Fatty liver and lipotoxicity |
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Authors: | Michael Trauner Marco Arrese Martin Wagner |
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Affiliation: | 1. Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria;2. Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile |
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Abstract: | Fatty liver disease comprises a spectrum ranging from simple steatosis to steatohepatitis which can progress to liver cirrhosis and hepatocellular cancer. Hepatic lipotoxicity may ensue when the hepatic capacity to utilize, store and export fatty acids (FA) as triglycerides is overwhelmed. Additional mechanisms of hepatic lipotoxicity include abnormal FA oxidation with formation of reactive oxygen species, disturbances in cellular membrane FA and phospholipid composition, alterations of cholesterol content and ceramide signalling. Lipotoxicity is a key factor for the progression of fatty liver disease by inducing hepatocellular death, activating Kupffer cells and an inflammatory response, impairing hepatic insulin signalling resulting in insulin resistance, and activation of a fibrogenic response in hepatic stellate cells that can ultimately lead to cirrhosis. Therefore, the concept of hepatic lipotoxicity should be considered in future therapeutic concepts for fatty liver disease. |
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Keywords: | CAR (NR1I3), constitutive androstane receptor CYP2E1, cytochrome P450 2E1 ER, endoplasmic reticulum NAFLD, non-alcoholic fatty liver disease NASH, non-alcoholic steatohepatitis IR, insulin resistance FA, fatty acids PPAR, peroxisome proliferator-activated receptor ROS, reactive oxygen species TG, triglyceride TNF-α, tumor necrosis factor-α WAT, white adipose tissue |
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