Conclusion: Our study identifies CD154 as a new mediator of hepatic steatosis. (HEPATOLOGY 2010) The accumulation of triglycerides (TG) in hepatocytes is a common phenomenon in liver disease. Several mechanisms can account for hepatic steatosis, including increased free fatty acid flux to the liver through diet or peripheral TG lipolysis, defective fat oxidation, this website increased lipogenesis or decreased very low-density lipoprotein (VLDL) export. These mechanisms have

been proposed as causal explanations for hepatic steatosis associated with nonalcoholic fatty liver disease.1-4 The endoplasmic reticulum (ER) is an essential organelle in lipid metabolism. First, VLDL generation depends on a functional ER.5-9 Second, excessive lipid input in hepatocytes, as observed in nonalcoholic fatty liver disease Staurosporine ic50 patients, in animal models of fatty livers or in cultured cells is associated with ER stress, though the underlying mechanisms are poorly understood.10-16 In these contexts,

ER stress contributes to steatosis through various mechanisms, including increased degradation of apolipoprotein B100 (apoB100) and hepatic lipogenesis through insulin-independent activation of the transcription factor sterol regulatory element binding protein-1c (SREBP-1c).14, 17-20 ER stress signaling pathways, collectively named the unfolded protein response (UPR), regulate ER homeostasis.21-24 The UPR is important for hepatocyte ER adaptation to excessive lipid input in conditions associated with ER stress.21-23 Indeed, the genetic ablation of either branch of the UPR leads to hepatic steatosis in acute ER stress conditions,25, 26 whereas learn more enforced maintenance of ER homeostasis increases apoB100 secretion, prevents SREBP-1c activation, and reduces hepatic steatosis in mice or cell culture models.9, 14, 18-20 Beyond their conventional role in monitoring ER homeostasis in acute ER stress, UPR effectors are activated under physiological conditions and regulate glucose and lipid metabolic pathways,

thus contributing to basal cellular homeostasis.27, 28 Importantly, UPR signaling intersects with other signaling cascades, rendering the former amenable to regulation by signals other than directly resulting from ER stress. Among them, inflammatory signals may have a specific importance.27 Inflammation is a key parameter in the progression of hepatic steatosis29-31 and the deregulation of the interface between the UPR and inflammation signaling pathways is likely to be of importance in metabolic disorders.30, 32-34 Here, we study CD154, a member of the tumor necrosis factor (TNF) superfamily, and a critical mediator of inflammation.35 The main reservoir of CD154 in the organism is the blood platelet.36, 37 CD154 expression is inducible by proinflammatory cytokines, and a soluble form (sCD154) retaining biological activity is released from cell surface by a poorly defined mechanism.38 sCD154 levels are increased in the metabolic syndrome.