High-density Lipoprotein Cholesterol Metabolism Research Articles

Low childhood high density lipoprotein cholesterol levels and subsequent risk for chronic inflammatory bowel disease

Background and aimsSeveral genetic and environmental risk factors have been linked to chronic inflammatory bowel disease (IBD). The incidence of IBD has significantly increased in developed countries during last decades. The aim of the present study was to examine childhood risk factors for subsequent IBD diagnosis in a longitudinal cohort study of children and adolescents. MethodsA Finnish study population consisting of 3551 children and adolescents originally evaluated as part of the Cardiovascular Risk in Young Finns study in 1980. At baseline, participant BMI, insulin, lipid, C-reactive protein and blood pressure levels, socioeconomic position, dietary habits, and physical activity, were evaluated. In addition, information was gathered on rural residency, severe infections, breast feeding, parental smoking and birth weight. Subsequent IBD diagnosis status was evaluated based on nationwide registries on hospitalisations and drug imbursement decisions. ResultsAltogether, 49 participants (1.4%) had IBD diagnosed during the 34 years of register follow-up, of which 31 had ulcerative colitis, 12 Crohn's disease and 6 undetermined colitis. In univariate analyses, significant correlations were observed between childhood HDL-cholesterol (risk ratio (95% CI) for 1-SD change (0.58 (0.42–0.79)) and CRP concentrations (1.20 (1.01–1.43)) with IBD. The inverse association between HDL-cholesterol and IBD remained significant (0.57 (0.39–0.82)) in a multivariable model including data on age, sex and CRP. In addition, a weighted genetic z-score of 71 single nucleotide polymorphisms associated with elevated HDL-cholesterol levels was significantly lower in IBD patients, P=0.01). ConclusionLow childhood HDL-cholesterol levels are associated with subsequent IBD diagnosis. In addition, a genetic risk score associated with low HDL-cholesterol levels predict later IBD suggesting that HDL-cholesterol metabolism might have a role in the pathogenesis of IBD.

Endothelial Lipase Gene Polymorphism (584 C/T) in Coronary Artery Patients Among a Turkish Population.

The endothelial lipase gene (LIPG) has a major role in regulating high density lipoprotein cholesterol (HDL-C), therefore this study investigated whether LIPG is associated with coronary artery disease (CAD) in a Turkish population. The LIPG (584 C/T) mutation was analyzed in 74 CAD patients and 73 controls. There was a significant difference between the two groups regarding the mutant T allele frequencies (χ2=0.456, p=0.020; 26.7% and 41.8% in patient and control groups, respectively) for 584 C/T. Even though the TT genotype was not significantly different, it had p=0.054 which supported our results. The endothelial lipase gene (584 C/T) T allele might be protective in association with coronary artery disease. Therefore, LIPG gene is related to risk for CAD in the Turkish population probably through altering HDL-C metabolism.

HDL Cholesterol Metabolism and the Risk of CHD: New Insights from Human Genetics.

Elevated high-density lipoprotein cholesterol levels in the blood (HDL-C) represent one of the strongest epidemiological surrogates for protection against coronary heart disease (CHD), but recent human genetic and pharmacological intervention studies have raised controversy about the causality of this relationship. Here, we review recent discoveries from human genome studies using new analytic tools as well as relevant animal studies that have both addressed, and in some cases, fueled this controversy. Methodologic developments in genotyping and sequencing, such as genome-wide association studies (GWAS), exome sequencing, and exome array genotyping, have been applied to the study of HDL-C and risk of CHD in large, multi-ethnic populations. Some of these efforts focused on population-wide variation in common variants have uncovered new polymorphisms at novel loci associated with HDL-C and, in some cases, CHD risk. Other efforts have discovered loss-of-function variants for the first time in genes previously implicated in HDL metabolism through common variant studies or animal models. These studies have allowed the genetic relationship between these pathways, HDL-C and CHD to be explored in humans for the first time through analysis tools such as Mendelian randomization. We explore these discoveries for selected key HDL-C genes CETP, LCAT, LIPG, SCARB1, and novel loci implicated from GWAS including GALNT2, KLF14, and TTC39B. Recent human genetics findings have identified new nodes regulating HDL metabolism while reshaping our current understanding of known candidate genes to HDL and CHD risk through the study of critical variants across model systems. Despite their effect on HDL-C, variants in many of the reviewed genes were found to lack any association with CHD. These data collectively indicate that HDL-C concentration, which represents a static picture of a very dynamic and heterogeneous metabolic milieu, is unlikely to be itself causally protective against CHD. In this context, human genetics represent an extremely valuable tool to further explore the biological mechanisms regulating HDL metabolism and investigate what role, if any, HDL plays in the pathogenesis of CHD.

Sex-dependent difference in the relationship between adipose-tissue cholesterol efflux and estradiol concentrations in young healthy humans

BackgroundImpaired adipose tissue function and lower levels of high density lipoprotein cholesterol (HDL-C) have been implicated in the development of vascular dementia, and metabolic diseases such as hypertension, atherosclerosis, type 2 diabetes (T2D) and metabolic syndrome. Interestingly, both the substrate fluxes in adipose tissue and HDL-C concentration differ between men and women. Moreover, adipose tissue cholesterol efflux has been implicated in modulation of HDL-C levels. Thus, we aimed to determine if the association between serum estradiol levels and adipose tissue cholesterol efflux is sex-dependent. MethodWe evaluated the serum estradiol levels and adipose tissue cholesterol efflux in young healthy men (n=5) and women (n=3). Adipose tissue cholesterol efflux was determined using subcutaneous microdialysis probes. Linear regression analyses were used to determine the relationship between the parameters, p<0.05 was considered as statistically significant. ResultsOur data demonstrated that serum estradiol levels directly associated with adipose tissue cholesterol efflux; however, the relationships may be sex-dependent. We discussed our results in the context of currently available data regarding sex-dependent variability in adipose tissue function and HDL-C metabolism as a potential contributor to higher rates of vascular dementia in men. Further research is required to understand the sex-dependent and −independent variabilities in adipose tissue metabolism to determine novel targets for interventions to prevent the development of vascular dementia.

Factors affecting high-density lipoprotein cholesterol in HIV-infected patients on nevirapine-based antiretroviral therapy.

Background & objectives:Cardiovascular disease (CVD) risk with low high-density lipoprotein cholesterol (HDL-C) and high triglycerides is common in the general population in India. As nevirapine (NVP)-based antiretroviral therapy (ART) tends to increase HDL-C, gene polymorphisms associated with HDL-C metabolism in HIV-infected adults on stable NVP-based ART were studied.Methods:A cross-sectional study was conducted between January 2013 and July 2014 among adults receiving NVP-based ART for 12-15 months. Blood lipids were estimated and gene polymorphisms in apolipoprotein C3 (APOC3), cholesteryl ester transfer protein (CETP) and lipoprotein lipase (LPL) genes were analyzed by real-time polymerase chain reaction. Framingham's 10-yr CVD risk score was estimated. Logistic regression was done to show factors related to low HDL-C levels.Results:Of the 300 patients included (mean age: 38.6±8.7 yr; mean CD4 count 449±210 cell/μl), total cholesterol (TC) >200 mg/dl was observed in 116 (39%) patients. Thirty nine per cent males and 47 per cent females had HDL-C levels below normal while 32 per cent males and 37 per cent females had TC/HDL ratio of 4.5 and 4.0, respectively. Body mass index [adjusted odds ratio (aOR)=1.70, 95% confidence interval (CI) 1.01-2.84, P=0.04] and viral load (aOR=3.39, 95% CI: 1.52-7.52, P=0.003) were negatively associated with serum HDL-C levels. The 10-yr risk score of developing CVD was 11-20 per cent in 3 per cent patients. Allelic variants of APOC3 showed a trend towards low HDL-C.Interpretation & conclusions:High-risk lipid profiles for atherosclerosis and cardiovascular disease were common among HIV-infected individuals, even after 12 months of NVP-based ART. Targeted interventions to address these factors should be recommended in the national ART programmes.

Effects of the SGLT2 inhibitor dapagliflozin on HDL cholesterol, particle size, and cholesterol efflux capacity in patients with type 2 diabetes: a randomized placebo-controlled trial

BackgroundSodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce glucose levels, body weight, and blood pressure, possibly resulting in cardiovascular protection. In phase III trials, SGLT2i were shown to increase HDL cholesterol. We aimed to evaluate whether the SGLT2i dapagliflozin affects HDL function in a randomized placebo-controlled trial.MethodsThirty-three type 2 diabetic patients were randomized to receive dapagliflozin 10 mg or placebo for 12 weeks on top of their glucose lowering medications. The primary end-point was the change in cholesterol efflux capacity (CEC) from macrophages at study end versus baseline. Secondary endpoints were changes in: distribution of HDL subfractions, lipid profile, activity of enzymes that mediate HDL antioxidant properties (PON1 and ARE) and cholesterol metabolism (CETP), HbA1c, body weight and composition.ResultsThirty-one patients completed the study, n = 16 in the placebo group and n = 15 in the dapagliflozin group. Patients randomized to dapagliflozin were older and had lower adiposity indexes, although these differences disappeared after correction for multiple testing. Therapy with dapagliflozin reduced HbA1c by 0.9% and body weight by 3.1 kg, mainly attributable to reduction of body water and lean mass. As compared to placebo, dapagliflozin reduced CEC (−6.7 ± 2.4 versus 0.3 ± 1.8%; p = 0.043), but this effect was no longer significant after adjusting for age and BMI. No change was detected in HDL cholesterol, HDL subfractions, activity of PON1, ARE, and CETP.ConclusionsDespite improvements in glucose control and reduction in body weight, therapy with dapagliflozin exerted no significant effect on HDL cholesterol levels and HDL functionality.Trial registration EudraCT 2014-004270-42; NCT02327039

Current and future therapies for addressing the effects of inflammation on HDL cholesterol metabolism.

This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.

Relationship between plasma homocysteine level and lipid profiles in a community-based Chinese population

BackgroundPrevious studies established a possible link among hyperhomocysteinemia (HHcy), dyslipidemia, and atherosclerosis. However, there was limited epidemic data concerning the relation between HHcy and lipid profiles, especially in community-based Chinese populations. This study aim to investigate the association of plasma homocysteine (Hcy) level with lipid profiles in a Chinese community-based population without lipid-lowering treatment.MethodA total of 4660 Chinese subjects from a cohort of the Shijingshan district in Beijing were included in the analysis. Plasma total Hcy, serum lipid files including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) as well as relevant metabolic risk factors were measured. Multivariate regression models adjusting for age, gender, smoking, drinking, physical activity, vitamin B supplement, body mass index, fasting blood glucose level, serum creatinine, systolic and diastolic blood pressure were used to evaluate associations of Hcy and lipid profiles.ResultSubjects were 56.75 ± 8.91 years old, and 38.15% were male. Median (IQR) Hcy was 11.98 (10.00–14.93) μmol/L, and 24.4% had HHcy (defined as Hcy ≥ 15 μmol/L). Mean (SD) baseline TC was 5.34 ± 0.98 mmol/L, LDL-C was 3.27 ± 0.81 mmol/L, and HDL-C was 1.43 ± 0.38 mmol/L. Median (IQR) of TG was 1.28 (0.91–1.85) mmol/L. In multivariable linear-regression analyses, lnHcy (ln transformation for Hcy) level was positively associated with lnTG (adjusted β = 0.075, SE = 0.021, P = 0.001). Using Hcy < 15 μmol/L as a reference, HHcy was independently associated with both lnTG (adjusted β = 0.056, SE = 0.020, P = 0.004) and lnHDL (adjusted β = −0.018, SE = 0.009, P = 0.038). In multivariable logistic-regression analyses, HHcy was associated with increasing risk of low HDL-C (HDL-C < 1.04 mmol/L; adjusted odds ratio [OR] =1.406, 95% confidence interval [CI]: 1.143 – 1.728, P = 0.001) and hypertriglyceridemia (TG ≥ 1.7 mmol/L; adjusted OR = 1.293, 95% CI: 1.096–1.524, P = 0.002) after adjusting the confounders. However, there were no significant associations between Hcy and TC or LDL-C.ConclusionThe present study showed that HHcy was independently associated with hypertriglyceridemia and low levels of HDL-C, which provides evidence that Hcy levels might affect HDL-C and TG metabolism.

Demystifying HDL Cholesterol-A "Human Knockout" to the Rescue?

The substantial cost associated with failure of a therapeutic approach in a large outcomes-based clinical trial, as has occurred recently for multiple compounds targeting HDL cholesterol metabolism, has led to intense interest in improved target selection. Careful study of humans who carry mutations that inactivate a putative drug target leverages naturally occurring genetic variation to study the impact of lifelong deficiency of a specific protein. As such, human genetics research can provide an opportunity to confirm the physiologic relevance of a target in humans before large-scale investments in drug development. Naturally occurring human DNA sequence variation can provide the foundation for important insights into disease biology and novel therapeutic strategies. Within the field of lipid metabolism, the rapid clinical development of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors to reduce LDL cholesterol provides proof-of-concept for the potential of this approach. Following the initial 2003 discovery of a gain-of-function mutation in the gene PCSK9 (proprotein convertase subtilisin/kexin type 9)3 associated with significantly increased LDL cholesterol, a 2005 report noted that about 2% of black individuals harbor an inactivating (premature stop) mutation in the PCSK9 gene. Carriers of this mutation benefitted from lifelong lower LDL cholesterol concentrations and inborn protection from coronary disease without detectable toxicity (1). Further, the identification of healthy individuals with 2 inactivating mutations, effectively “human knockouts” for PCSK9, further increased optimism that the protein could be targeted without off-target effects. These observations provided additional support for the hypothesis that pharmacologic inhibition of PCSK9 might similarly lower LDL cholesterol and decrease vascular risk. Translational research studies demonstrated that PCSK9 plays a previously unrecognized role in preventing hepatic uptake of LDL cholesterol by accelerating the catabolism of LDL receptors. These findings led to a pharmaceutical arms race to develop PCSK9 inhibitors using monoclonal antibody or RNA interference approaches. …

Cardiometabolic Risk Related to the Association of hypertriglyceridemia-Low HDLc.

High levels of plasma triglycerides (TG) are a risk factor for cardiovascular diseases often associated with anomalies in other lipids or lipoproteins. However, results from randomized trials, suggesting that low high density lipoprotein cholesterol (HDLc) might not cause cardiovascular disease, as originally thought, have generated renewed interest in increased concentrations of TG. The objective has been to determine the prevalence and factors associated with hypertrigliceridemia (HTG) and with low HDLc. Patients, included in the HTG Registry of the Spanish Association of Atherosclerosis, have been analyzed and anthropometric as well as metabolic data have been collected from them. 1349 patients have been evaluated. Low HDLc has been found in 60.86% (821). Factors significantly associated with low HDLc and HTG were the female sex, being overweight with an increase in the body mass index, using tobacco, diabetes mellitus, low-alcohol consumption and a low exercise rate. Among them, two types of association may be identified with anthropometric variables (especially in men) and metabolic variables (diabetes mellitus and metabolic syndrome). No significant differences have been found insofar as the prevalence of cardiovascular illness between both groups. HTG - low HDLc association is very frequent and it is related to overweight-obesity and other metabolic disorders such as diabetes mellitus with or without metabolic syndrome. In addition, these findings underscore the intricate relationship between HDLc, TG, and glucose metabolism that need to be studied simultaneously. In this context, TG lowering treatment is suggested to be more strongly recommended to address the residual risk of atherosclerotic cardiovascular disease.

Lipidomic Profiling of Liver Tissue from Obesity-Prone and Obesity-Resistant Mice Fed a High Fat Diet

Obesity is a multifactorial health problem resulting from genetic, environmental, and behavioral factors. A particularly interesting aspect of obesity is the differences observed in response to the same high-fat diet (HFD). In this study, we performed lipidomic profiling on livers from HFD-fed C57BL/6J mice using ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry. Mice were divided into three groups: normal diet (ND), HFD-obesity prone (HFD-OP), and HFD-obesity resistant (HFD-OR). Principal components analyses showed a difference between the HFD-OP and HFD-OR groups. Individuals in the HFD-OR group were closer to those in the ND group compared with those in the HFD-OP group. In particular, phosphocholine (PC) and triglyceride (TG) levels differed significantly depending on the length of the acyl chain and degree of unsaturation, respectively. PC species were either positively or negatively correlated with concentrations of glucose, insulin, leptin, and hepatic cholesterol according to the length of the acyl chain. Decreased expression of the scavenger receptor B1 and ATP-binding cassette A1 in HFD-OP mice indicated that the acyl chain length of PC species may be related to high-density lipoprotein cholesterol metabolism. This study demonstrates that lipidomic profiling is an effective approach to analyzing global lipid alterations as they pertain to obesity.

What does procollagen C-endopeptidase enhancer protein 2 have to do with HDL-cholesteryl ester uptake? Or how I learned to stop worrying and love reverse cholesterol transport?

Purpose of reviewThe purpose of this study is to provide an update on the role HDL apolipoprotein A-I plays in reducing the risk of cardiovascular disease (CVD) and how it relates to reverse cholesterol transport (RCT).Recent findingsDespite numerous studies showing that plasma HDL cholesterol concentrations are correlated with a reduced risk of CVD, pharmacologic elevation of HDL has not shown any beneficial effects to date. In contrast, studies correlating the measure of an individual's plasma cholesterol efflux capacity show greater promise as a tool for assessing CVD risk. Although ATP-binding cassette transporter 1-mediated lipidation of apoA-I is considered the principal source of plasma HDL, it represents only one side of the RCT pathway. Equally important is the second half of the RCT pathway in which the liver scavenger receptor class B1 selectively removes HDL cholesteryl esters for excretion. The combined action of the two enzyme systems is reflected in the overall steady-state concentration of plasma HDL cholesterol. For example, reduced ATP-binding cassette transporter 1-mediated production of nascent HDL lowers plasma HDL concentration, just as an increase in cholesteryl ester uptake by scavenger receptor class B1 reduces HDL levels. Thus, the complexity of intravascular HDL metabolism suggests that steady-state plasma HDL concentrations do not provide adequate information regarding an individual's HDL quality or function. Herein, we describe a new player, procollagen C-endopeptidase enhancer 2, which shows atheroprotective function and influences both sides of RCT by enhancing production and catabolism of HDL cholesteryl esters.SummaryThe discovery of a new molecule, procollagen C-endopeptidase enhancer 2, implicated in the regulation of HDL cholesteryl ester concentrations suggests that the extracellular matrix and the proteins that regulate its function represent a new and as yet unexplored realm of HDL cholesterol metabolism.

HDL-cholesterol and cardiovascular disease: rethinking our approach.

A low level of plasma high density lipoprotein cholesterol (HDL-C) is a strong and independent risk factor for atherosclerotic cardiovascular disease (ASCVD). However, several large studies recently revealed that pharmacologic interventions that increase HDL-C concentration have not improved cardiovascular outcomes when added to standard therapy. In addition, specific genetic variants that raise HDL-C levels are not clearly associated with reduced risk of coronary heart disease. These observations have challenged the 'HDL hypothesis' that HDL-C is causally related to ASCVD and that intervention to raise HDL-C will reduce ASCVD events. This article will present the current data on the HDL hypothesis and provide a revised paradigm of considering HDL in the atherosclerotic pathway. Recent evidence has shed light on the complex nature of HDL-C metabolism and function. There are compelling data that the ability of HDL to promote cholesterol efflux from macrophages, the first step in the 'reverse cholesterol transport' (RCT) pathway, is inversely associated with risk for ASCVD even after controlling for HDL-C. This has led to the 'HDL flux hypothesis' that therapeutic intervention that targets macrophage cholesterol efflux and RCT may reduce risk. Preclinical studies of such interventions show promise and early phase clinical studies, though small, are encouraging. The role of HDL-C in modulating atherosclerotic disease is as yet uncertain. However, new findings and therapies targeting HDL-C show early promise and may provide an important intervention in attenuating the burden of ASCVD in the future.

Association of endothelial lipase gene−384A/C with coronary artery disease in Han Chinese people

ObjectivesThe endothelial lipase gene (LIPG) is one of the important genes in the metabolism of high-density lipoprotein cholesterol (HDL-C) and may be involved in the pathogenesis of coronary artery disease...

MicroRNAs and High-Density Lipoprotein Cholesterol Metabolism.

MicroRNAs (miRNAs) are small non-protein-coding RNAs that negatively regulate gene expression. They bind to the 3'-untranslated region of specific mRNAs and inhibit translation or promote mRNA degradation. Dyslipidemia/hyperlipidemia is a well-accepted risk factor for the development of atherosclerosis. The pathogenesis factors involved in lipid abnormalities are being examined extensively, and there is emerging evidence linking miRNAs to lipid metabolism. Among them, recent studies, including ours, have demonstrated that miRNAs control the expression of genes associated with high-density lipoprotein (HDL) cholesterol (HDL-C) metabolism, including ABCA1, ABCG1, and scavenger receptor class B, type I. Moreover, HDL-C itself was proved to carry miRNAs and deliver them to several different types of cells. In this review, we describe the current understanding of the functions of miRNAs in HDL metabolism and their potential in therapy for treating cardiometabolic diseases.

Intake levels of dietary polyunsaturated fatty acids modify the association between the genetic variation in PCSK5 and HDL cholesterol

BackgroundA low serum level of high-density lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 5 (PCSK5) modulates HDL-C metabolism through the inactivation of endothelial...

Impact of genetic variants in human scavenger receptor class B type I (SCARB1) on plasma lipid traits.

Scavenger receptor class B type 1 (SCARB1) plays an important role in high-density lipoprotein cholesterol (HDL-C) metabolism in selective cholesteryl ester uptake and in free cholesterol cellular efflux. This study aims to identify common (minor allele frequency ≥5%) and low-frequency/rare (minor allele frequency <5%) variants, using resequencing all 13 exons and exon-intron boundaries of SCARB1 in 95 individuals with extreme HDL-C levels selected from a population-based sample of 623 US non-Hispanic whites. The sequencing step identified 44 variants, of which 11 were novel with minor allele frequency <1%. Seventy-six variants (40 sequence variants, 32 common HapMap tag single nucleotide polymorphisms, and 4 relevant variants) were selected for genotyping in the total sample of 623 subjects followed by association analyses with lipid traits. Seven variants were nominally associated with apolipoprotein B (apoB; n=4) or HDL-C (n=3; P<0.05). Three variants associated with apoB remained significant after controlling false discovery rate. The most significant association was observed between rs4765615 and apoB (P=0.0059), while rs11057844 showed the strongest association with HDL-C (P=0.0035). A set of 17 rare variants (minor allele frequency ≤1%) showed significant association with apoB (P=0.0284). Haplotype analysis revealed 4 regions significantly associated with either apoB or HDL-C. Our findings provide new information about the genetic role of SCARB1 in affecting plasma apoB levels in addition to its established role in HDL-C metabolism.

Gender-dependent association of HSD11B1 single nucleotide polymorphisms with glucose and HDL-C levels.

In this study, we investigated the influence of two SNPs (rs846910 and rs12086634) of the HSD11B1 gene that encodes 11β-hydroxysteroid dehydrogenase type 1(11β-HSD1), the enzyme that catalyzes the conversion of cortisol to cortisone, on variables associated with obesity and metabolic syndrome in 215 individuals of both sexes from southern Brazil. The HSD11B1 gene variants were genotyped using the TaqMan SNP genotyping assay. Glucose, triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol were measured by standard automated methods. Significant results were found in women, with carriers of the G allele of SNP rs12086634 having higher glucose levels than non-carriers. Carriers of the A allele of SNP rs846910 had higher levels of HDL-cholesterol. The involvement of both polymorphisms as independent factors in determining the levels of glucose and HDL-cholesterol was confirmed by multiple regression analysis (β = 0.19 ±0.09, p = 0.03 and β= 0.22 ± 0.10, p = 0.03, respectively). Our findings suggest that the HSD11B1SNPs studied may indirectly influence glucose and HDL-cholesterol metabolism in women, possibly through down-regulation of the HSD11B1 gene by estrogen.

Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol.

The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease (CVD), and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association (GWA) scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p < 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly Long Life Family Study (LLFS) subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in Encyclopedia of DNA Elements (ENCODE); however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region.

P2Y13 receptor regulates HDL metabolism and atherosclerosis in vivo.

High-density lipoprotein (HDL) is known to protect against atherosclerosis by promoting the reverse cholesterol transport. A new pathway for the regulation of HDL-cholesterol (HDL-c) removal involving F1-ATPase and P2Y13 receptor (P2Y13R) was described in vitro, and recently in mice. However, the physiological role of F1-ATPase/P2Y13R pathway in the modulation of vascular pathology i.e. in the development of atherosclerotic plaques is still unknown. We designed a specific novel agonist (CT1007900) of the P2Y13R that caused stimulation of bile acid secretion associated with an increased uptake of HDL-c in the liver after single dosing in mice. Repeated dose administration in mice, for 2 weeks, stimulated the apoA-I synthesis and formation of small HDL particles. Plasma samples from the agonist-treated mice had high efflux capacity for mobilization of cholesterol in vitro compared to placebo group. In apoE−/− mice this agonist induced a decrease of atherosclerotic plaques in aortas and carotids. The specificity of P2Y13R pathway in those mice was assessed using adenovirus encoding P2Y13R-shRNA. These results demonstrate that P2Y13R plays a pivotal role in the HDL metabolism and could also be a useful therapeutic agent to decrease atherosclerosis. In this study, the up-regulation of HDL-c metabolism via activation of the P2Y13R using agonists could promote reverse cholesterol transport and promote inhibition of atherosclerosis progression in mice.