High-density Lipoprotein Metabolism Research Articles

Formation of the list of genes, functioning in human blood cells involved in atherogenesis and metabolism of high density lipoproteins

Formation of the list of genes, functioning in human blood cells involved in atherogenesis and metabolism of high density lipoproteins

Weight Loss and Exercise Alter the High-Density Lipoprotein Lipidome and Improve High-Density Lipoprotein Functionality in Metabolic Syndrome.

High-density lipoprotein (HDL) lipid composition and function may better reflect cardiovascular risk than HDL cholesterol concentration. This study characterized the relationships between HDL composition, metabolism, and function in metabolic syndrome (MetS) patients and how changes in composition after weight loss (WL) and exercise treatments are related to function. Plasma samples from MetS patients (n=95) and healthy individuals (n=40) were used in this study. Subsets of the MetS group underwent 12 weeks of no treatment (n=17), WL (n=19), or WL plus exercise (WLEX; n=17). HDL was isolated using density-gradient ultracentrifugation. The HDL lipidome was analyzed by mass spectrometry, and particle size determined by nuclear magnetic resonance. Cholesteryl ester transfer protein activity and ex vivo HDL cholesterol efflux capacity (CEC) were assessed. The HDL lipidome in the MetS patients was substantially different from that in healthy individuals, mean particle size was smaller, and CEC was lower. Several HDL phospholipid and sphingolipid species were associated with HDL diameter and CEC. The HDL lipidome and particle size were modified toward the healthy individuals after WL and WLEX treatments, with greater effects observed in the latter group. Cholesteryl ester transfer protein activity was reduced after WL and WLEX, and CEC was improved after WLEX. WLEX treatment in MetS patients normalizes the HDL lipidome and particle size profile and enhances CEC. HDL lipids associated with diminished CEC may represent novel biomarkers for early prediction of HDL dysfunction and disease risk and may represent potential therapeutic targets for future HDL therapies. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00163943.

High-density lipoprotein and cardiac glucose metabolism: Implications for management of acute coronary syndromes.

High-density lipoprotein and cardiac glucose metabolism: Implications for management of acute coronary syndromes.

Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults

Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes. This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries. Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels. Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases. Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P = 9.4 × 10-47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003). CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD.

A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state.

Apolipoprotein (apo)A-I is an organizing scaffold protein that is critical to high density lipoprotein (HDL) structure and metabolism, likely mediating many of its cardioprotective properties. However, HDL biogenesis is poorly understood as lipid-free apoA-I has been notoriously resistant to high resolution structural study. Published models from low resolution techniques share certain features but vary considerably in shape and secondary structure. To tackle this central issue in lipoprotein biology, we assembled an unprecedented team of lipoprotein structural biologists and set out to build a consensus model of monomeric lipid-free human apoA-I. Combining novel and published cross-link constraints, small angle X-ray scattering (SAXS), hydrogen-deuterium exchange (H-DX) and crystallography data, we propose a time averaged model consistent with much of the experimental data published over the last 40 years. The model provides a long sought platform for understanding and testing details of HDL biogenesis, structure and function.

High-density lipoprotein cholesterol efflux capacity is inversely associated with cardiovascular risk: a systematic review and meta-analysis

BackgroundA low plasma level of high-density lipoprotein (HDL) cholesterol (HDL-C) is associated with cardiovascular risk. A key cardioprotective property of HDL is cholesterol efflux capacity (CEC), the ability of HDL to accept cholesterol from macrophages. In this study, we aimed to identify the predictive value of CEC for cardiovascular risk.MethodsThe relative risks (RRs) and 95% confidence intervals (CIs) were pooled to analyze the association between CEC and the incidence of cardiovascular events and all-cause mortality. The odds ratios (ORs) and 95% CIs were pooled to estimate the association of CEC and the prevalence of cardiovascular events.ResultsA total of 15 studies were included. Results showed that the highest CEC was significantly associated with a reduced risk of cardiovascular events incidents compared to the lowest CEC (RR, 0.56; 95% CI, 0.37 to 0.85; I2, 89%); the pooled RR of cardiovascular risk for per unit SD increase was 0.87 (95% CI, 0.73 to 1.04; I2, 67%). Dose-response curve indicated that cardiovascular risk decreased by 39% (RR, 0.61; 95% CI, 0.51 to 0.74) for per unit CEC increase. Similarly, an inverse association was observed between CEC and the prevalence of cardiovascular events (highest vs. lowest, OR, 0.30; 95% CI, 0.17 to 0.5; I2 = 63%; per unit SD increase, OR, 0.94; 95% CI, 0.90 to 0.98; I2 = 71%). However, based on the current data, CEC was not significantly associated with all-cause mortality.ConclusionsFindings from this meta-analysis suggest that HDL-mediated CEC is inversely associated with cardiovascular risk, which appears to be independent of HDL concentration. The growing understanding of CEC and its role in cardiovascular risk decrease may improve the accuracy of cardiovascular risk prediction and also open important avenues to develop novel therapeutic targeting HDL metabolism.

Glycation Reduces the Stability of ApoAI and Increases HDL Dysfunction in Diet-Controlled Type 2 Diabetes.

Hyperglycemia plays a key role in the pathogenesis of cardiovascular complications of diabetes. Type 2 diabetes mellitus (T2DM) is associated with high-density lipoprotein (HDL) dysfunction and increased degradation of apolipoprotein I (ApoAI). The mechanism(s) of these changes is largely unknown. To study the role of hyperglycemia-induced glycation on ApoAI kinetics and stability in patients with diet-controlled T2DM. 2H2O-metabolic labeling approach was used to study ApoAI turnover in patients with diet-controlled T2DM [n = 9 (5 F); 59.3 ± 8.5 years] and matched healthy controls [n = 8 (4 F); 50.7 ± 11.6 years]. The effect of Amadori glycation on in vivo ApoAI stability and the antioxidant and cholesterol efflux properties of HDL were assessed using a proteomics approach and in vitro assays. Patients with T2DM had increased turnover of ApoAI and impaired cholesterol efflux and antioxidant properties of HDL. Glycated hemoglobin was negatively correlated with the half-life of ApoAI and cholesterol efflux function of HDL. Proteomics analysis identified several nonenzymatic early (Amadori) glycations of ApoAI at lysine sites. The kinetics analysis of glycated and native ApoAI peptides in patients with T2DM revealed that glycation resulted in a threefold shorter ApoAI half-life. The 2H2O method allowed the detection of early in vivo impairments in HDL metabolism and function that were related to hyperglycemia-induced glycation of ApoAI in T2DM.

Regulated efflux of photoreceptor outer segment-derived cholesterol by human RPE cells

Genetic studies have linked age-related macular degeneration (AMD) to genes involved in high-density lipoprotein (HDL) metabolism, including ATP-binding cassette transporter A1 (ABCA1). The retinal pigment epithelium (RPE) handles large amounts of lipids, among others cholesterol, partially derived from internalized photoreceptor outer segments (OS) and lipids physiologically accumulate in the aging eye. To analyze the potential function of ABCA1 in the eye, we measured cholesterol efflux, the first step of HDL generation, in RPE cells. We show the expression of selected genes related to HDL metabolism in mouse and human eyecups as well as in ARPE-19 and human primary RPE cells. Immunofluorescence staining revealed localization of ABCA1 on both sides of polarized RPE cells. This was functionally confirmed by directional efflux to apolipoprotein AI (ApoA-I) of 3H-labeled cholesterol given to the cells via serum or via OS. ABCA1 expression and activity was modulated using a liver-X-receptor (LXR) agonist and an ABCA1 neutralizing antibody, demonstrating that the efflux was ABCA1-dependent. We concluded that the ABCA1-mediated lipid efflux pathway, and hence HDL biosynthesis, is functional in RPE cells towards both the basal (choroidal) and apical (subretinal) space. Impaired activity of the pathway might cause age-related perturbations of lipid homeostasis in the outer retina and thus may contribute to disease development and/or progression.

Gugulipid causes hypercholesterolemia leading to endothelial dysfunction, increased atherosclerosis, and premature death by ischemic heart disease in male mice.

For proper cholesterol metabolism, normal expression and function of scavenger receptor class B type I (SR-BI), a high-density lipoprotein (HDL) receptor, is required. Among the factors that regulate overall cholesterol homeostasis and HDL metabolism, the nuclear farnesoid X receptor plays an important role. Guggulsterone, a bioactive compound present in the natural product gugulipid, is an antagonist of this receptor. This natural product is widely used globally as a natural lipid-lowering agent, although its anti-atherogenic cardiovascular benefit in animal models or humans is unknown. The aim of this study was to determine the effects of gugulipid on cholesterol homeostasis and development of mild and severe atherosclerosis in male mice. For this purpose, we evaluated the impact of gugulipid treatment on liver histology, plasma lipoprotein cholesterol, endothelial function, and development of atherosclerosis and/or ischemic heart disease in wild-type mice; apolipoprotein E knockout mice, a model of atherosclerosis without ischemic complications; and SR-B1 knockout and atherogenic–diet-fed apolipoprotein E hypomorphic (SR-BI KO/ApoER61h/h) mice, a model of lethal ischemic heart disease due to severe atherosclerosis. Gugulipid administration was associated with histological abnormalities in liver, increased alanine aminotransferase levels, lower hepatic SR-BI content, hypercholesterolemia due to increased HDL cholesterol levels, endothelial dysfunction, enhanced atherosclerosis, and accelerated death in animals with severe ischemic heart disease. In conclusion, our data show important adverse effects of gugulipid intake on HDL metabolism and atherosclerosis in male mice, suggesting potential and unknown deleterious effects on cardiovascular health in humans. In addition, these findings reemphasize the need for rigorous preclinical and clinical studies to provide guidance on the consumption of natural products and regulation of their use in the general population.

CETP (Cholesteryl Ester Transfer Protein) Inhibition With Anacetrapib Decreases Production of Lipoprotein(a) in Mildly Hypercholesterolemic Subjects.

Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib. We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using 2H3-leucine at the end of each treatment to measure apo(a) fractional catabolic rate and production rate. Median baseline Lp(a) levels were 21.5 nmol/L (interquartile range, 9.9-108.1 nmol/L) in the complete cohort (39 subjects) and 52.9 nmol/L (interquartile range, 38.4-121.3 nmol/L) in the subset selected for kinetic studies. Anacetrapib treatment lowered Lp(a) by 34.1% (P≤0.001) and 39.6% in the complete and subset cohort, respectively. The decreases in Lp(a) levels were because of a 41% reduction in the apo(a) production rate, with no effects on apo(a) fractional catabolic rate. Anacetrapib reduces Lp(a) levels by decreasing its production. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808.

A genome-wide sirna screen as a tool to unveil new players in hepatic high density lipoprotein and low density lipoprotein metabolism

A genome-wide sirna screen as a tool to unveil new players in hepatic high density lipoprotein and low density lipoprotein metabolism

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

Background ANGPTL4 (angiopoietin‐like protein 4) is a LPL (lipoprotein lipase) inhibitor and is present in high‐density lipoprotein (HDL). However, it is not defined whether ANGPTL4 in HDLs could affect HDL metabolism and function in type 2 diabetes mellitus (T2DM).Methods and Results ANGPTL4 levels in the circulation and HDLs were quantified in nondiabetic participants (n=201, 68.7% females) and T2DM patients (n=185, 66.5% females). HDLs were isolated from nondiabetic controls and T2DM patients to assess cholesterol efflux or subjected to endothelial lipase (EL)‐overexpressed HEK293 cells for EL hydrolysis in vitro. The association between ANGPTL4 in HDLs and HDL components and function was analyzed in nondiabetic participants or diabetic patients, respectively. Plasma or HDLs of ANGPTL4+/+ and ANGPTL4−/− mice was subjected for cholesterol efflux or EL hydrolysis, respectively. ANGPTL4 levels in the plasma and HDLs were 1.7‐ and 2.0‐fold higher in T2DM patients than nondiabetic controls, respectively (P<0.0001). Multivariable analysis demonstrated that per 1 doubling increase of ANGPTL4 levels in HDLs, the changes amounted to +0.27% cholesterol efflux (P=0.03), +0.06 μg/mL apolipoprotein A‐I (P=0.09) and −9.41 μg/L serum amyloid A (P=0.02) in nondiabetic controls. In T2DM patients, the corresponding estimates were −0.06% cholesterol efflux (P=0.10), −0.06 μg/mL apolipoprotein A‐I (P=0.38), and +3.64 μg/L serum amyloid A (P=0.72). HDLs isolated from ANGPTL4−/− mice showed accelerated hydrolysis by EL and reduced cholesterol efflux compared with ANGPTL4+/+ littermates.ConclusionsPhysically, ANGPTL4 in HDLs protected HDLs from hydrolysis. Resulting from increased circulating ANGPTL4 levels in T2DM, ANGPTL4 levels in HDLs were elevated but with compromised inhibitory effect on EL, leading to increased HDL hydrolysis and dysfunction.

Down Syndrome, Increased Risk of Dementia and Lipid Disturbances

Down syndrome (DS) is the most common chromosomal aberration and genetically determined cause of intellectual disability. DS patients often present with some congenital defects and chronic diseases, including early onset dementia, which affects 70% of DS patients over 55 years of age and has a clinical presentation similar to Alzheimer disease (AD). The symptoms of DS originate from excessive genetic material within the “critical region” of the 21st chromosome. The “critical region” encompasses genes potentially associated with increase risk of dementia, e.g. the APP gene (amyloid beta precursor protein) which leads to excessive amyloid beta production. Post-mortem studies of DS patients’ brains revealed diffuse deposition of the insoluble form of amyloid beta (Aβ), which is a characteristic feature of AD. Moreover, those changes were commonly observed in subjects > 31 years old. The pathomechanisms of AD have not been fully elucidated and scientists are still searching for new risk factors that may contribute to the development of this common illness. Recent research proved that lipid disturbance, especially disorders in the metabolism of HDL (high density lipoprotein) may play a crucial role in this pathogenic process. There are many studies examining lipid and lipoprotein concentration in the DS population, but up to now there are insufficient studies comparing these parameters with memory impairment, which may be a useful model for better understanding of the dementia pathomechanism.

High density lipoprotein from coronary artery disease patients caused abnormal expression of long non-coding RNAs in vascular endothelial cells

Increased evidence has showed that normal high density lipoprotein (HDL) could convert to dysfunctional HDL in diseases states including coronary artery disease (CAD), which regulated vascular endothelial cell function differently. Long non-coding RNAs (lncRNAs) play an extensive role in various important biological processes including endothelial cell function. However, whether lncRNAs are involved in the regulation of HDL metabolism and HDL-induced changes of vascular endothelial function remains unclear. Cultured human umbilical vein endothelial cells (HUVECs) were treated with HDL from healthy subjects and patients with CAD and hypercholesterolemia for 24 h, then the cells were collected for lncRNA-Seq and the expressions of lncRNAs, genes and mRNAs were identified. The bioinformatic analysis was used to evaluate the relationship among lncRNAs, encoding genes and miRNAs. HDL from healthy subjects and patients with CAD and hypercholesterolemia leaded to different expressions of lncRNAs, genes and mRNAs, and further analysis suggested that the differentially expressed lncRNAs played an important role in the regulation of vascular endothelial function. Thus, HDL from patients with CAD and hypercholesterolemia could cause abnormal expression of lncRNAs in vascular endothelial cells to affect vascular function.

Metabolism of high density lipoprotein and the research progress of its effects on sepsis

Sepsis is a high-risk factor for the death of critical patients. High density lipoprotein (HDL) are the major protective serum proteins, and the serum levels of HDL are closely related to the severity of sepsis. The anti-inflammatory and anti-oxidation properties of HDL, may be able to play an important role in the innate immune response. Thereby it may reduce the damage of septic shock and multiple organ dysfunction syndrome (MODS) in animals or human beings, and improve the prognosis. In order to unveil the metabolism of HDL in septic patients and its effects on both progression and prognosis of sepsis, this review not only focuses on the composition and structure of HDL, but also analyzes its pivotal role in inflammatory immune response and anti-oxidation.

Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport

Brown and beige adipocytes combust nutrients for thermogenesis and through their metabolic activity decrease pro-atherogenic remnant lipoproteins in hyperlipidemic mice. However, whether the activation of thermogenic adipocytes affects the metabolism and anti-atherogenic properties of high-density lipoproteins (HDL) is unknown. Here, we report a reduction in atherosclerosis in response to pharmacological stimulation of thermogenesis linked to increased HDL levels in APOE*3-Leiden.CETP mice. Both cold-induced and pharmacological thermogenic activation enhances HDL remodelling, which is associated with specific lipidomic changes in mouse and human HDL. Furthermore, thermogenic stimulation promotes HDL-cholesterol clearance and increases macrophage-to-faeces reverse cholesterol transport in mice. Mechanistically, we show that intravascular lipolysis by adipocyte lipoprotein lipase and hepatic uptake of HDL by scavenger receptor B-I are the driving forces of HDL-cholesterol disposal in liver. Our findings corroborate the notion that high metabolic activity of thermogenic adipocytes confers atheroprotective properties via increased systemic cholesterol flux through the HDL compartment.

Could high-density lipoprotein cholesterol predict increased cardiovascular risk?

Serum high-density lipoprotein (HDL) is considered to be protective against cardiovascular disease. However, there is emerging evidence that under certain conditions the HDL molecule can become dysfunctional and proinflammatory, paradoxically leading to increased risk of cardiovascular disease. This review will provide a brief outline of the potential mechanisms by which HDL can become atherogenic and summarize some of the clinical evidence on this topic. HDL metabolism, structure, and function in addition to its level can be profoundly altered under conditions of marked oxidative stress and chronic inflammation. These abnormalities, in turn, lead to impaired reverse cholesterol transport, increased systemic oxidative stress/inflammation, and endothelial dysfunction that subsequently may contribute to atherogenesis and progression of cardiovascular disease. Association of serum HDL cholesterol level with outcomes is not only dependent on its serum concentration but also on the qualities/properties of this lipoprotein at a given point in time. Hence, it is essential that future studies examining association of HDL with risk of cardiovascular disease take into account the complexities of HDL metabolism and function and address the impact of the HDL particle as a whole (quantity as well as various properties) on atherosclerosis and cardiovascular outcomes.

Association between Dietary Xanthophyll (Lutein and Zeaxanthin) Intake and Early Age-Related Macular Degeneration: The Atherosclerosis Risk in Communities Study

ABSTRACTPurpose: To examine the association between xanthophyll intake and prevalent early age-related macular degeneration (AMD) using data from the Atherosclerosis Risk in Communities Study (n = 10,295). Potential effect modification by genetic polymorphisms and biomarkers of high-density lipoprotein (HDL) metabolism was explored.Methods: Xanthophyll intake was assessed at visit 1 (1987–1989) using food frequency questionnaires. Prevalent early AMD was assessed at visit 3 (1993–1995) via retinal photographs. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for AMD by quintiles of xanthophyll intake, adjusted for age, sex, race, field center, and pack-years of smoking. To evaluate effect modification, the association between tertiles (T) of xanthophyll intake and AMD was stratified by complement factor H (CFH) rs1061170 and age-related maculopathy susceptibility 2 (ARMS2) rs10490924 genotypes, as well as by median cutpoints of HDL biomarkers.Results: Xanthophyll intake was not associated with AMD in the overall sample, Caucasians (n = 8257), or African-Americans (n = 2038). Exploratory analyses observed that the association between xanthophyll intake and AMD varied statistically significantly by CFH rs1061170 genotype among Caucasians (p for interaction = 0.045) but not African Americans. No interactions were observed between xanthophyll intake and ARMS2 rs10490924. Moreover, higher xanthophyll intake was associated with decreased odds of AMD among participants with lower HDL (OR = 0.79, 95% CI 0.57–1.09) but not higher HDL (p for interaction = 0.048).Conclusion: Xanthophyll intake was not associated with early AMD. Further studies to investigate this association by genetic susceptibility or variations in HDL metabolism are needed.

High-density lipoprotein (HDL) metabolism and bone mass.

It is well appreciated that high-density lipoprotein (HDL) and bone physiology and pathology are tightly linked. Studies, primarily in mouse models, have shown that dysfunctional and/or disturbed HDL can affect bone mass through many different ways. Specifically, reduced HDL levels have been associated with the development of an inflammatory microenvironment that affects the differentiation and function of osteoblasts. In addition, perturbation in metabolic pathways of HDL favors adipoblastic differentiation and restrains osteoblastic differentiation through, among others, the modification of specific bone-related chemokines and signaling cascades. Increased bone marrow adiposity also deteriorates bone osteoblastic function and thus bone synthesis, leading to reduced bone mass. In this review, we present the current knowledge and the future directions with regard to the HDL-bone mass connection. Unraveling the molecular phenomena that underline this connection will promote the deeper understanding of the pathophysiology of bone-related pathologies, such as osteoporosis or bone metastasis, and pave the way toward the development of novel and more effective therapies against these conditions.

ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion

Despite the recognized role of the ATP-binding Cassette Transporter A1 (ABCA1) in high-density lipoprotein (HDL) metabolism, our understanding of ABCA1 deficiency in human hepatocytes is limited. To define the functional effects of human hepatocyte ABCA1 deficiency, we generated induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) from Tangier disease (TD) and matched control subjects. Control HLCs exhibited robust cholesterol efflux to apolipoprotein A-I (apoA-I) and formed nascent HDL particles. ABCA1-deficient HLCs failed to mediate lipid efflux or nascent HDL formation, but had elevated triglyceride (TG) secretion. Global transcriptome analysis revealed significantly increased ANGPTL3 expression in ABCA1-deficient HLCs. Angiopoietin-related protein 3 (ANGPTL3) was enriched in plasma of TD relative to control subjects. These results highlight the required role of ABCA1 in cholesterol efflux and nascent HDL formation by hepatocytes. Furthermore, our results suggest that hepatic ABCA1 deficiency results in increased hepatic TG and ANGPTL3 secretion, potentially underlying the elevated plasma TG levels in TD patients.