.H., Brunzell J.D., Kahn S.E. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: Evidence for independent roles of age and sex. Diabetologia. 2003;46:459-469.

    Not in our library10.1007/s00125-003-1074-z

  112. 112.

    Martin L.J., Woo J.G., Daniels S.R., Goodman E., Dolan L.M. The relationships of adiponectin with insulin and lipids are strengthened with increasing adiposity. J. Clin. Endocrinol. Metab. 2005;90:4255-4259.

    Not in our library10.1210/jc.2005-0019

  113. 113.

    Baratta R., Amato S., Degano C., Farina M.G., Patanè G., Vigneri R., Frittitta L. Adiponectin relationship with lipid metabolism is independent of body fat mass: Evidence from both cross-sectional and intervention studies. J. Clin. Endocrinol. Metab. 2004;89:2665-2671.

    Not in our library10.1210/jc.2003-031777

  114. 114.

    Després J.P., Couillard C., Gagnon J., Bergeron J., Leon A.S., Rao D.C., Skinner J.S., Wilmore J.H., Bouchard C. Race, visceral adipose tissue, plasma lipids, and lipoprotein lipase activity in men and women: The Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) family study. Arterioscler. Thromb. Vasc. Biol. 2000;20:1932-1938.

    Not in our library10.1161/01.atv.20.8.1932

  115. 115.

    Carr M.C., Ayyobi A.F., Murdoch S.J., Deeb S.S., Brunzell J.D. Contribution of hepatic lipase, lipoprotein lipase, and cholesteryl ester transfer protein to LDL and HDL heterogeneity in healthy women. Arterioscler. Thromb. Vasc. Biol. 2002;22:667-673.

    Not in our library10.1161/01.atv.0000013284.47317.95

  116. 116.

    Lewis G.F., Lamarche B., Uffelman K.D., Heatherington A.C., Honig M.A., Szeto L.W., Barrett P.H. Clearance of postprandial and lipolytically modified human HDL in rabbits and rats. J. Lipid Res. 1997;38:1771-1778.

    Not in our library

  117. 117.

    Rashid S., Trinh D.K., Uffelman K.D., Cohn J.S., Rader D.J., Lewis G.F. Expression of human hepatic lipase in the rabbit model preferentially enhances the clearance of triglyceride-enriched versus native high-density lipoprotein apolipoprotein A-I. Circulation. 2003;107:3066-3072.

    Not in our library10.1161/01.cir.0000070947.64595.47

  118. 118.

    Lewis G.F., Murdoch S., Uffelman K., Naples M., Szeto L., Albers A., Adeli K., Brunzell J.D. Hepatic lipase mRNA, protein, and plasma enzyme activity is increased in the insulin-resistant, fructose-fed Syrian golden hamster and is partially normalized by the insulin sensitizer rosiglitazone. Diabetes. 2004;53:2893-2900.

    Not in our library10.2337/diabetes.53.11.2893

  119. 119.

    Ishida T., Choi S., Kundu R.K., Hirata K.-I., Rubin E.M., Cooper A.D., Quertermous T. Endothelial lipase is a major determinant of HDL level. J. Clin. Investig. 2003;111:347-355.

    Not in our library10.1172/jci16306

  120. 120.

    Jin W., Millar J.S., Broedl U., Glick J.M., Rader D.J. Inhibition of endothelial lipase causes increased HDL cholesterol levels in vivo. J. Clin. Investig. 2003;111:357-362.

    Not in our library10.1172/jci16146

  121. 121.

    Ma K., Cilingiroglu M., Otvos J.D., Ballantyne C.M., Marian A.J., Chan L. Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism. Proc. Natl. Acad. Sci. USA. 2003;100:2748-2753.

    Not in our library10.1073/pnas.0438039100

  122. 122.

    Maugeais C., Tietge U.J.F., Broedl U.C., Marchadier D., Cain W., McCoy M.G., Lund-Katz S., Glick J.M., Rader D.J. Dose-dependent acceleration of high-density lipoprotein catabolism by endothelial lipase. Circulation. 2003;108:2121-2126.

    Not in our library10.1161/01.cir.0000092889.24713.dc

  123. 123.

    Jaye M., Lynch K.J., Krawiec J., Marchadier D., Maugeais C., Doan K., South V., Amin D., Perrone M., Rader D.J. A novel endothelial-derived lipase that modulates HDL metabolism. Nat. Genet. 1999;21:424-428.

    Not in our library10.1038/7766

  124. 124.
    Endothelial Lipase Concentrations Are Increased in Metabolic Syndrome and Associated with Coronary Atherosclerosis · 2005
    No notice
  125. 125.

    De Lemos A.S., Wolfe M.L., Long C.J., Sivapackianathan R., Rader D.J. Identification of genetic variants in endothelial lipase in persons with elevated high-density lipoprotein cholesterol. Circulation. 2002;106:1321-1326.

    Not in our library10.1161/01.cir.0000028423.07623.6a

  126. 126.

    Castro A.M., Macedo-de la Concha L.E., Pantoja-Meléndez C.A. Low-grade inflammation and its relation to obesity and chronic degenerative diseases. Rev. Méd. Hosp. Gen. México. 2017;80:101-105.

    Not in our library10.1016/j.hgmx.2016.06.011

  127. 127.

    Weisberg S.P., McCann D., Desai M., Rosenbaum M., Leibel R.L., Ferrante A.W. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Investig. 2003;112:1796-1808.

    Not in our library10.1172/jci200319246

  128. 128.

    Chung S., Cuffe H., Marshall S.M., McDaniel A.L., Ha J.H., Kavanagh K., Hong C., Tontonoz P., Temel R.E., Parks J.S. Dietary Cholesterol Promotes Adipocyte Hypertrophy and Adipose Tissue Inflammation in Visceral, but Not in Subcutaneous, Fat in Monkeys. Arterioscler. Thromb. Vasc. Biol. 2014;34:1880-1887.

    Not in our library10.1161/atvbaha.114.303896

  129. 129.

    Kovanen P.T., Nikkilä E.A., Miettinen T.A. Regulation of cholesterol synthesis and storage in fat cells. J. Lipid Res. 1975;16:211-223.

    Not in our library

  130. 130.

    Farkas J., Angel A., Avigan M.I. Studies on the compartmentation of lipid in adipose cells. II. Cholesterol accumulation and distribution in adipose tissue components. J. Lipid Res. 1973;14:344-356.

    Not in our library

  131. 131.

    Schreibman P.H., Dell R.B. Human adipocyte cholesterol. Concentration, localization, synthesis, and turnover. J. Clin. Investig. 1975;55:986-993.

    Not in our library10.1172/jci108028

  132. 132.

    Krause B.R., Hartman A.D. Adipose tissue and cholesterol metabolism. J. Lipid Res. 1984;25:97-110.

    Not in our library

  133. 133.

    McGillicuddy F.C., Reilly M.P. Adipose tissue modulation of HDL. Clin. Lipidol. 2010;5:601-606.

    Not in our library10.2217/clp.10.60

  134. 134.

    Zhang Y., McGillicuddy F.C., Hinkle C.C., O’Neill S., Glick J.M., Rothblat G.H., Reilly M.P. Adipocyte Modulation of High-Density Lipoprotein Cholesterol. Circulation. 2010;121:1347-1355.

    Not in our library10.1161/circulationaha.109.897330

  135. 135.

    Woudberg N.J., Goedecke J.H., Blackhurst D., Frias M., James R., Opie L.H., Lecour S. Association between ethnicity and obesity with high-density lipoprotein (HDL) function and subclass distribution. Lipids Health Dis. 2016;15:92.

    Not in our library10.1186/s12944-016-0257-9

  136. 136.
    Exercise intervention alters HDL subclass distribution and function in obese women · 2018
    Not checked
  137. 137.

    Davidson W.S., Heink A., Sexmith H., Dolan L.M., Gordon S.M., Otvos J.D., Melchior J.T., Elder D.A., Khoury J., Geh E., et al. Obesity is associated with an altered HDL subspecies profile among adolescents with metabolic disease. J. Lipid Res. 2017;58:1916-1923.

    Not in our library10.1194/jlr.m078667

  138. 138.

    Holzer M., Schilcher G., Curcic S., Trieb M., Ljubojevic S., Stojakovic T., Scharnagl H., Kopecky C.M., Rosenkranz A.R., Heinemann A., et al. Dialysis Modalities and HDL Composition and Function. J. Am. Soc. Nephrol. 2015;26:2267-2276.

    Not in our library10.1681/asn.2014030309

  139. 139.

    Holzer M., Birner-Gruenberger R., Stojakovic T., El-Gamal D., Binder V., Wadsack C., Heinemann A., Marsche G. Uremia Alters HDL Composition and Function. J. Am. Soc. Nephrol. 2011;22:1631-1641.

    Not in our library10.1681/asn.2010111144

  140. 140.

    Farbstein D., Levy A.P. HDL dysfunction in diabetes: Causes and possible treatments. Expert Rev. Cardiovasc. Ther. 2012;10:353-361.

    Not in our library10.1586/erc.11.182

  141. 141.

    Trieb M., Horvath A., Birner-Gruenberger R., Spindelboeck W., Stadlbauer V., Taschler U., Curcic S., Stauber R.E., Holzer M., Pasterk L., et al. Liver disease alters high-density lipoprotein composition, metabolism and function. Biochim. Biophys. Acta. 2016;1861:630-638.

    Not in our library10.1016/j.bbalip.2016.04.013

  142. 142.

    Holzer M., Wolf P., Curcic S., Birner-Gruenberger R., Weger W., Inzinger M., El-Gamal D., Wadsack C., Heinemann A., Marsche G. Psoriasis alters HDL composition and cholesterol efflux capacity. J. Lipid Res. 2012;53:1618-1624.

    Not in our library10.1194/jlr.m027367

  143. 143.

    Trieb M., Wolf P., Knuplez E., Weger W., Schuster C., Peinhaupt M., Holzer M., Trakaki A., Eichmann T., Lass A., et al. Abnormal composition and function of high-density lipoproteins in atopic dermatitis patients. Allergy. 2019;74:398-402.

    Not in our library10.1111/all.13620

  144. 144.

    Trakaki A., Sturm G.J., Pregartner G., Scharnagl H., Eichmann T.O., Trieb M., Knuplez E., Holzer M., Stadler J.T., Heinemann A., et al. Allergic rhinitis is associated with complex alterations in high-density lipoprotein composition and function. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2019;1864:1280-1292.

    Not in our library10.1016/j.bbalip.2019.06.007

  145. 145.

    Sorrentino S.A., Besler C., Rohrer L., Meyer M., Heinrich K., Bahlmann F.H., Mueller M., Horváth T., Doerries C., Heinemann M., et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation. 2010;121:110-122.

    Not in our library10.1161/circulationaha.108.836346

  146. 146.

    Perségol L., Vergès B., Foissac M., Gambert P., Duvillard L. Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation. Diabetologia. 2006;49:1380-1386.

    Not in our library10.1007/s00125-006-0244-1

  147. 147.

    Sasahara T., Nestel P., Fidge N., Sviridov D. Cholesterol transport between cells and high density lipoprotein subfractions from obese and lean subjects. J. Lipid Res. 1998;39:544-554.

    Not in our library

  148. 148.

    Marsche G., Zelzer S., Meinitzer A., Kern S., Meissl S., Pregartner G., Weghuber D., Almer G., Mangge H. Adiponectin Predicts High-Density Lipoprotein Cholesterol Efflux Capacity in Adults Irrespective of Body Mass Index and Fat Distribution. J. Clin. Endocrinol. Metab. 2017;102:4117-4123.

    Not in our library10.1210/jc.2017-00933

  149. 149.

    Talbot C.P.J., Plat J., Joris P.J., Konings M., Kusters Y.H.A.M., Schalkwijk C.G., Ritsch A., Mensink R.P. HDL cholesterol efflux capacity and cholesteryl ester transfer are associated with body mass, but are not changed by diet-induced weight loss: A randomized trial in abdominally obese men. Atherosclerosis. 2018;274:23-28.

    Not in our library10.1016/j.atherosclerosis.2018.04.029

  150. 150.

    Saleheen D., Scott R., Javad S., Zhao W., Rodrigues A., Picataggi A., Lukmanova D., Mucksavage M.L., Luben R., Billheimer J., et al. Association of HDL cholesterol efflux capacity with incident coronary heart disease events: A prospective case-control study. Lancet Diabetes Endocrinol. 2015;3:507-513.

    Not in our library10.1016/s2213-8587(15)00126-6

  151. 151.

    Khera A.V., Cuchel M., de la Llera-Moya M., Rodrigues A., Burke M.F., Jafri K., French B.C., Phillips J.A., Mucksavage M.L., Wilensky R.L., et al. Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis. N. Engl. J. Med. 2011;364:127-135.

    Not in our library10.1056/nejmoa1001689

  152. 152.
    New Insight into Adiponectin Role in Obesity and Obesity-Related Diseases · 2014
    No notice
  153. 153.

    Ouchi N., Kihara S., Arita Y., Nishida M., Matsuyama A., Okamoto Y., Ishigami M., Kuriyama H., Kishida K., Nishizawa H., et al. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation. 2001;103:1057-1063.

    Not in our library10.1161/01.cir.103.8.1057

  154. 154.

    Matsuura F., Oku H., Koseki M., Sandoval J.C., Yuasa-Kawase M., Tsubakio-Yamamoto K., Masuda D., Maeda N., Tsujii K., Ishigami M., et al. Adiponectin accelerates reverse cholesterol transport by increasing high density lipoprotein assembly in the liver. Biochem. Biophys. Res. Commun. 2007;358:1091-1095.

    Not in our library10.1016/j.bbrc.2007.05.040

  155. 155.

    Oku H., Matsuura F., Koseki M., Sandoval J.C., Yuasa-Kawase M., Tsubakio-Yamamoto K., Masuda D., Maeda N., Ohama T., Ishigami M., et al. Adiponectin deficiency suppresses ABCA1 expression and ApoA-I synthesis in the liver. FEBS Lett. 2007;581:5029-5033.

    Not in our library10.1016/j.febslet.2007.09.038

  156. 156.

    Tsubakio-Yamamoto K., Matsuura F., Koseki M., Oku H., Sandoval J.C., Inagaki M., Nakatani K., Nakaoka H., Kawase R., Yuasa-Kawase M., et al. Adiponectin prevents atherosclerosis by increasing cholesterol efflux from macrophages. Biochem. Biophys. Res. Commun. 2008;375:390-394.

    Not in our library10.1016/j.bbrc.2008.08.009

  157. 157.

    Liang B., Wang X., Guo X., Yang Z., Bai R., Liu M., Xiao C., Bian Y. Adiponectin upregulates ABCA1 expression through liver X receptor alpha signaling pathway in RAW 264.7 macrophages. Int. J. Clin. Exp. Pathol. 2015;8:450-457.

    Not in our library

  158. 158.

    Chawla A., Boisvert W.A., Lee C.-H., Laffitte B.A., Barak Y., Joseph S.B., Liao D., Nagy L., Edwards P.A., Curtiss L.K., et al. A PPARγ-LXR-ABCA1 Pathway in Macrophages Is Involved in Cholesterol Efflux and Atherogenesis. Mol. Cell. 2001;7:161-171.

    Not in our library10.1016/s1097-2765(01)00164-2

  159. 159.

    Vergès B., Petit J.M., Duvillard L., Dautin G., Florentin E., Galland F., Gambert P. Adiponectin is an important determinant of apoA-I catabolism. Arterioscler. Thromb. Vasc. Biol. 2006;26:1364-1369.

    Not in our library10.1161/01.atv.0000219611.50066.bd

  160. 160.

    Hafiane A., Daskalopoulou S.S. Adiponectin’s mechanisms in high-density lipoprotein biogenesis and cholesterol efflux. Metabolism. 2020;113:154393.

    Not in our library10.1016/j.metabol.2020.154393

  161. 161.

    Posadas-Sánchez R., Posadas-Romero C., Mendoza-Pérez E., Caracas-Portilla N.A., Cardoso-Saldaña G., Medina-Urrutia A., Jorge-Galarza E., Juárez-Rojas J.G. Cholesterol efflux and metabolic abnormalities associated with low high-density-lipoprotein-cholesterol and high triglycerides in statin-treated coronary men with low-density lipoprotein-cholesterol <70 mg/dl. Am. J. Cardiol. 2012;109:636-641.

    Not in our library10.1016/j.amjcard.2011.10.017

  162. 162.

    Wang M., Wang D., Zhang Y., Wang X., Liu Y., Xia M. Adiponectin increases macrophages cholesterol efflux and suppresses foam cell formation in patients with type 2 diabetes mellitus. Atherosclerosis. 2013;229:62-70.

    Not in our library10.1016/j.atherosclerosis.2013.01.017

  163. 163.

    Clarenbach J., Vega G., Adams-Huet B., Considine R., Ricks M., Sumner A. Variability in Postheparin Hepatic Lipase Activity Is Associated with Plasma Adiponectin Levels in African Americans. J. Investig. Med. Off. Publ. Am. Fed. Clin. Res. 2007;55:187-194.

    Not in our library10.2310/6650.2007.07001

  164. 164.

    Schneider J.G., von Eynatten M., Schiekofer S., Nawroth P.P., Dugi K.A. Low Plasma Adiponectin Levels Are Associated With Increased Hepatic Lipase Activity In Vivo: Response to Kobayashi et al. Diabetes Care. 2006;29:181.

    Not in our library10.2337/diacare.29.01.06.dc05-1962

  165. 165.

    Magge S.N., Stettler N., Koren D., Levitt Katz L.E., Gallagher P.R., Mohler E.R., Rader D.J. Adiponectin is associated with favorable lipoprotein profile, independent of BMI and insulin resistance, in adolescents. J. Clin. Endocrinol. Metab. 2011;96:1549-1554.

    Not in our library10.1210/jc.2010-2364

  166. 166.

    Weiss R., Otvos J.D., Flyvbjerg A., Miserez A.R., Frystyk J., Sinnreich R., Kark J.D. Adiponectin and Lipoprotein Particle Size. Diabetes Care. 2009;32:1317-1319.

    Not in our library10.2337/dc09-0084

  167. 167.

    Tsubakio-Yamamoto K., Sugimoto T., Nishida M., Okano R., Monden Y., Kitazume-Taneike R., Yamashita T., Nakaoka H., Kawase R., Yuasa-Kawase M., et al. Serum adiponectin level is correlated with the size of HDL and LDL particles determined by high performance liquid chromatography. Metabolism. 2012;61:1763-1770.

    Not in our library10.1016/j.metabol.2012.05.011

  168. 168.

    Shin M.J., Kim O.Y. Plasma adiponectin is associated with less atherogenic lipoprotein phenotype. Nutr. Metab. Cardiovasc. Dis. 2011;21:770-775.

    Not in our library10.1016/j.numecd.2010.01.014

  169. 169.

    Kobayashi J., Kusunoki M., Murase Y., Kawashiri M., Higashikata T., Miwa K., Katsuda S., Takata M., Asano A., Nohara A., et al. Relationship of Lipoprotein Lipase and Hepatic Triacylglycerol Lipase Activity to Serum Adiponectin Levels in Japanese Hyperlipidemic Men. Horm. Metab. Res. 2005;37:505-509.

    Not in our library10.1055/s-2005-870318

  170. 170.

    Von Eynatten M., Schneider J.G., Humpert P.M., Rudofsky G., Schmidt N., Barosch P., Hamann A., Morcos M., Kreuzer J., Bierhaus A., et al. Decreased plasma lipoprotein lipase in hypoadiponectinemia: An association independent of systemic inflammation and insulin resistance. Diabetes Care. 2004;27:2925-2929.

    Not in our library10.2337/diacare.27.12.2925

  171. 171.

    Van Greevenbroek M.M.J., Schalkwijk C.G., Stehouwer C.D.A. Obesity-associated low-grade inflammation in type 2 diabetes mellitus: Causes and consequences. Neth. J. Med. 2013;71:174-187.

    Not in our library

  172. 172.
    Chronic Inflammation in Obesity and the Metabolic Syndrome · 2010
    No notice
  173. 173.

    Kaser S., Tatarczyk T., Stadlmayr A., Ciardi C., Ress C., Tschoner A., Sandhofer A., Paulweber B., Ebenbichler C.F., Patsch J.R. Effect of obesity and insulin sensitivity on adiponectin isoform distribution. Eur. J. Clin. Investig. 2008;38:827-834.

    Not in our library10.1111/j.1365-2362.2008.02028.x

  174. 174.

    Meyer L.K., Ciaraldi T.P., Henry R.R., Wittgrove A.C., Phillips S.A. Adipose tissue depot and cell size dependency of adiponectin synthesis and secretion in human obesity. Adipocyte. 2013;2:217-226.

    Not in our library10.4161/adip.24953

  175. 175.

    Blachnio-Zabielska A.U., Koutsari C., Tchkonia T., Jensen M.D. Sphingolipid content of human adipose tissue: Relationship to adiponectin and insulin resistance. Obesity. 2012;20:2341-2347.

    Not in our library10.1038/oby.2012.126

  176. 176.

    Kimura T., Sato K., Kuwabara A., Tomura H., Ishiwara M., Kobayashi I., Ui M., Okajima F. Sphingosine 1-phosphate may be a major component of plasma lipoproteins responsible for the cytoprotective actions in human umbilical vein endothelial cells. J. Biol. Chem. 2001;276:31780-31785.

    Not in our library10.1074/jbc.m104353200

  177. 177.

    Venkataraman K., Lee Y.-M., Michaud J., Thangada S., Ai Y., Bonkovsky H.L., Parikh N.S., Habrukowich C., Hla T. Vascular endothelium as a contributor of plasma sphingosine 1-phosphate. Circ. Res. 2008;102:669-676.

    Not in our library10.1161/circresaha.107.165845

  178. 178.

    Gazit S.L., Mariko B., Thérond P., Decouture B., Xiong Y., Couty L., Bonnin P., Baudrie V., Le Gall S.M., Dizier B., et al. Platelet and Erythrocyte Sources of S1P Are Redundant for Vascular Development and Homeostasis, but Both Rendered Essential After Plasma S1P Depletion in Anaphylactic Shock. Circ. Res. 2016;119:e110-e126.

    Not in our library10.1161/circresaha.116.308929

  179. 179.

    Lee M.J., Van Brocklyn J.R., Thangada S., Liu C.H., Hand A.R., Menzeleev R., Spiegel S., Hla T. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science. 1998;279:1552-1555.

    Not in our library10.1126/science.279.5356.1552

  180. 180.
    Plasma Sphingosine-1-Phosphate Is Elevated in Obesity · 2013
    No notice
  181. 181.

    Majumdar I., Mastrandrea L.D. Serum sphingolipids and inflammatory mediators in adolescents at risk for metabolic syndrome. Endocrine. 2012;41:442-449.

    Not in our library10.1007/s12020-011-9589-4

  182. 182.

    Green C.L., Mitchell S.E., Derous D., Wang Y., Chen L., Han J.-D.J., Promislow D.E.L., Lusseau D., Douglas A., Speakman J.R. The effects of graded levels of calorie restriction: IX. Global metabolomic screen reveals modulation of carnitines, sphingolipids and bile acids in the liver of C57BL/6 mice. Aging Cell. 2017;16:529-540.

    Not in our library10.1111/acel.12570

  183. 183.

    Silva V.R.R., Micheletti T.O., Pimentel G.D., Katashima C.K., Lenhare L., Morari J., Mendes M.C.S., Razolli D.S., Rocha G.Z., de Souza C.T., et al. Hypothalamic S1P/S1PR1 axis controls energy homeostasis. Nat. Commun. 2014;5:4859.

    Not in our library10.1038/ncomms5859

  184. 184.
    The Apolipoprotein M/S1P Axis Controls Triglyceride Metabolism and Brown Fat Activity · 2018
    Not checked
  185. 185.

    Dahlbäck B. Lean ApoM-/-Mice with Hyperactive Brown Adipose Tissue. Trends Endocrinol. Metab. 2018;29:283-284.

    Not in our library10.1016/j.tem.2018.02.011

  186. 186.

    Frej C., Mendez A.J., Ruiz M., Castillo M., Hughes T.A., Dahlbäck B., Goldberg R.B. A Shift in ApoM/S1P Between HDL-Particles in Women With Type 1 Diabetes Mellitus Is Associated with Impaired Anti-Inflammatory Effects of the ApoM/S1P Complex. Arterioscler. Thromb. Vasc. Biol. 2017;37:1194-1205.

    Not in our library10.1161/atvbaha.117.309275

  187. 187.

    Brolin R.E. Bariatric surgery and long-term control of morbid obesity. JAMA. 2002;288:2793-2796.

    Not in our library10.1001/jama.288.22.2793

  188. 188.

    Steinbrook R. Surgery for severe obesity. N. Engl. J. Med. 2004;350:1075-1079.

    Not in our library10.1056/nejmp048029

  189. 189.
    Effects of Bariatric Surgery on Cardiovascular Disease: A Concise Update of Recent Advances · 2019
    Not checked
  190. 190.

    Benraoune F., Litwin S.E. Reductions in Cardiovascular Risk after Bariatric Surgery. Curr. Opin. Cardiol. 2011;26:555-561.

    Not in our library10.1097/hco.0b013e32834b7fc4

  191. 191.

    Lorkowski S.W., Brubaker G., Rotroff D.M., Kashyap S.R., Bhatt D.L., Nissen S.E., Schauer P.R., Aminian A., Smith J.D. Bariatric Surgery Improves HDL Function Examined by ApoA1 Exchange Rate and Cholesterol Efflux Capacity in Patients with Obesity and Type 2 Diabetes. Biomolecules. 2020;10:551.

    Not in our library10.3390/biom10040551

  192. 192.

    Raffaelli M., Guidone C., Callari C., Iaconelli A., Bellantone R., Mingrone G. Effect of gastric bypass versus diet on cardiovascular risk factors. Ann. Surg. 2014;259:694-699.

    Not in our library10.1097/sla.0b013e31829d6989

  193. 193.

    Christou N.V., Sampalis J.S., Liberman M., Look D., Auger S., McLean A.P.H., MacLean L.D. Surgery decreases long-term mortality, morbidity, and health care use in morbidly obese patients. Ann. Surg. 2004;240:416-424.

    Not in our library10.1097/01.sla.0000137343.63376.19

  194. 194.

    Williams D.B., Hagedorn J.C., Lawson E.H., Galanko J.A., Safadi B.Y., Curet M.J., Morton J.M. Gastric bypass reduces biochemical cardiac risk factors. Surg. Obes. Relat. Dis. Off. J. Am. Soc. Bariatr. Surg. 2007;3:8-13.

    Not in our library10.1016/j.soard.2006.10.003

  195. 195.

    Zlabek J.A., Grimm M.S., Larson C.J., Mathiason M.A., Lambert P.J., Kothari S.N. The effect of laparoscopic gastric bypass surgery on dyslipidemia in severely obese patients. Surg. Obes. Relat. Dis. Off. J. Am. Soc. Bariatr. Surg. 2005;1:537-542.

    Not in our library10.1016/j.soard.2005.09.009

  196. 196.

    Swarbrick M.M., Austrheim-Smith I.T., Stanhope K.L., Van Loan M.D., Ali M.R., Wolfe B.M., Havel P.J. Circulating concentrations of high-molecular-weight adiponectin are increased following Roux-en-Y gastric bypass surgery. Diabetologia. 2006;49:2552-2558.

    Not in our library10.1007/s00125-006-0452-8

  197. 197.

    Kopp H.-P., Krzyzanowska K., Möhlig M., Spranger J., Pfeiffer A.F.H., Schernthaner G. Effects of marked weight loss on plasma levels of adiponectin, markers of chronic subclinical inflammation and insulin resistance in morbidly obese women. Int. J. Obes. 2005;29:766-771.

    Not in our library10.1038/sj.ijo.0802983

  198. 198.

    Sjöström C.D., Lissner L., Wedel H., Sjöström L. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: The SOS Intervention Study. Obes. Res. 1999;7:477-484.

    Not in our library10.1002/j.1550-8528.1999.tb00436.x

  199. 199.

    Schauer P.R., Kashyap S.R., Wolski K., Brethauer S.A., Kirwan J.P., Pothier C.E., Thomas S., Abood B., Nissen S.E., Bhatt D.L. Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes. N. Engl. J. Med. 2012;366:1567-1576.

    Not in our library10.1056/nejmoa1200225

  200. 200.

    Schauer P.R., Bhatt D.L., Kirwan J.P., Wolski K., Brethauer S.A., Navaneethan S.D., Aminian A., Pothier C.E., Kim E.S.H., Nissen S.E., et al. Bariatric surgery versus intensive medical therapy for diabetes—3-year outcomes. N. Engl. J. Med. 2014;370:2002-2013.

    Not in our library10.1056/nejmoa1401329

  201. 201.

    Schauer P.R., Bhatt D.L., Kirwan J.P., Wolski K., Aminian A., Brethauer S.A., Navaneethan S.D., Singh R.P., Pothier C.E., Nissen S.E., et al. Bariatric Surgery versus Intensive Medical Therapy for Diabetes—5-Year Outcomes. N. Engl. J. Med. 2017;376:641-651.

    Not in our library10.1056/nejmoa1600869

  202. 202.

    Mingrone G., Panunzi S., De Gaetano A., Guidone C., Iaconelli A., Nanni G., Castagneto M., Bornstein S., Rubino F. Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet Lond. Engl. 2015;386:964-973.

    Not in our library10.1016/s0140-6736(15)00075-6

  203. 203.

    Lorkowski S.W., Brubaker G., Li L., Li X.S., Hazen S.L., Smith J.D. A Novel Cell-Free Fluorescent Assay for HDL Function: Low Apolipoprotein A1 Exchange Rate Associated with Increased Incident Cardiovascular Events. J. Appl. Lab. Med. 2020;5:544-557.

    Not in our library10.1093/jalm/jfaa002

  204. 204.

    Heffron S.P., Lin B.-X., Parikh M., Scolaro B., Adelman S.J., Collins H.L., Berger J.S., Fisher E.A. Changes in High-Density Lipoprotein Cholesterol Efflux Capacity After Bariatric Surgery Are Procedure Dependent. Arterioscler. Thromb. Vasc. Biol. 2018;38:245-254.

    Not in our library10.1161/atvbaha.117.310102

  205. 205.

    Zvintzou E., Skroubis G., Chroni A., Petropoulou P.-I., Gkolfinopoulou C., Sakellaropoulos G., Gantz D., Mihou I., Kalfarentzos F., Kypreos K.E. Effects of bariatric surgery on HDL structure and functionality: Results from a prospective trial. J. Clin. Lipidol. 2014;8:408-417.

    Not in our library10.1016/j.jacl.2014.05.001

  206. 206.

    Longitudinal Assessment of Bariatric Surgery (LABS) Consortium, Flum D.R., Belle S.H., King W.C., Wahed A.S., Berk P., Chapman W., Pories W., Courcoulas A., McCloskey C., et al. Perioperative safety in the longitudinal assessment of bariatric surgery. N. Engl. J. Med. 2009;361:445-454.

    Not in our library10.1056/nejmoa0901836

  207. 207.

    Coimbra S., Reis F., Ferreira C., Nunes S., Viana S., Catarino A., Rocha-Pereira P., Belo L., Monteiro L., Catarino C., et al. Weight loss achieved by bariatric surgery modifies high-density lipoprotein subfractions and low-density lipoprotein oxidation towards atheroprotection. Clin. Biochem. 2019;63:46-53.

    Not in our library10.1016/j.clinbiochem.2018.10.007

  208. 208.

    Kjellmo C.A., Karlsson H., Nestvold T.K., Ljunggren S., Cederbrant K., Marcusson-Ståhl M., Mathisen M., Lappegård K.T., Hovland A. Bariatric surgery improves lipoprotein profile in morbidly obese patients by reducing LDL cholesterol, apoB, and SAA/PON1 ratio, increasing HDL cholesterol, but has no effect on cholesterol efflux capacity. J. Clin. Lipidol. 2018;12:193-202.

    Not in our library10.1016/j.jacl.2017.10.007

  209. 209.

    Osto E., Doytcheva P., Corteville C., Bueter M., Dörig C., Stivala S., Buhmann H., Colin S., Rohrer L., Hasballa R., et al. Rapid and body weight-independent improvement of endothelial and high-density lipoprotein function after Roux-en-Y gastric bypass: Role of glucagon-like peptide-1. Circulation. 2015;131:871-881.

    Not in our library10.1161/circulationaha.114.011791

  210. 210.

    Ding S., Huang H., Xu Y., Zhu H., Zhong C. MiR-222 in Cardiovascular Diseases: Physiology and Pathology. BioMed Res. Int. 2017;2017.

    Not in our library10.1155/2017/4962426

  211. 211.

    Taïbi F., Metzinger-Le Meuth V., Massy Z.A., Metzinger L. miR-223: An inflammatory oncomiR enters the cardiovascular field. Biochim. Biophys. Acta BBA-Mol. Basis Dis. 2014;1842:1001-1009.

    Not in our library10.1016/j.bbadis.2014.03.005

  212. 212.
    High density lipoprotein-associated miRNA is increased following Roux-en-Y gastric bypass surgery for severe obesity · 2021
    Not checked
  213. 213.

    MacLean P.S., Wing R.R., Davidson T., Epstein L., Goodpaster B., Hall K.D., Levin B.E., Perri M.G., Rolls B.J., Rosenbaum M., et al. NIH working group report: Innovative research to improve maintenance of weight loss. Obesity. 2015;23:7-15.

    Not in our library10.1002/oby.20967

  214. 214.

    Thomas C.E., Mauer E.A., Shukla A.P., Rathi S., Aronne L.J. Low adoption of weight loss medications: A comparison of prescribing patterns of antiobesity pharmacotherapies and SGLT2s. Obesity. 2016;24:1955-1961.

    Not in our library10.1002/oby.21533

  215. 215.

    Kim K.K., Cho H.-J., Kang H.-C., Youn B.-B., Lee K.-R. Effects on Weight Reduction and Safety of Short-Term Phentermine Administration in Korean Obese People. Yonsei Med. J. 2006;47:614-625.

    Not in our library10.3349/ymj.2006.47.5.614

  216. 216.

    Bessesen D.H., Van Gaal L.F. Progress and challenges in anti-obesity pharmacotherapy. Lancet Diabetes Endocrinol. 2018;6:237-248.

    Not in our library10.1016/s2213-8587(17)30236-x

  217. 217.

    Davidson M.H., Tonstad S., Oparil S., Schwiers M., Day W.W., Bowden C.H. Changes in cardiovascular risk associated with phentermine and topiramate extended-release in participants with comorbidities and a body mass index ≥27 kg/m(2). Am. J. Cardiol. 2013;111:1131-1138.

    Not in our library10.1016/j.amjcard.2012.12.038

  218. 218.

    Garvey W.T., Ryan D.H., Look M., Gadde K.M., Allison D.B., Peterson C.A., Schwiers M., Day W.W., Bowden C.H. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): A randomized, placebo-controlled, phase 3 extension study. Am. J. Clin. Nutr. 2012;95:297-308.

    Not in our library10.3945/ajcn.111.024927

  219. 219.

    Mittendorfer B., Ostlund R.E., Patterson B.W., Klein S. Orlistat Inhibits Dietary Cholesterol Absorption. Obes. Res. 2001;9:599-604.

    Not in our library10.1038/oby.2001.79

  220. 220.

    Berne C., Orlistat Swedish Type 2 diabetes Study Group. A randomized study of orlistat in combination with a weight management programme in obese patients with Type 2 diabetes treated with metformin. Diabet. Med. J. Br. Diabet. Assoc. 2005;22:612-618.

    Not in our library10.1111/j.1464-5491.2004.01474.x

  221. 221.

    Hanefeld M., Sachse G. The effects of orlistat on body weight and glycaemic control in overweight patients with type 2 diabetes: A randomized, placebo-controlled trial. Diabetes Obes. Metab. 2002;4:415-423.

    Not in our library10.1046/j.1463-1326.2002.00237.x

  222. 222.

    Torgerson J.S., Hauptman J., Boldrin M.N., Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27:155-161.

    Not in our library10.2337/diacare.27.1.155

  223. 223.

    Kelley D.E., Bray G.A., Pi-Sunyer F.X., Klein S., Hill J., Miles J., Hollander P. Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes: A 1-year randomized controlled trial. Diabetes Care. 2002;25:1033-1041.

    Not in our library10.2337/diacare.25.6.1033

  224. 224.

    Hollander P.A., Elbein S.C., Hirsch I.B., Kelley D., McGill J., Taylor T., Weiss S.R., Crockett S.E., Kaplan R.A., Comstock J., et al. Role of Orlistat in the Treatment of Obese Patients With Type 2 Diabetes: A 1-year randomized double-blind study. Diabetes Care. 1998;21:1288-1294.

    Not in our library10.2337/diacare.21.8.1288

  225. 225.

    Miles J.M., Leiter L., Hollander P., Wadden T., Anderson J.W., Doyle M., Foreyt J., Aronne L., Klein S. Effect of Orlistat in Overweight and Obese Patients With Type 2 Diabetes Treated With Metformin. Diabetes Care. 2002;25:1123-1128.

    Not in our library10.2337/diacare.25.7.1123

  226. 226.

    Nordestgaard B.G., Langsted A., Mora S., Kolovou G., Baum H., Bruckert E., Watts G.F., Sypniewska G., Wiklund O., Borén J., et al. Fasting is not routinely required for determination of a lipid profile: Clinical and laboratory implications including flagging at desirable concentration cut-points-a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur. Heart J. 2016;37:1944-1958.

    Not in our library10.1093/eurheartj/ehw152

  227. 227.

    Langsted A., Freiberg J.J., Nordestgaard B.G. Fasting and nonfasting lipid levels: Influence of normal food intake on lipids, lipoproteins, apolipoproteins, and cardiovascular risk prediction. Circulation. 2008;118:2047-2056.

    Not in our library10.1161/circulationaha.108.804146

  228. 228.

    Fidler M.C., Sanchez M., Raether B., Weissman N.J., Smith S.R., Shanahan W.R., Anderson C.M., BLOSSOM Clinical Trial Group. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: The BLOSSOM trial. J. Clin. Endocrinol. Metab. 2011;96:3067-3077.

    Not in our library10.1210/jc.2011-1256

  229. 229.

    O’Neil P.M., Smith S.R., Weissman N.J., Fidler M.C., Sanchez M., Zhang J., Raether B., Anderson C.M., Shanahan W.R. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: The BLOOM-DM study. Obesity. 2012;20:1426-1436.

    Not in our library10.1038/oby.2012.66

  230. 230.

    Tuccinardi D., Farr O.M., Upadhyay J., Oussaada S.M., Mathew H., Paschou S.A., Perakakis N., Koniaris A., Kelesidis T., Mantzoros C.S. Lorcaserin treatment decreases body weight and improves cardiometabolic risk factors of obese adults: A 6-month-long, randomized, placebo-controlled, double-blind clinical trial. Diabetes Obes. Metab. 2019;21:1487-1492.

    Not in our library10.1111/dom.13655

  231. 231.

    Burcelin R., Gourdy P. Harnessing glucagon-like peptide-1 receptor agonists for the pharmacological treatment of overweight and obesity. Obes. Rev. 2017;18:86-98.

    Not in our library10.1111/obr.12465

  232. 232.

    Christou G.A., Katsiki N., Kiortsis D.N. The Current Role of Liraglutide in the Pharmacotherapy of Obesity. Curr. Vasc. Pharmacol. 2016;14:201-207.

    Not in our library10.2174/1570161113666150615111951

  233. 233.

    Engelbrechtsen L., Lundgren J., Wewer Albrechtsen N.J., Mahendran Y., Iepsen E.W., Finocchietto P., Jonsson A.E., Madsbad S., Holst J.J., Vestergaard H., et al. Treatment with liraglutide may improve markers of CVD reflected by reduced levels of apoB. Obes. Sci. Pract. 2017;3:425-433.

    Not in our library10.1002/osp4.133

  234. 234.
    Obesity and the Mediterranean Diet: A Review of Evidence of the Role and Sustainability of the Mediterranean Diet · 2019
    No notice
  235. 235.

    Mozaffarian D. Dietary and Policy Priorities for Cardiovascular Disease, Diabetes, and Obesity–A Comprehensive Review. Circulation. 2016;133:187-225.

    Not in our library10.1161/circulationaha.115.018585

  236. 236.

    Fontana L. Calorie restriction and cardiometabolic health. Eur. J. Cardiovasc. Prev. Rehabil. 2008;15:3-9.

    Not in our library10.1097/hjr.0b013e3282f17bd4

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