Improvements in identification and metabolic characterization of this GSK126 in vivo NAFLD at-risk population, combined with targeted therapeutics, can then result in the greatest impact on overall and cardiovascular mortality. Dr. Chalasani serves as a paid consultant for many pharmaceutical companies but none represent a potential conflict for

this article. “
“Nonalcoholic steatosis is a liver pathology characterized by fat accumulation and severe metabolic alterations involving early mitochondrial impairment and late hepatocyte cell death. However, mitochondrial dysfunction mechanisms remain elusive. Using four models of nonalcoholic steatosis, i.e., livers from patients with fatty liver disease, ob/ob mice, mice fed a high-fat diet, and in vitro models of lipotoxicity, we show that outer mitochondrial membrane permeability is altered and

identified a posttranslational modification of voltage-dependent anion channel (VDAC), a membrane channel and NADH oxidase, as a cause of early mitochondrial dysfunction. Thus, in nonalcoholic steatosis VDAC exhibits reduced threonine phosphorylation, which increases the influx of water and calcium into mitochondria, sensitizes the organelle to matrix swelling, depolarization, and cytochrome c release without inducing cell death. This also amplifies VDAC enzymatic and channel activities regulation by calcium and modifies its interaction with proteic partners. Moreover,

lipid accumulation triggers a rapid lack of VDAC phosphorylation by glycogen synthase kinase 3 (GSK3). Pharmacological and check details genetic manipulations proved GSK3 to be responsible for VDAC phosphorylation in normal cells. Notably, VDAC phosphorylation level correlated with steatosis severity in patients. Conclusion: VDAC acts as an early sensor of lipid toxicity and its GSK3-mediated phosphorylation status controls outer mitochondrial membrane permeabilization in Dichloromethane dehalogenase hepatosteatosis. (HEPATOLOGY 2013) Nonalcoholic fatty liver disease (NAFLD) is accompanied by hepatosteatosis, a clinical condition characterized by excessive accumulation of lipids within hepatocytes and complex metabolic alterations.1, 2 Although reversible in early stages, steatosis can lead to more aggressive forms of liver injury such as hepatitis, cirrhosis, and hepatocarcinoma.3 Investigation of patients with hepatosteatosis showed that mitochondria harbor prominent morphologic and functional abnormalities, suggesting a central role of these organelles in the pathogenesis.4 Mitochondria can influence cell fate at the levels of energy production, lipid metabolism, production, and detoxification of reactive oxygen species (ROS) and release of proapoptotic proteins.5 All these alterations favor an increase in apoptotic and necrotic hepatocyte cell death.