HDL Production Research Articles

Obesity and adiposity promote the development of non-suppurative otitis media: a Mendelian randomization study.

Observational studies have found that obesity is associated with the development of non-suppurative otitis media (NSOM), but the causality and pathogenesis are unclear. This study aimed to investigate the association between obesity, lipid metabolism, and NSOM at the genetic level. We performed a bidirectional two-sample Mendelian randomization (MR) study to examine the causal relationship between obesity, lipid metabolism-related factors, and NSOM by using the datasets obtained from the IEU Open genome-wide association studies (GWAS) Project. Furthermore, a multivariate MR (MVMR) analysis on lipid indicators was conducted to validate the results. We then used obesity or body mass index (BMI) as the exposure and NSOM as the outcome to search for possible mediators in lipids and adipokines. Using NSOM as the outcome, we found nine positive exposure results related to obesity and lipid metabolism. Among them, obesity, BMI, body fat percentage, waist circumference, hip circumference, and resistin were risk factors, while apolipoprotein A1 (apoA1), high-density lipoprotein cholesterol (HDL-C), and nerve growth factor (NGF) were protective factors. Then, we used the obesity and lipid metabolism-related factors as outcomes and NSOM as the exposure to perform the MR analysis, which failed to obtain positive results. In the MVMR analysis, we found that HDL cholesterol and apoA1 remained causally associated with NSOM after correction for other potential confounders. Simultaneously, when obesity or BMI was used as the exposure and NSOM as the outcome, HDL cholesterol or apoA1 served as mediators through a two-step MR analysis. The MR analysis for mediation, obesity, and BMI reduced the production of HDL or apoA1, which served as protective factors affecting the development of NSOM. At the genetic level, obesity and adiposity may promote the development of NSOM, while NSOM has no effect on obesity and adiposity. Obesity can also encourage the progress of NSOM by reducing HDL cholesterol/apoA1. Resistin may be a potential risk factor for NSOM, whereas NGF may be a potential protective factor.

Is microRNA-33 an Appropriate Target in the Treatment of Atherosclerosis?

The maintenance of cholesterol homeostasis is a complicated process involving regulation of cholesterol synthesis, dietary uptake and bile acid synthesis and excretion. Reverse cholesterol transport, described as the transfer of cholesterol from non-hepatic cells, including foam cells in atherosclerotic plaques, to the liver and then its excretion in the feces is important part of this regulation. High-density lipoproteins are the key mediators of reverse cholesterol transport. On the other hand, microRNA-33 was identified as a key regulator of cholesterol homeostasis. Recent studies indicate the impact of microRNA-33 not only on cellular cholesterol efflux and HDL production but also on bile metabolism in the liver. As proper coordination of cholesterol metabolism is essential to human health, discussion of recent findings in this field may open new perspectives in the microRNA-dependent treatment of a cholesterol imbalance.

MiRNA-target genes interactome associated with heat and immune homeostasis in evolutionarily-adapted cattle

Abstract Heat stress (HS) response is a direct consequence of thermal imbalance, connected to a cascade of protein activation and altered gene expression. Micro-RNAs (miRNAs) are notable for modulating gene expression, during immune and cellular response to confounding stressors. To date, the mechanism by which miRNAs regulate HS response in cattle is unknown. We hypothesize that miRNAs involved in this process are distinctly regulated between evolutionarily-adapted animals, and are important diagnostic or drug targets. We analyzed miRNA-target gene interactome in RNA-seq data from temperate and tropical cattle. A total of 3,692 genes were generated, including miRNAs that are differentially regulated. The top 10 upregulated genes, including C-C motif chemokine associated with leukocyte differentiation, APOA2 and APOH involved in HDL production, CYP1A2 and CYP2E1 involve in oxidation by cytochrome P450 were significantly upregulated in tropical animals. Conversely, GLPIR, GHSR and LOC539009, essential for homeostasis, regulation of glucose metabolism, and signaling cascades for insulin secretion were downregulated in temperate animals. Forty-one and eleven miRNAs were down- and upregulated in temperate cattle respectively. Notably, miRNA-2333 and miRNA-544b targeting GLPIR, miRNA-1248 and miRNA-6516 targeting GHSR and miRNA-2424 targeting LOC539009 were all upregulated. The downregulation of target genes in our interactome is linked to upregulation of miRNAs in temperate animals, possibly for energy conservation. This molecular interaction is significant for thermoregulation and a balanced immune response, necessities for environmental or pathogenic perturbations associated with adaptation and climate change. Supported by None

Pre-beta-1-high density lipoprotein (HDL) re-evaluation

Background and Aims: Human serum preβ1-HDL has been defined by 2-dementional gel and apoA-I immuno-blotting (2-D). Preβ1-HDL should have anti-atherosclerosis property, since it plays roles in HDL production and reverse cholesterol transport. However, there are still debatable questions for its quantification by 2-D and its clinical relevance, because reports indicated that 2-D determined preβ1-HDL is a risk factor for cardiovascular diseases (CVD). Thus, preβ1-HDL needs to be re-evaluated precisely.

The Rise and Fall "ing" of the HDL Hypothesis.

Earlier epidemiological studies have shown an inverse correlation between high-density lipoprotein cholesterol (HDLc) and coronary heart disease (CHD). This observation along with the finding that reverse cholesterol transport is mediated by HDL, supported the hypothesis that the HDL molecule has a cardioprotective role. More recently, epidemiological data suggest a U-shaped curve correlating HDLc and CHD. In addition, randomized clinical trials of drugs that significantly increase plasma HDLc levels, such as nicotinic acid and cholesterol ester transfer protein (CETP) inhibitors failed to show a reduction in major adverse cardiovascular events. These observations challenge the hypothesis that HDL has a cardioprotective role. It is possible that HDL quality and function is optimal only when de novo synthesis of apo A-I occurs. Inhibition of turnover of HDL with currently available agents yields HDL molecules that are ineffective in reverse cholesterol transport. To test this hypothesis, newer therapeutic drugs that increase de novo production of HDL and apo A-I should be tested in clinical trials.

Amoxicillin Modulates ApoA-I Transcription and Secretion, Predominantly via PPARα Transactivation Inhibition.

In a recent human study, we observed that amoxicillin treatment decreased HDL-C concentration. We hypothesize that antibiotics lower the transcription and secretion of ApoA-I, the responsible protein for HDL production. HepG2 and Caco-2 cells were exposed to increasing dose of amoxicillin, penicillin, and streptomycin. Secreted ApoA-I protein and mRNA transcripts were analyzed using ELISA and qPCR, respectively. To unravel underlying mechanisms, KEAP1, CPT1, and CHOP mRNA expressions were determined as well as PPARα transactivation. In HepG2 and Caco-2, amoxicillin decreased ApoA-I transcription and secretion. Effects on ApoA-I expression were clearly there for amoxicillin while no effects were observed for penicillin or streptomycin. KEAP1, CPT1, and CHOP mRNA expressions were reduced by amoxicillin treatments. Moreover, a significant correlation between ApoA-I and CPT1 mRNA expressions was found. Furthermore, amoxicillin lowered PPARα transactivation. All together, these data suggest that inhibited PPARα transactivation is involved in the effects of amoxicillin on ApoA-I. In conclusion, the direct effect of amoxicillin in treated HepG2 and Caco-2 cells was a lower ApoA-I secretion and transcription. Based on evaluating alterations in KEAP1, CPT1, and CHOP mRNA expressions plus PPARα transactivation, we suggest that a reduced PPARα activation is a potential mechanism behind the observed amoxicillin effects on ApoA-I expression.

Hyperlipidemia Determines Dysfunctional HDL Production and Impedes Cholesterol Efflux in the Small Intestine: Alleviation by Ginger Extract.

To assess the impact of ginger extract (GIN) in stimulating the production of quality HDL and the cholesterol efflux in the small intestine (SI), key processes in the management of hyperlipidemia (HL)-induced hepatic steatosis, and atherosclerosis. Three groups of hamsters are used: (i) N, fed standard diet, (ii) HL, fed high-fat diet for 21 weeks, and (iii) HL-GIN, HL treated with GIN for the last 5 weeks of diet. Apolipoprotein A-I (apoA-I), malondialdehyde-apoA-I (MDA-apoA-I), paraoxonase1 (PON1), and myeloperoxidase (MPO) are measured in plasma and SI. ATP-binding cassette A1 transporter (ABCA1), ABCG5/G8, liver X receptor α/β (LXRα/β), peroxisome proliferator-activated receptor γ (PPARγ), and sirtuin1 (SIRT1) are assessed in the SI. Results show that in HL plasma, GIN decreases MDA-apoA-I, MPO/PON1 ratio and increases HDL-cholesterol/total cholesterol. In HL-SI, GIN decreases MDA-apoA-I and MPO, increases ApoA-I, PON1, and ABCA1, and restores cholesterol efflux disturbed by HL (SIRT1-LXRα/β-PPARγ-ABCG8). GIN administration is associated with the reduction of the aortic valves lipid-deposits. In HL conditions, GIN stimulates the functional HDL production by restoring apoA-I quality and quantity through inhibition of the oxidative stress, and increases cholesterol efflux in the SI. These effects are associated with the restoration of SIRT1-LXRα/β-PPARγ pathway.

Chylomicron retention disease: genetics, biochemistry, and clinical spectrum.

Chylomicron retention disease (CRD) is an autosomic recessive disorder, in which intestinal fat malabsorption is the main cause of diverse severe manifestations. The specific molecular defect was identified in 2003 and consists of mutations in the SAR1B or SARA2 gene encoding for intracellular SAR1B GTPase protein. The aim of this review is first to provide an update of the recent biochemical, genetic and clinical findings, and second to discuss novel mechanisms related to hallmark symptoms. CRD patients present with SAR1B mutations, which disable the formation of coat protein complex II and thus blocks the transport of chylomicron cargo from the endoplasmic reticulum to the Golgi. Consequently, there is a total absence of chylomicron and apolipoprotein B-48 in the blood circulation following a fat meal, accompanied by a deficiency in liposoluble vitamins and essential fatty acids. The recent discovery of Transport and Golgi organization and Transport and Golgi organization-like proteins may explain the intriguing export of large chylomicron, exceeding coat protein complex II size. Hypocholesterolemia could be accounted for by a decrease in HDL cholesterol, likely a reflection of limited production of intestinal HDL in view of reduced ATP-binding cassette family A protein 1 and apolipoprotein A-I protein. In experimental studies, the paralog SAR1A compensates for the lack of the SAR1B GTPase protein. Molecular testing for CRD is recommended to distinguish the disease from other congenital fat malabsorptions, and to early define molecular aberrations, accelerate treatment, and prevent complications.

Abstract 398: Gut Microbiota Facilitates Apolipoprotein A1 and HDL Production Through Hepatic TLR5

Gut microbiota is considered as an external organ as these trillions of commensal microbes in our gut interact with our body to regulate various physiological responses. The pattern and composition of gut bacteria is subject to alteration by our diet. High fat diet not only decreases the β-diversity of gut microbiota but also increases gut permeability, leading to the leak of bacterial products into circulation, which aggravates various diseases including atherosclerosis by escalating inflammation. Paradoxically high fat intake can augment HDL level (J Clin Invest 91:1665-71, 1993). Moreover, gut microbiota was shown to contribute the variation of HDL but not LDL or total cholesterol level in a human study. (Circ Res 117: 817-24, 2015) We speculate that gut microbiota may provide an adaptive protection by upregulating HDL level. In this study, we investigated the possible underlying mechanism of how gut microbiota affects HDL level. C57BL/6J mice were fed a normal chow diet and a high fat diet (HFD, 45% fat kcal) for 10 weeks. Other than decreasing the β-diversity of gut microbiota, HFD increased the portion of flagellated bacteria, resulting in the increase of hepatic but not circulating level of flagellin, the ligand of toll-like receptor (TLR5). Deletion of TLR5 in mice suppressed HFD-stimulated HDL level. Treatment with flagellin in hepatocytes was able to stimulate apolipoprotein A1 (apoA), the primary apolipoprotein on HDL in TLR5-dependent manner. Blocking the downstream signaling of TLR5 by silencing MYD88 blocked the flagellin-induced apoA1 production in wild type hepatocytes. Lipopolysaccharides, another important bacterial product which can activate MYD88 signaling, failed to elicit the same effect. It might be due to the different degree of sensitivity of these TLRs in hepatocytes. In addition, supplementation of flagellin to atherogenic mice (apoE knockout mice) by oral gavage was able to elevate apoA1 and HDL levels in circulation, partially protecting against atherosclerosis. Our data provides a molecular explanation of how commensal bacteria in gut stimulate HDL production upon HFD, and such finding will provide an insight in developing alternative strategy to stimulate HDL production and prevent atherosclerosis.

Implications of the Mediterranean diet and physical exercise on the lipid profile of metabolically healthy obese women as measured by nuclear magnetic resonance spectroscopy (1H NMR)

ObjectiveThere is a lack of consensus when it comes to establishing the biochemical parameters that define metabolically healthy obese (MHO) subjects. Indeed, most studies do not include subjects’ lipid profiles. Our objective was to characterize lipoprotein size, particle and subclass concentration using 1H NMR in MHO women after two years of weight loss with a hypocaloric Mediterranean diet and physical exercise. Methods115 non-diabetic women (aged 35–55 years) with a body mass index (BMI) of 30–40 kg/m2 and ≤1 of the following criteria: blood pressure ≥135/85 mmHg, fasting plasma glucose ≥100 mg/dL, HDL cholesterol ≤50 mg/dL and triglycerides ≥150 mg/dL were included. After two years of intensive lifestyle modification (Mediterranean diet and physical exercise), they were classified according to their weight loss: <5%, ≥5%-<10% and ≥10%. Lipoprotein size, particle and subclass concentrations were measured using 1H NMR. ResultsThe final population, after dropouts, were 67 women (age: 44.5 ± 3.7 years, BMI: 36.3 ± 4.7 kg/m2), of whom 23 (38.3%) lost <5%, and 22 (36.7%), lost ≥5% to <10% and ≥10% of baseline body weight, respectively. The lipid profile showed no significant changes after intervention, especially in small LDL particles or in production of HDL. The diameter of LDL and HDL particles did not change after two years of a Mediterranean diet and physical exercise. ConclusionThese results indicate that intensive lifestyle modification does not produce significant changes in the lipid profile of MHO women. Levels of more atherogenic or atheroprotective particles did not change after two years, despite the intervention.

(Invited) Plasma Membrane Cholesterol as a Diagnostic

Cholesterol is a tightly regulated major structural component of the cell plasma membrane (PM) where it forms stoichiometric complexes with phospholipids and sphingolipids. The amount of cholesterol in the PM exhibits a regulatory role in basal activity of several biomolecular processes by direct binding to proteins and by indirect local environmental effects within the PM that are also coupled to overall cellular cholesterol homeostasis. The term “active cholesterol” refers to PM cholesterol not complexed to lipids, a cholesterol state that arises above a threshold mole fraction of cholesterol in the PM. Active cholesterol level in the PM provides a control mechanism for cellular cholesterol homeostasis through its recognition by membrane bound proteins that activate genes of cholesterol synthesis enzymes. Uptake of LDL, production and release of HDL as well as reversible storage of cholesterol in the cytosol by covalent modification are also regulated and dependent on PM cholesterol (thermodynamic) activity: active cholesterol. A number of human disease states have been found to have associated alterations in PM cholesterol. Thus, an experimental aim of this research group has been the ability to monitor PM cholesterol thermodynamic activity at live cells and tissues without significant perturbation of the native physiological state. In particular, the active cholesterol pool is easily depleted leading to its physiological determination by traditional assays being out of reach. Our approach is to measure the rate of cholesterol diffusion from the PM at the point-of-contact of a microelectrode. The enzyme-modified electrode consumes the sparingly-soluble aqueous-cholesterol adjacent to the PM thus perturbing the equilibrium between aqueous- and PM-cholesterol resulting in diffusion of cholesterol from the PM only at the site of electrode contact. That is, the enzyme modified electrode creates a demand for cholesterol at the site of contact and measures the diffusional response. The rate of cholesterol diffusion (micro-extraction) is related to the thermodynamic activity of cholesterol (which is controlled by the active cholesterol concentration) in the PM by classic kinetic theory. The transition state is cholesterol that has exited the PM and has not yet formed a solvent cage. Through Collaboration with Minchul Shin at Georgia Southern University, ongoing work for human cholesterol sensing is using nano/micro manufacturing to produce sensor chips containing well-spaced regions of SiO2 that are circular with a 10-20 µm diameter for attachment of oxidase. This general approach to noninvasive human sensing could serve as a platform for screening children for hypercholesterolemia and for other markers such as glucose.

Cell Plasma Membrane Cholesterol as a Diagnostic.

Cholesterol is a tightly regulated major structural component of the cell plasma membrane (PM) where it forms stoichiometric complexes with phospholipids and sphingolipids. The amount of cholesterol in the PM exhibits a regulatory role in basal activity of several biomolecular processes by direct binding to proteins and by indirect local environmental effects within the PM that are also coupled to overall cellular cholesterol homeostasis. The term "active cholesterol" refers to PM cholesterol not complexed to lipids, a cholesterol state that arises above a threshold mole fraction of cholesterol in the PM. Active cholesterol level in the PM provides a control mechanism for cellular cholesterol homeostasis through its recognition by membrane bound proteins that activate genes of cholesterol synthesis enzymes. Uptake of LDL, production and release of HDL as well as reversible storage of cholesterol in the cytosol by covalent modification are also regulated and dependent on PM cholesterol (thermodynamic) activity: active cholesterol. A number of human disease states have been found to have associated alterations in PM cholesterol and thus a method for its determination is described.

Re-evaluation of cholesteryl ester transfer protein function in atherosclerosis based upon genetics and pharmacological manipulation.

To re-evaluate the functions of plasma cholesteryl ester transfer protein (CETP) in atherosclerosis based upon recent findings from human genetics and pharmacological CETP manipulation. CETP is involved in the transfer of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins, a key step of reverse cholesterol transport (RCT). CETP inhibitors have been developed to raise serum HDL-cholesterol (HDL-C) levels and reduce cardiovascular events. However, outcome studies of three CETP inhibitors (torcetrapib, dalcetrapib and evacetrapib) were prematurely terminated because of increased mortality or futility despite marked increases in HDL-cholesterol and decreases in LDL-cholesterol except for dalcetrapib. Patients with CETP deficiency show remarkable changes in HDL and LDL and are sometimes accompanied by atherosclerotic cardiovascular diseases. Recent prospective epidemiological studies demonstrated atheroprotective roles of CETP. CETP inhibition induces formation of small dense LDL and possibly dysfunctional HDL and downregulates hepatic scavenger receptor class B type I (SR-BI). Therefore, CETP inhibitors may interrupt LDL receptor and SR-BI-mediated cholesterol delivery back to the liver. For future drug development, the opposite strategy, namely enhancers of RCT via CETP and SR-BI activation as well as the inducers of apolipoprotein A-I or HDL production might be a better approach rather than delaying HDL metabolism by inhibiting a main stream of RCT in vivo.

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.

Lipoprotein (a) upregulates ABCA1 in liver cells via scavenger receptor-B1 through its oxidized phospholipids

Elevated levels of lipoprotein (a) [Lp(a)] are a well-established risk factor for developing CVD. While Lp(a) levels are thought to be independent of other plasma lipoproteins, some trials have reported a positive association between Lp(a) and HDL. Whether Lp(a) has a direct effect on HDL is not known. Here we investigated to determine whether Lp(a) had any effect on the ABCA1 pathway of HDL production in liver cells. Incubation of HepG2 cells with Lp(a) upregulated the PPARγ protein by 1.7-fold and the liver X receptor α protein by 3-fold. This was accompanied by a 1.8-fold increase in ABCA1 protein and a 1.5-fold increase in cholesterol efflux onto apoA1. We showed that Lp(a) was internalized by HepG2 cells, however, the ABCA1 response to Lp(a) was mediated by the selective uptake of oxidized phospholipids (oxPLs) from Lp(a) via the scavenger receptor-B1 and not by Lp(a) internalization per se. We conclude that there is a biological connection between Lp(a) and HDL through the ability of Lp(a)’s oxPLs to upregulate HDL biosynthesis.

Hepatic ABCA1 expression improves β-cell function and glucose tolerance.

Low HDL is a risk factor for the development of type 2 diabetes. Hepatic ABCA1 is the rate-limiting protein in HDL biogenesis, and mice lacking hepatic ABCA1 (ABCA1(-l/-l)) have very low plasma HDL concentrations. To investigate the role of hepatic ABCA1 in glucose tolerance and β-cell function, we used ABCA1(-l/-l) mice, which showed impaired glucose tolerance without changes in insulin sensitivity. Insulin secretion was reduced following glucose gavage. Ex vivo, glucose stimulated insulin secretion from β-cells from wild-type (WT) and ABCA1(-l/-l) mice was similar. Insulin secretion was, however, reduced upon addition of ABCA1(-l/-l) serum to the medium compared with WT serum, whereas islets lacking β-cell ABCA1 were not affected differently by ABCA1(-l/-l) or WT serum. After high-fat feeding, WT and ABCA1(-l/-l) mice showed no difference in glucose tolerance or insulin secretion, and serum from ABCA1(-l/-l) and WT mice fed a high-fat diet did not affect insulin secretion differently. We conclude that hepatic ABCA1 improves glucose tolerance by improving β-cell function through both HDL production and interaction with β-cell ABCA1. The beneficial effect of hepatic ABCA1 is decreased under metabolic stress. Increasing hepatic ABCA1 may represent a novel therapeutic strategy for improving glucose homeostasis in diabetes.

Athérosclérose au cours du lupus érythémateux systémique

Evidence from epidemiological studies demonstrates that patients with systemic lupus erythematosus (SLE) are at increased risk for the development of cardiovascular disease. Traditional cardiovascular risk factors' play an important role in this phenomenon but do not account for the entire risk in lupus patients. The incidence and prevalence of cardiovascular events and infraclinical atherosclerosis are reviewed. Combinations of traditional risk factors with lupus-specific and treatment-related variables are detailed. Atherosclerosis is more prevalent and occurs prematurely in lupus patients. Relative risk of myocardial infarction is between 5 to 8 times greater that of general population, and may exceed 50 in women between 35 and 44years old. SLE was also found as an independent risk factor for subclinical atherosclerosis, and more than one third of lupus patient show evidence of carotid plaques of coronary artery calcifications. Lupus patients have more frequent traditional risk factors compared with general population of similar age and sex. Besides the traditional risk factors, SLE specific risk factors have been identified among witch advanced age at diagnosis, current disease activity, duration of the disease and renal activity. Moreover, lipid abnormalities in patients with SLE are common and likely are one of the major causes of premature atherosclerosis in these patients; the dyslipoprotein associated increased triglycerides and depressed HDL-cholesterol with proinflammatory HDL production. Autoimmunity may have a part of responsibility, but data's in favour of this hypothesis are not strong. Other mechanisms such as vascular inflammation, oxidative stress, immune complexes and complement activation may also elicit endothelial damage and promote atherosclerosis are associated with the pathogenesis of both SLE and atherosclerosis. Steroids may have a true double-edged role with a pro-atherogenic risk regarding the exacerbation of metabolic risk factors and a "beneficial" anti-inflammatory role. It is becoming increasingly apparent that antimalarials treatment in SLE has an atheroprotective and a cardioprotective effect. The other immunosuppressive drugs may reduce progression of atherosclerosis and cardiovascular events but their precise role remains to be elucidated. Despite their role in primary prevention in target general population, for now, systematic prescription of statins does not show a great benefit in the cardiovascular risk in lupus patients. Mechanisms of atherosclerosis in SLE remain elusive. It is partially explained by the interaction of traditional cardiovascular risk factors, lupus-specific factors and therapy specially corticosteroids. Management strategies of lupus should include early all those items.

TTC39B deficiency promotes HDL production and impairs non-hdl absorption in small intestine

TTC39B deficiency promotes HDL production and impairs non-hdl absorption in small intestine

Selective evaluation of high density lipoprotein from mouse small intestine by an in situ perfusion technique

The small intestine (SI) is the second-greatest source of HDL in mice. However, the selective evaluation of SI-derived HDL (SI-HDL) has been difficult because even the origin of HDL obtained in vivo from the intestinal lymph duct of anesthetized rodents is doubtful. To shed light on this question, we have developed a novel in situ perfusion technique using surgically isolated mouse SI, with which the possible filtration of plasma HDL into the SI lymph duct can be prevented. With the developed method, we studied the characteristics of and mechanism for the production and regulation of SI-HDL. Nascent HDL particles were detected in SI lymph perfusates in WT mice, but not in ABCA1 KO mice. SI-HDL had a high protein content and was smaller than plasma HDL. SI-HDL was rich in TG and apo AIV compared with HDL in liver perfusates. SI-HDL was increased by high-fat diets and reduced in apo E KO mice. In conclusion, with our in situ perfusion model that enables the selective evaluation of SI-HDL, we demonstrated that ABCA1 plays an important role in intestinal HDL production, and SI-HDL is small, dense, rich in apo AIV, and regulated by nutritional and genetic factors.

THE ROLE OF CHOLINE DEPLETION IN PERFLUOROOCTANESULFONATE‐INDUCED HEPATIC STEATOSIS

Perfluorooctanesulfonate (PFOS) exposure has resulted in hepatic steatosis and hypolipidemia, believed to be the result of decreased production and secretion of VLDL and HDL and increased uptake of VLDL‐triglyceride. The hypothesis that PFOS produces hepatic steatosis via ionic sequestration of available choline necessary for the production of VLDL was examined. Plausibility was supported by identification of an ion‐triad between two molecules of choline and one molecule of PFOS in vitro. We fed male C57BL/6 mice either a control diet or a marginal methionine/choline‐deficient (mMCD) diet, both with and without PFOS. After a two‐week run‐in period on diets without PFOS, control or mMCD diets containing 0, 30, 60, or 120 mg K+PFOS/kg diet were fed for three weeks. There was a dose‐dependent increase in the relative liver weight in both control and mMCD fed mice. Dietary PFOS was also associated with dose‐dependent decreases in body weight, increases in hepatic triglyceride concentration, and increases in serum ALT, ALP, and bile acids, all with larger effects observed in mice fed mMCD compared to those fed the control diet. Serum and liver concentrations of PFOS were increased in a dose‐dependent manner on both diets; however, serum PFOS concentrations were higher and liver concentrations lower in mMCD‐fed mice compared to corresponding control‐fed mice. Metabolomic analysis demonstrated that PFOS caused a significant decrease in the hepatic concentration of many phosphatidylcholines in the PFOS‐fed mice compared to controls. Further, the average serum concentration of choline was reduced by dietary PFOS. These studies are the first to provide evidence that PFOS may cause hepatic steatosis through depletion of choline required for hepatic VLDL production and export.