Liver X Receptor Regulates Arachidonic Acid Distribution and Eicosanoid Release in Human Macrophages
Objective— Liver X receptors (LXRs) are oxysterol-activated nuclear receptors that are highly expressed in macrophages and regulate lipid homeostasis and inflammation. Among putative LXR target genes, lysophosphatidylcholine acyltransferase 3 (LPCAT3) involved in the Lands cycle controls the fatty acid composition at the sn-2 position of glycerophospholipids and, therefore, the availability of fatty acids, such as arachidonic acid (AA), used for eicosanoid synthesis. The aim of our study was to determine whether LXRs could regulate the Lands cycle in human macrophages, to assess the consequences in terms of lipid composition and inflammatory response, and to work out the relative contribut…
High Plasma Concentration of Non-Esterified Polyunsaturated Fatty Acids Is a Specific Feature of Severe COVID-19 Pneumonia
Background: The pathogenesis of severe COVID-19 is frequently associated with an uncontrolled inflammatory response. Severe forms of COVID-19 appear to be more frequent in obese patients, but an association with metabolic disorders is not established. Here, we focused on lipoprotein metabolism in patients hospitalized for severe pneumonia, depending on COVID-19 status. Methods: Thirty-four non-COVID-19 and 27 COVID-19 patients with severe pneumonia were enrolled. Most of them required intensive care. Plasma lipid levels, lipoprotein metabolism, and clinical and biological features were assessed. Findings: Despite similar initial metabolic comorbidities and respiratory severity, COVID-19 pat…
Liver X Receptor–Mediated Induction of Cholesteryl Ester Transfer Protein Expression Is Selectively Impaired in Inflammatory Macrophages
Objective— Cholesteryl ester transfer protein (CETP) is a target gene for the liver X receptor (LXR). The aim of this study was to further explore this regulation in the monocyte-macrophage lineage and its modulation by lipid loading and inflammation, which are key steps in the process of atherogenesis. Methods and Results— Exposure of bone marrow–derived macrophages from human CETP transgenic mice to the T0901317 LXR agonist increased CETP, PLTP, and ABCA1 mRNA levels. T0901317 also markedly increased CETP mRNA levels and CETP production in human differentiated macrophages, whereas it had no effect on CETP expression in human peripheral blood monocytes. In inflammatory mouse and human mac…
Reduced VLDL clearance in ApoeNpc1 mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels
Niemann-Pick type C1 (NPC1) promotes the transport of LDL receptor (LDL-R)-derived cholesterol from late endosomes/lysosomes to other cellular compartments. NPC1-deficient cells showed impaired regulation of liver_X receptor (LXR) and sterol regulatory element-binding protein (SREBP) target genes. We observed that Apoe(-/-)Npc1(-/-) mice displayed a marked increase in total plasma cholesterol mainly due to increased VLDL, reflecting decreased clearance. Although nuclear SREBP-2 and Ldlr mRNA levels were increased in Apoe(-/-)Npc1(-/-) liver, LDL-R protein levels were decreased in association with marked induction of proprotein convertase subtilisin/kexin type 9 (Pcsk9) and inducible degrade…
Low preoperative cholesterol level is a risk factor of sepsis and poor clinical outcome in patients undergoing cardiac surgery with cardiopulmonary bypass.
Systemic inflammatory response syndrome and sepsis frequently occur after cardiac surgery with cardiopulmonary bypass. The aim of the present study was to investigate whether preoperative cholesterol levels can predict sepsis onset and postoperative complications in patients undergoing cardiac surgery with cardiopulmonary bypass.Prospective observational study.Surgical ICU of a French university hospital.Two hundred and seventeen consecutive patients older than 18 years admitted for planned cardiac surgery with cardiopulmonary bypass.Measurements of plasma blood lipids and inflammation markers before anesthesia induction (baseline), at cardiopulmonary bypass start, at cardiopulmonary bypass…
PNPLA3 polymorphism influences liver fibrosis in unselected patients with type 2 diabetes
Context: Recently, it has been shown that an allele in the adiponutrin (PNPLA3) gene was strongly associated with increased liver fat content (LFC) and liver fibrosis independent of visceral adiposity and insulin resistance. Objective: In this study, we set out to determine whether the PNPLA3 rs738409 polymorphism was associated with liver fibrosis in unselected patients with type 2 diabetes. Design, setting and participants: Two hundred and thirty-four patients with type 2 diabetes were included in this study. Main outcome measures: LFC was evaluated using 1H-MR spectroscopy; fibrosis was measured using the non-invasive FibroTest®. Results: Advanced liver fibrosis (stage F2 or above) was o…
Apolipoprotein CI is a physiological regulator of cholesteryl ester transfer protein activity in human plasma but not in rabbit plasma
Plasma cholesteryl ester transfer protein (CETP) activity is high in rabbits, intermediate in humans, and nondetectable in rodents. Human apolipoprotein CI (apoCI) was found to be a potent inhibitor of CETP. The aim of this study was to compare the ability of rabbit and human apoCI to modulate the interaction of CETP with HDLs and to evaluate to which extent apoCI contributes to plasma cholesteryl ester transfer rate in normolipidemic humans and rabbits. Rabbit apoCI gene was cloned and sequenced, rabbit and human apoCI were purified to homogeneity, and their ability to modify the surface charge properties and the CETP inhibitory potential of HDL were compared. It is demonstrated that unlik…
Stat3 and Gfi-1 Transcription Factors Control Th17 Cell Immunosuppressive Activity via the Regulation of Ectonucleotidase Expression
International audience; Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the cytokines IL-6 and TGF-β expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4(+) and CD8(+) T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-β-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to thei…
The role of plasma lipid transfer proteins in lipoprotein metabolism and atherogenesis.
The plasma lipid transfer proteins promote the exchange of neutral lipids and phospholipids between the plasma lipoproteins. Cholesteryl ester transfer protein (CETP) facilitates the removal of cholesteryl esters from HDL and thus reduces HDL levels, while phospholipid transfer protein (PLTP) promotes the transfer of phospholipids from triglyceride-rich lipoproteins into HDL and increases HDL levels. Studies in transgenic mouse models and in humans with rare genetic deficiencies (CETP) or common genetic variants (CETP and PLTP) highlight the central role of these molecules in regulating HDL levels. Human CETP deficiency is associated with dramatic elevations of HDL cholesterol and apolipopr…
Muricholic Acids Promote Resistance to Hypercholesterolemia in Cholesterol-Fed Mice
International audience; Background and aims: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular diseases. Although resistant to hypercholesterolemia, the mouse is a prominent model in cardiovascular research. To assess the contribution of bile acids to this protective phenotype, we explored the impact of a 2-week-long dietary cholesterol overload on cholesterol and bile acid metabolism in mice. Methods: Bile acid, oxysterol, and cholesterol metabolism and transport were assessed by quantitative real-time PCR, western blotting, GC-MS/MS, or enzymatic assays in the liver, the gut, the kidney, as well as in the feces, the blood, and the urine. Results: Plasma tr…
Identification of biological markers of liver X receptor (LXR) activation at the cell surface of human monocytes.
Background Liver X receptor (LXR) α and LXR β (NR1H3 and NR1H2) are oxysterol-activated nuclear receptors involved in the control of major metabolic pathways such as cholesterol homeostasis, lipogenesis, inflammation and innate immunity. Synthetic LXR agonists are currently under development and could find applications in various fields such as cardiovascular diseases, cancer, diabetes and neurodegenerative diseases. The clinical development of LXR agonists requires the identification of biological markers for pharmacodynamic studies. In this context, monocytes represent an attractive target to monitor LXR activation. They are easily accessible cells present in peripheral blood; they expres…
α-Tocopherol Modulates Phosphatidylserine Externalization in Erythrocytes
Objective— The aim of the present study was to assess the effect of α-tocopherol, the main vitamin E isomer on phosphatidylserine (PS) exposure at the surface of circulating erythrocytes, and to determine consequences on erythrocyte properties. Methods and Results— In vitro α-tocopherol enrichment of isolated erythrocytes significantly decreased PS externalization as assessed by lower Annexin V-fluorescein isothiocyanate labeling. Plasma phospholipid transfer protein (PLTP) transfers vitamin E, and both α-and γ-tocopherol accumulated in circulating erythrocytes from PLTP-deficient homozygous (PLTP −/− ) mice as compared with wild-type mice. In agreement with in vitro studies, vitamin E–enr…
Liver X receptor activation promotes polyunsaturated fatty acid synthesis in macrophages : relevance in the context of atherosclerosis
Objective— Liver X receptors (LXRs) modulate cholesterol and fatty acid homeostasis as well as inflammation. This study aims to decipher the role of LXRs in the regulation of polyunsaturated fatty acid (PUFA) synthesis in macrophages in the context of atherosclerosis. Approach and Results— Transcriptomic analysis in human monocytes and macrophages was used to identify putative LXR target genes among enzymes involved in PUFA biosynthesis. In parallel, the consequences of LXR activation or LXR invalidation on PUFA synthesis and distribution were determined. Finally, we investigated the impact of LXR activation on PUFA metabolism in vivo in apolipoprotein E–deficient mice. mRNA levels of acyl…
Intravoxel incoherent motion diffusion-weighted imaging in nonalcoholic fatty liver disease: a 3.0-T MR study.
International audience; PURPOSE: To compare pure molecular diffusion, D, perfusion-related diffusion, D*, and perfusion fraction, f, determined from diffusion-weighted (DW) magnetic resonance (MR) imaging on the basis of the intravoxel incoherent motion (IVIM) theory in patients with type 2 diabetes with and without liver steatosis. MATERIALS AND METHODS: This prospective study was approved by the appropriate ethics committee, and written informed consent was obtained from all patients. Between December 2009 and September 2011, 108 patients with type 2 diabetes (51 men, 57 women; mean age, 50 years) underwent 3.0-T single-voxel point-resolved proton MR spectroscopy of the liver (segment VII…
Increased Phospholipid Transfer Protein Activity Is Associated With Markers of Enhanced Lipopolysaccharide Clearance in Human During Cardiopulmonary Bypass
Introduction: Lipopolysaccharide (LPS) is a component of gram-negative bacteria, known for its ability to trigger inflammation. The main pathway of LPS clearance is the reverse lipopolysaccharide transport (RLT), with phospholipid transfer protein (PLTP) and lipoproteins playing central roles in this process in experimental animal models. To date, the relevance of this pathway has never been studied in humans. Cardiac surgery with cardiopulmonary bypass is known to favor LPS digestive translocation. Our objective was to determine whether pre-operative PLTP activity and triglyceride or cholesterol-rich lipoprotein concentrations were associated to LPS concentrations in patients undergoing ca…
Knock-down of the oxysterol receptor LXRα impairs cholesterol efflux in human primary macrophages: lack of compensation by LXRβ activation.
Liver X Receptors (LXRs) α and β are oxysterol-activated nuclear receptors involved in the control of lipid metabolism and inflammation. Pharmacological activation of LXR is promising in the treatment of atherosclerosis since it can promote cholesterol efflux from macrophages and prevent foam cell formation. However, the development of LXR agonists has been limited by undesirable side-effects such as hepatic steatosis mediated by LXRα activation. Therefore, it has been proposed that targeting LXRα activators to extrahepatic tissues or using LXRβ-specific activators could be used as alternative strategies. It is not clear whether these molecules will retain the full atheroprotective potentia…
Activation of liver x receptors promotes polyunsaturated fatty acid synthesis and eicosanoid secretion in human macrophages
Induction of Transglutaminase 2 by a Liver X Receptor/Retinoic Acid Receptor α Pathway Increases the Clearance of Apoptotic Cells by Human Macrophages
Rationale: Liver X receptors (LXRs) are oxysterol-activated nuclear receptors that are involved in the control of cholesterol homeostasis and inflammatory response. Human monocytes and macrophages express high levels of these receptors and are appropriate cells to study the response to LXR agonists. Objective: The purpose of this study was to identify new LXR targets in human primary monocytes and macrophages and the consequences of their activation. Methods and Results: We show that LXR agonists significantly increase the mRNA and protein levels of the retinoic acid receptor (RAR)α in primary monocytes and macrophages. LXR agonists promote RARα gene transcription through binding to a spec…
Impact pronostique de la concentration de 3-hydroxymyristate sur la survie des patients atteints de cirrhose alcoolique ou virale
Etat de la question Le role de l’endotoxemie liee a la translocation bacterienne sur l’aggravation de la cirrhose fait l’objet de nombreuses etudes, mais son impact sur la mortalite au cours de la cirrhose est mal connu. Le but de ce travail etait d’etudier l’impact de la concentration sanguine de 3-hydroxymyristate (3-HM) total (composant specifique des lipopolysaccharides, endotoxine), sur le risque de deces et de complications des malades cirrhotiques. Materiel et methodes Au total, 593 patients atteints de cirrhose alcoolique ou virale, sans carcinome hepatocellulaire ont ete inclus entre 2008 et 2012 dans six centres hospitalo-universitaires francais. Le dosage de 3-HM total, libre et …
Constitutive androstane receptor activation stimulates faecal bile acid excretion and reverse cholesterol transport in mice.
The constitutive androstane receptor (CAR) is a nuclear receptor expressed in the liver and involved in xenobiotic metabolism. The aim of this study was to assess whether pharmacological CAR activation could affect neutral sterol and bile acid elimination under conditions of cholesterol overload.Wild type, Car-/-, ApoE-/-, and low-density lipoprotein receptor (Ldlr)-/- mice fed a western-type diet were treated with the CAR agonist TCPOBOP.CAR activation was associated with a decrease in faecal cholesterol output related to the repression of the Abcg5/g8 cholesterol transporters. In contrast, TCPOBOP treatment induced a marked increase (up to three fold, p0.01) in the elimination of faecal b…
Liver methylene fraction by dual- and triple-echo gradient-echo imaging at 3.0T: Correlation with proton MR spectroscopy and estimation of robustness after SPIO administration
Purpose To assess the systematic errors in liver methylene fraction (LMF) resulting from fat–fat interference effects with dual- and triple-echo gradient-recalled-echo Dual/Triple GRE) sequences and to test the robustness of these sequences after iron overloading. Materials and Methods Forty type-2 diabetic patients underwent LMF measurement by 3.0T 1H magnetic resonance spectroscopy (corrected for T1 and T2 decays) as the reference standard and liver fat fraction (%Fat) measurement by four Dual/Triple GRE sequences with 20° and 60° flip angle (α), corrected for T1 recovery. The same four sequences were repeated in eight patients after ferumoxide injection. Corrections for systematic errors…
LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis
International audience; Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN …
Biological activities of the LXRα and β agonist, 4β-hydroxycholesterol, and of its isomer, 4α-hydroxycholesterol, on oligodendrocytes: effects on cell growth and viability, oxidative and inflammatory status.
The biochemical and biological properties of 4β-hydroxycholesterol and of its isomer, 4α-hydroxycholesterol, are not well known. So, we determined the ability of 4α- and 4β-hydroxycholesterol to react with LXRα and LXRβ, and we characterized the activities of these oxysterols on oligodendrocytes which are myelin synthesizing cells. The effects of 4α- and 4β-hydroxycholesterol were studied on 158N murine oligodendrocytes to assess their activities on cell growth and viability, oxidative and inflammatory status. To this end different parameters were used: cell counting with trypan blue; identification of dead cells and cell cycle analysis with propidium iodide; evaluation of mitochondrial dep…
Specific enrichment of 2-arachidonoyl-lysophosphatidylcholine in carotid atheroma plaque from type 2 diabetic patients
IF 3.942; International audience; Background and aims: Diabetic patients are at high risk of stroke and coronary artery disease. Recent data suggest that arachidonic acid metabolism is altered in diabetic conditions and that these alterations contribute to accelerated atherosclerosis. Little is known about how these alterations affect the metabolism and the proportions of different lipid species within the atherosclerotic plaque. The aim of our study was to perform a targeted lipidomic analysis of human atherosclerotic lesions, with a specific focus on PUFA-containing lipid species, to reveal differences in the fatty-acid composition of plaque in diabetic patients compared with non-diabetic…
Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation
IF 4.258; International audience; Diabetes is characterized by increased lipogenesis as well as increased endoplasmic reticulum (ER) stress and inflammation. The nuclear hormone receptor liver X receptor (LXR) is induced by insulin and is a key regulator of lipid metabolism. It promotes lipogenesis and cholesterol efflux, but suppresses endoplasmic reticulum stress and inflammation. The goal of these studies was to dissect the effects of insulin on LXR action. We used antisense oligonucleotides to knock down Lxr alpha in mice with hepatocytespecific deletion of the insulin receptor and their controls. We found, surprisingly, that knock-out of the insulin receptor and knockdown of Lxr alpha …
Lipid Activates mTORC1 and mTORC2 in the Absorption of Dietary Triglycerides
Mechanistic target of rapamycin (mTOR) senses amino acids; however, its role in lipid metabolism is less established. Organismal lipid requirements are largely met through dietary intake. How nutrient sensing mechanisms in gut interface with dietary fat remains unclear. Here we reveal fundamental and cooperative roles for mTOR complexes 1 and 2 (mTORC1/2) in absorption of dietary triglycerides. Dietary lipid activates mTORC1/2 signaling in gut. Hyperactivating mTORC1 by deleting Tsc1 is sufficient to promote triglyceride absorption and metabolic disease in high fat-fed mice. Conversely, blocking mTORC1/2 by deleting Raptor or Rictor each decreases triglyceride absorption. Loss of Raptor seq…
Biological activities of Schottenol and Spinasterol, two natural phytosterols present in argan oil and in cactus pear seed oil, on murine miroglial BV2 cells
International audience; The objective of this study was to evaluate the biological activities of the major phytosterols present in argan oil (AO) and in cactus seed oil (CSO) in BV2 microglial cells. Accordingly, we first determined the sterol composition of AO and CSO, showing the presence of Schottenol and Spinasterol as major sterols in AO. While in CSO, in addition to these two sterols, we found mainly another sterol, the Sitosterol. The chemical synthesis of Schottenol and Spinasterol was performed. Our results showed that these two phytosterols, as well as sterol extracts from AO or CSO, are not toxic to microglial BV2 cells. However, treatments by these phytosterols impact the mitoch…
Are Adiponectin and Leptin Good Predictors of Surgical Infection after Colorectal Surgery? A Prospective Study
Infections are the most frequent complication after colorectal surgery. It has been suggested that adipose tissue metabolism could be related to the risk of post-operative infection, but this could be partially related to the body-mass index. The aim of this study was to look for a relation between adipocytokine levels and the risk of post-operative infection and its type.This prospective cohort study was conducted between March 2013 and March 2014 in two French teaching hospitals. Pre-operative plasma levels of adiponectin and leptin were measured in consecutive patients undergoing elective colorectal surgery. All infections in the 30 d following surgery were recorded.Among the 142 patient…
High Serum Cholesteryl Ester Transfer Rates and Small High-Density Lipoproteins Are Associated With Young Age in Patients With Acute Myocardial Infarction
Objectives Our aim was to characterize cholesteryl ester transfer protein (CETP) activity in the early phase of acute myocardial infarction (MI). Background Cholesteryl ester transfer protein catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) donors to apolipoprotein B-containing lipoprotein acceptors. Methods The CETP concentration, lipid profiles, and the rate of cholesteryl ester transfer (CET) from a tracer dose of radiolabeled HDL toward endogenous lipoproteins were determined within 24 h after symptom onset. Results Among 347 patients with first MI, CETP concentration, triglycerides, and non–HDL-cholesterol increased across tertiles of the CET rate, where…
164P Effect of ELOVL5 expression on breast cancer development
Development of Abdominal Aortic Aneurysm Is Decreased in Mice with Plasma Phospholipid Transfer Protein Deficiency
International audience; Plasma phospholipid transfer protein (PLTP) increases the circulating levels of proatherogenic lipoproteins, accelerates blood coagulation, and modulates inflammation. The role of PLTP in the development of abdominal aortic aneurysm (AAA) was investigated by using either a combination of mechanical and elastase injury at one site of mouse aorta (elastase model) or continuous infusion of angiotensin II in hyperlipidemic ApoE-knockout mice (Ang II model). With the elastase model, complete PLTP deficiency was associated with a significantly lower incidence and a lesser degree of AAA expansion. With the Ang II model, findings were consistent with those in the elastase mo…