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 cardiac surgery with cardiopulmonary bypass. Methods: A post-hoc analysis was conducted on plasma samples obtained from patients recruited in a randomized controlled trial.Total cholesterol, high density lipoprotein cholesterol (HDLc), low density lipoprotein cholesterol (LDLc), triglyceride and PLTP activity were measured before surgery. LPS concentration was measured by mass spectrometry before surgery, at the end of cardiopulmonary bypass and 24 h after admission to the intensive care unit. Results: High PLTP activity was associated with lower LPS concentration but not with inflammation nor post-operative complications. HDLc, LDLc and total cholesterol were not associated with LPS concentration but were lower in patients developing post-operative adverse events. HDLc was negatively associated with inflammation biomarkers (CRP, PCT). Triglyceride concentrations were positively correlated with LPS concentration, PCT and were higher in patients with post-operative complications. Conclusion: Our study supports the role of PLTP in LPS elimination and the relevance of RLT in human. PLTP activity, and not cholesterol rich lipoproteins pool size seemed to be the limiting factor for RLT. PLTP activity was not directly related to post-operative inflammation and adverse events, suggesting that LPS clearance is not the main driver of inflammation in our patients. However, HDLc was associated with lower inflammation and was associated with favorable outcomes, suggesting that HDL beneficial anti-inflammatory effects could be, at least in part independent of LPS clearance.

Glucagon-like peptide-1 is associated with poor clinical outcome, lipopolysaccharide translocation and inflammation in patients undergoing cardiac surgery with cardiopulmonary bypass.

INTRODUCTION: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with gut barrier dysfunction. Gut barrier dysfunction might be estimated non-invasively by lipopolysaccharide (LPS) plasma concentration. Glucagon-like peptide-1 (GLP-1) is a gut secreted hormone that is a potential marker of mucosal integrity. Our objective was to evaluate GLP-1 as a peri-operative marker of gut barrier dysfunction in patients undergoing cardiac surgery with CPB. METHODS: GLP-1, intestinal fatty acid binding protein (I-FABP) and lipopolysaccharide were assayed: at induction, after CPB and 24 h after admission in the intensive care unit. The primary end-point was peri-operative lipopolysaccharide concentration (LPS concentration at those 3 time points). RESULTS: Seventy-two patients were included in the present analysis. The highest measured post-operative GLP-1 concentration was in the sample taken 24 h after admission to intensive care, which was associated with peri-operative lipopolysaccharide plasma concentration. Patients who had the highest GLP-1 concentrations at 24 h experienced more severe inflammation and worse clinical outcomes. CONCLUSION: Our study supports that GLP-1 is not only a hormone of glucose metabolism but is also secreted when gut barrier is impaired in cardiac surgery with CPB. The GLP-1 levels measured 24 h after admission to the intensive care unit were associated with LPS concentration, inflammation and clinical outcomes.

Enteroendocrine L Cells Sense LPS after Gut Barrier Injury to Enhance GLP-1 Secretion.

Glucagon-like peptide 1 (GLP-1) is a hormone released from enteroendocrine L cells. Although first described as a glucoregulatory incretin hormone, GLP-1 also suppresses inflammation and promotes mucosal integrity. Here, we demonstrate that plasma GLP-1 levels are rapidly increased by lipopolysaccharide (LPS) administration in mice via a Toll-like receptor 4 (TLR4)-dependent mechanism. Experimental manipulation of gut barrier integrity after dextran sodium sulfate treatment, or via ischemia/reperfusion experiments in mice, triggered a rapid rise in circulating GLP-1. This phenomenon was detected prior to measurable changes in inflammatory status and plasma cytokine and LPS levels. In human subjects, LPS administration also induced GLP-1 secretion. Furthermore, GLP-1 levels were rapidly increased following the induction of ischemia in the human intestine. These findings expand traditional concepts of enteroendocrine L cell biology to encompass the sensing of inflammatory stimuli and compromised mucosal integrity, linking glucagon-like peptide secretion to gut inflammation.

Immune cell Toll-like receptor 4 mediates the development of obesity- and endotoxemia-associated adipose tissue fibrosis.

Adipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFß1. Together, these results indicate that obesity and endotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resistance, through immune cell Toll-like receptor 4.

Constitutive androstane receptor activation decreases plasma apolipoprotein B-containing lipoproteins and atherosclerosis in low-density lipoprotein receptor-deficient mice.

OBJECTIVE: The goal of this study was to determine the impact of the nuclear receptor constitutive androstane receptor (CAR) on lipoprotein metabolism and atherosclerosis in hyperlipidemic mice. METHODS AND RESULTS: Low-density lipoprotein receptor-deficient (Ldlr(-/-)) and apolipoprotein E-deficient (ApoE(-/-)) mice fed a Western-type diet were treated weekly with the Car agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or the vehicle only for 8 weeks. In Ldlr(-/-) mice, treatment with TCPOBOP induced a decrease in plasma triglyceride and intermediate-density lipoprotein/low-density lipoprotein cholesterol levels (≈30% decrease in both cases after 2 months, P<0.01). These mice also showed a significant reduction in the production of very-low-density lipoproteins associated with a decrease in hepatic triglyceride content and the repression of several genes involved in lipogenesis. TCPOBOP treatment also induced a marked increase in the very-low-density lipoprotein receptor in the liver, which probably contributed to the decrease in intermediate-density lipoprotein/low-density lipoprotein levels. Atherosclerotic lesions in the aortic valves of TCPOBOP-treated Ldlr(-/-) mice were also reduced (-60%, P<0.001). In ApoE(-/-) mice, which lack the physiological apoE ligand for the very-low-density lipoprotein receptor, the effect of TCPOBOP on plasma cholesterol levels and the development of atherosclerotic lesions was markedly attenuated. CONCLUSIONS: CAR is a potential target in the prevention and treatment of hypercholesterolemia and atherosclerosis.

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 macrophages, LXR-mediated CETP gene upregulation was inhibited, even though ABCA1, ABCG1, and SREBP1c inductions were maintained. The inhibition of CETP gene response to LXR agonists in inflammatory cells was independent of lipid loading (ie, oxidized LDL increased CETP production in noninflammatory macrophages with a synergistic effect of synthetic LXR agonists). CONCLUSIONS: LXR-mediated induction of human CETP expression is switched on during monocyte-to-macrophage differentiation, is magnified by lipid loading, and is selectively lost in inflammatory macrophages, which suggests that inflammatory cells may not increase the circulating CETP pool on LXR agonist treatment.

Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent.

Statins are drugs widely used in humans to treat hypercholesterolemia. Statins act by inhibiting cholesterol synthesis resulting in the activation of the transcription factor sterol-responsive element-binding protein-2 that controls the expression of genes involved in cholesterol homeostasis. Statin therapy also decreases plasma triglyceride and non-esterified fatty acid levels, but the mechanism behind this effect remains more elusive. Liver fatty acid-binding protein (L-FABP) plays a role in the influx of long-chain fatty acids into hepatocytes. Here we show that L-FABP is a target for statins. In rat hepatocytes, simvastatin treatment induced L-FABP mRNA levels in a dose-dependent manner. Moreover, L-FABP promoter activity was induced by statin treatment. Progressive 5'-deletion analysis revealed that the peroxisome proliferator-activated receptor (PPAR)-responsive element located at position -67/-55 was responsible for the statin-mediated transactivation of the rat L-FABP promoter. Moreover, treatment with simvastatin and the PPARalpha agonist Wy14,649 resulted in a synergistic induction of L-FABP expression (mRNA and protein) in rat Fao hepatoma cells. This effect was also observed in vivo in wild-type mice but not in PPARalpha-null animals demonstrating the direct implication of PPARalpha in L-FABP regulation by statin treatment. Statin treatment resulted in a rise in PPARalpha mRNA levels both in vitro and in vivo and activated the mouse PPARalpha promoter in a reporter assay. Altogether, these data demonstrate that L-FABP expression is up-regulated by statins through a mechanism involving PPARalpha. Moreover, PPARalpha might be a statin target gene. These effects might contribute to the triglyceride/non-esterified fatty acid-lowering properties of statins.