9 Because simple hepatic steatosis is a benign process in the majority of patients, NASH might be a separate disease with a different pathogenesis. Here, we propose a new model suggesting that many hits may act in parallel, finally resulting in liver inflammation and that especially gut-derived

and adipose tissue–derived factors may play a central role. Inflammation may precede steatosis in NASH, as inflammatory events may lead to subsequent steatosis. Furthermore, we want to highlight GSK1120212 in vitro the potential importance of endoplasmic reticulum (ER) stress in various aspects of this disease. AhR, aryl hydrocarbon receptor; ATF-6, activating transcription factor 6; ChREBP, carbohydrate response element-binding protein; DGAT, diacylglycerol acyltransferase; DNL, de novo lipogenesis; ER, endoplasmic reticulum; IKKβ, inhibitor of nuclear factor-κB kinase-β; Gpr, G protein–coupled receptor; IL, interleukin; IRE1, inositol-requiring enzyme 1; JNK1, c-jun N-terminal protein kinase 1; LPS, lipopolysaccharide; mRNA, messenger RNA; PERK, pancreatic ER kinase; PI3K, phosphatidyl inositol 3-kinase; patatin-like phospholipase 3 PNPLA3; PPARγ, peroxisome proliferator-activated receptor-gamma; ROS, reactive oxygen species; SCFA, short chain fatty acid; SOCS3,

suppressor of cytokine signaling 3; SREBP, sterol regulatory element-binding protein; TLR, toll-like receptor; TNF, tumor necrosis factor; UDCA, ursodeoxycholic acid; UPR, unfolded protein response; XBP1, X-box binding protein 1. A fatty liver FK228 concentration is the result of the accumulation of various lipids.10 Several learn more mechanisms may lead to a fatty liver: (1) increased free fatty acids supply due to increased lipolysis from both visceral/subcutaneous adipose tissue and/or increased intake of dietary fat; (2) decreased free fatty oxidation oxidation; (3) increased de novo hepatic lipogenesis (DNL) and (4) decreased hepatic very low density lipoprotein–triglyceride secretion.11 Free fatty acid delivery to the liver accounts for almost two-thirds of its lipid accumulation.12 Elevated peripheral fatty acids and DNL therefore predominantly

contribute to the accumulation of hepatic fat in NAFLD. Besides the well-established lipogenesis-controlling factors such as sterol regulatory element-binding protein (SREBP) or carbohydrate response element-binding protein (ChREBP), X-box binding protein 1 (XBP1), known as a key regulator of the unfolded protein response (UPR) secondary to ER stress, is a only recently characterized regulator of hepatic lipogenesis.13 Triglycerides are the main lipids stored in the liver of patients with NAFLD. Although large epidemiological studies suggest triglyceride-mediated pathways might negatively affect disease,14 recent evidence indicates that trigylcerides might exert protective functions. Diacylglycerol acyltransferase 1 and 2 (DGAT1/2) catalyze the final step in triglyceride synthesis.

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