Apolipoprotein AV: Gene expression, physiological role in lipid metabolism and clinical relevance

The apolipoprotein APOA5 gene, a member of the gene cluster on chromosome 11q23 that includes APOA1, APOC3 and APOA4, has gained considerable interest as it encodes ApoAV, a key determinant of circulating levels of potentially atherogenic triglyceride-rich lipoproteins (TRL). Indeed, strong associations between genetic variants of the APOA5 gene sequence and elevated triglyceride (TG) levels have been established. This apolipoprotein may potentiate lipolysis of TRL through facilitation of lipoprotein interaction with lipoprotein lipase. In addition, ApoAV may enhance clearance of remnant lipoproteins by mediating their interaction with the LDL receptor-related protein (LRP)1. The implication of ApoAV in intravascular TRL metabolism is further supported by studies that have demonstrated upregulation of APOA5 gene expression by nuclear receptors (PPAR alpha, FXR and HNF4 alpha) and hormones (thyroxine) involved in hypotriglyceridemic pathways. APOA4 expression may equally be modulated by nutritional status and, more specifically, by stimulation of lipogenesis through transcriptional regulation mediated by insulin and SREBP-1c. However, despite the fact that studies in mice have clearly revealed that plasma levels of ApoAV are inversely correlated with plasma TG levels, the relationship between ApoAV and metabolism of TRL remains controversial in man. Indeed, positive correlations between ApoAV and TG levels have recently been observed in patients with hypertriglyceridemia and Type 2 diabetes. The question as to whether ApoAV is a key determinant of TG levels in humans therefore remains conjectural

Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice

Mice have been used widely to define the mechanism of action of fibric acid derivatives. The fibrates are pharmacological agonists of the peroxisome proliferator-activated receptor α (PPARα), whose activation in human subjects promotes potent reduction in plasma levels of triglycerides (TG) with concomitant increase in those of HDL-cholesterol. The impact of PPARα agonists on gene expression in humans and rodents is however distinct; such distinctions include differential regulation of key genes of lipid metabolism. We evaluated the question as to whether the human and murine genes encoding apolipoprotein apoAV, a regulator of plasma concentrations of TG-rich lipoproteins, might be differentially regulated in response to fibrates. Fenofibrate, a classic PPARα agonist, repressed expression of mouse Apoa5 in vivo in a mouse model transgenic for the human APOA5 gene; by contrast, expression of the human ortholog was up-regulated. Our findings are consistent with the presence of a functional PPAR-binding element in the promoter of the human APOA5 gene; this element is however degenerate and non-functional in the corresponding mouse Apoa5 sequence, as demonstrated by reporter assays and gel shift analyses. These data further highlights the distinct mechanisms which are implicated in the metabolism of TG-rich lipoproteins in mice as compared to man. They equally emphasize the importance of the choice of a mouse model for investigation of the impact of pharmaceutical modifiers on hypertriglyceridemia

Native spider silk as a biological optical fiber.

International audienceIn this study, we demonstrate the use of eco-friendly native spider silk as an efficient optical fiber in air, highly bent fibers, and physiological liquid. We also integrated the silk filament in a photonic chip made of polymer microstructures fabricated by UV lithography. The molding process is non-destructive for silk and leads to an efficient micro-optical coupling between silk and synthetic optical structures. These optical performances combined with the unique biocompatibility, bioresorbability, flexibility, and tensile strength of silk filaments pave the way for new applications in biological media and for original biophotonic purposes

Altered Methylation Profile of Lymphocytes Is Concordant with Perturbation of Lipids Metabolism and Inflammatory Response in Obesity

Obesity is associated with immunological perturbations that contribute to insulin resistance. Epigenetic mechanisms can control immune functions and have been linked to metabolic complications, although their contribution to insulin resistance still remains unclear. In this study, we investigated the link between metabolic dysfunction and immune alterations with the epigenetic signature in leukocytes in a porcine model of obesity. Global DNA methylation of circulating leukocytes, adipose tissue leukocyte trafficking, and macrophage polarisation were established by flow cytometry. Adipose tissue inflammation and metabolic function were further characterised by quantification of metabolites and expression levels of genes associated with obesity and inflammation. Here we show that obese pigs showed bigger visceral fat pads, higher levels of circulating LDL cholesterol, and impaired glucose tolerance. These changes coincided with impaired metabolism, sustained macrophages infiltration, and increased inflammation in the adipose tissue. Those immune alterations were linked to global DNA hypermethylation in both B-cells and T-cells. Our results provide novel insight into the possible contribution of immune cell epigenetics into the immunological disturbances observed in obesity. The dramatic changes in the transcriptomic and epigenetic signature of circulating lymphocytes reinforce the concept that epigenetic processes participate in the increased immune cell activation and impaired metabolic functions in obesity

Thyroid hormone regulates the hypotriglyceridemic gene APOA5*

The apolipoprotein AV gene (APOA5) is a key determinant of plasma triglyceride levels, a major risk factor for coronary artery disease and a biomarker for the metabolic syndrome. Since thyroid hormones influence very low density lipoprotein triglyceride metabolism and clinical studies have demonstrated an inverse correlation between thyroid status and plasma triglyceride levels, we examined whether APOA5 is regulated by thyroid hormone. Here we report that 3,5,3 -triiodo-Lthyronine (T3) and a synthetic thyroid receptor (TR ) ligand increase APOA5 mRNA and protein levels in hepatocytes. Our data revealed that T3-activated TR directly regulates APOA5 promoter through a functional direct repeat separated by four nucleotides (DR4). Interestingly, we show that upstream stimulatory factor 1, a transcription factor associated with familial combined hyperlipidemia and elevated triglyceride levels in humans, and upstream stimulatory factor 2 cooperate with TR, resulting in a synergistic activation of APOA5 promoter in a ligand-dependent manner via an adjacent E-box motif. In rats, we observed that apoAV levels declines with thyroid hormone depletion but returned to normal levels upon T3 administration. In addition, treatments with a TR -selective agonist increased apoAV and diminished triglyceride levels. The identification of APOA5 as a T3 target gene provides a new potential mechanism whereby thyroid hormones can influence triglyceride homeostasis. Additionally, these data suggest that TR may be a potential pharmacological target for the treatment of hypertriglyceridemia

Immune cell-mediated features of non-alcoholic steatohepatitis

International audienceNon-alcoholic fatty liver disease (NAFLD) includes a range of hepatic manifestations, starting with liver steatosis and potentially evolving towards non-alcoholic steatohepatitis (NASH), cirrhosis or even hepatocellular carcinoma. NAFLD is a major health burden, and its incidence is increasing worldwide. Although it is primarily a disease of disturbed metabolism, NAFLD involves several immune cell-mediated inflammatory processes, particularly when reaching the stage of NASH, at which point inflammation becomes integral to the progression of the disease. The hepatic immune cell landscape is diverse at steady state and it further evolves during NASH with direct consequences for disease severity. In this Review, we discuss current concepts related to the role of immune cells in the onset and progression of NASH. A better understanding of the mechanisms by which immune cells contribute to NASH pathogenesis should aid the design of innovative drugs to target NASH, for which current therapeutic options are limited

Evaluation des techniques de diagnostic prénatal de la toxoplasmose à la maternité du CHU de Dijon de 1995 à 2002

DIJON-BU Médecine Pharmacie (212312103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF