2) All of those three pathways, ie, JNK, IKK–NF-κB, and ROS, h

2). All of those three pathways, i.e., JNK, IKK–NF-κB, and ROS, have been demonstrated to be involved in the regulation of obesity-related insulin resistance and inflammation. Free fatty acids may also induce ER stress,88 whereas certain adipose tissue–derived unsaturated fatty acids such as palmitoleate (i.e., “lipokines”) might inhibit ER stress and related events.89, 90 The liver needs to adapt and to function in obesity-related

disorders under this chronic exposure to high energy and nutrient intake. Hepatocytes maintain one of the highest protein synthesis rates in the body and can produce millions of proteins per minute. Therefore, failure to maintain ER integrity may develop in such an organ more easily and lead to other ER-stress–controlled AZD4547 solubility dmso events such as inflammation. Importantly, two reports

have recently opened a completely new aspect for XBP1 demonstrating that certain subunits of the insulin signaling pathway (phosphatidyl inositol 3-kinase [PI3K], namely p85α and p85β) interact and increase the nuclear translocation of XBP1s.91, 92 XBP1 has evolved as a critical molecule that is able to regulate all aspects of NAFLD, namely lipid synthesis/accumulation, leptin resistance, adipogenesis, inflammation, and insulin signaling/resistance.93, 94 Autophagy has recently evolved as an additional pathway affecting hepatic lipid metabolism. Autophagy, a phylogenetically conserved response to cellular starvation, regulates DAPT concentration lipid metabolism because inhibition of autophagy in cultured hepatocytes and murine livers increases

triglyceride storage.95 Autophagy seems to critically interact with ER stress because impaired hepatic autophagy results in elevated ER stress and defective insulin signaling.96 Therefore, ER stress and autophagy appear as closely intertwined pathways in inflammatory diseases. Genetic factors might be attractive candidates to explain why a certain percentage of patients with fatty liver develop inflammation. NAFLD is a heritable disorder, suggesting there are genetic components that predispose to these traits. Polymorphisms in patatin-like phospholipase 3 (PNPLA3), encoding a protein of unknown function with homology to lipid acyl hydrolases, has been this website strongly associated with increased hepatic fat content in NAFLD.97 Several other genetic variants have been identified, although with less convincing evidence, except for apolipoprotein C3.98PNPLA3 findings have been confirmed by several groups99-101 and recent studies have demonstrated that homozygosity for the PNPLA3 148M polymorphism is associated with severity of disease (degree of inflammation, liver fibrosis).102-104PNPLA3-deficient mice develop neither fatty liver, elevated aminotransferases, nor insulin resistance.

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