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 [12
]. 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 [72
]. 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 [73
]. 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 [74
]. 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 [77
]. Therefore, considerable interest has recently focused on approaches to influence the biological functions of HDL in the search for new cardioprotective therapies [78
]. This is based on new findings that underline the importance of HDL functionality [85
], 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 [88
], 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 [89
]. 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 [92
], 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 [94
]. During this process, HDL is enriched in triglycerides and represents a better substrate for hepatic lipase and is hydrolyzed more rapidly [95
]. In obese insulin-resistant subjects, HDL is enriched in triglycerides and the activity of hepatic lipase is increased [96
]. Hydrolysis of triglyceride-rich HDL further leads to the formation of smaller HDL3 particles, which are susceptible to faster catabolism [99
]. 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 [100
]. Interestingly, a study in children showed that plasma leptin levels correlated with HDL-C [102
]. Further, a correlation between leptin and HDL-associated triglycerides and with HDL particle size has been reported in adults [103
]. In vivo experiments in leptin-deficient (ob/ob) mice suggest that leptin upregulates hepatic SR-BI and thereby influences levels of HDL-C [104
In the state of obesity, increased CETP levels are correlated with leptin levels [105
], in line with the fact that adipose tissue is one of the major sources of CETP expression [106
]. Therefore, the obesity-associated increase in CETP production is thought to affect HDL-C levels [107
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 [108
]. 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 [113
]. 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 [96
], leading to faster clearance of triglyceride-rich HDL [116
], which is produced by CETP-mediated transfer. The triglyceride-enriched HDL is a more susceptible substrate for hepatic lipase and, therefore, undergoes rapid hydrolysis [99
]. 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 [118
]. 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 [119
], while overexpression of endothelial lipase caused a reduction of HDL-C by increased catabolism rate [119
]. 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 [124
]. 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 [124
]. Obesity is characterized by low-grade inflammation, leading to infiltration of immune cells into adipose tissue [126
]. 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 [128
]. In adipose tissue, nearly all of the cholesterol is stored in the unesterified form, as free cholesterol, which makes adipocytes unique among cells [129
]. 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 [133
]. 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 [134
]. 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.
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 [187
]. 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 [191
]. RYGB surgeries resulted in significant improvements of plasma lipid levels, decreased risk of cardiovascular disease, and overall mortality [192
]. Further, after RYGB, levels of circulating adiponectin increased, insulin sensitivity improved, and blood pressure levels were reduced [196
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 [195
]. 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 [201
]. 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 [203
]. This apoA-I exchange rate has been linked with risk of major adverse cardiovascular events [203
]. 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 [204
]. However, after 12 months both operations resulted in improved cholesterol efflux capacity [204
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 [205
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 [206
]. Recently, the impact of laparoscopic adjustable gastric banding on HDL subclass distribution was studied [207
]. The authors observed an increase in large HDL and intermediate HDL subclasses and a decrease of the small HDL subfraction [207
]. 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 [208
Another study evaluated whether RYGB restores protective properties of HDL and reverses the obesity-induced endothelial dysfunction [209
]. 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 [209
]. 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 [210
], with markers of HDL function [212
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 [213
]. 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 [214
]. Twelve weeks of administration of phentermine reduced body weight and decreased levels of total cholesterol in Korean obese subjects [215
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 [216
]. 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 [217
]. 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 [218
Orlistat is an intestinal lipase inhibitor that prevents breakdown of triglycerides and has an excellent long-term safety record [216
]. Interestingly, orlistat causes a 25% reduction in cholesterol absorption [219
]. Regarding orlistat-induced changes in HDL-C levels, studies are inconsistent. Some studies reported a significant increase of HDL-C in patients receiving orlistat [200
], while others observed no significant changes [223
Noteworthily, food intake only minimally affects HDL-C [226
], 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 [228
]. A recent study showed that lorcaserin treatment for six months resulted in decrease of LDL-C, while plasma levels of HDL-C were increased [230
]. 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 [231
]. 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 [232
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 [234
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 [236
]. 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 [237
]. 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 [238
]. 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 [239
]. In line with this, another study with obese participants observed that a low-calorie diet reduced PON1 enzyme activity [240
]. Furthermore, weight loss through caloric restriction has been shown to decrease LCAT activity in obese [241
] as well as in normal-weight subjects [242
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 [243
]. Varady et al. demonstrated that the same ADF regimen was effective in both weight reduction and cardioprotection in normal-weight and overweight subjects [244
]. 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 [245
Mediterranean diet is a dietary approach to induce weight loss and to prevent cardiovascular events [234
]. 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 [246
]. 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 [247
]. 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 [248
]. 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 [249
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.