Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, emerging evidence suggests that bile acids (BA) may also play a key role as signaling molecules in the regulation of hepatic triglyceride (TG) metabolism and energy homeostasis. Therefore, hepatobiliary BA transporters, which maintain BA flux through the liver and the return of BA from the intestine to the liver via the enterohepatic circulation, as well as the key regulatory nuclear BA receptor (farnesoid X receptor, FXR) may play pivotal roles in the control of hepatic lipid homeostasis and pathogenesis of fatty liver disease.
Lipotoxicity resulting from excess of unsaturated fatty acids (FAs) may be a key event in the progression of NAFLD disease by inducing hepatocellular death, activating Kupffer cells as liver resident macrophages, impairing hepatic insulin signalling, and activation of a fibrogenic response in hepatic stellate cells that can ultimately lead to cirrhosis and hepatocellular cancer.Metabolic lipases may play a critical role in the progression of fatty liver disease by determining lipid partitioning and FA flux and signaling from the adipose tissue to the liver.
Based on our central hypothesis that metabolic lipases play a critical role in the progression of NAFLD by determining hepatic FA flux and signaling, we will explore the consequences of altered metabolic lipase action in the pathogenesis of hepatic lipotoxicity with subsequent hepatocellular injury, inflammation, fibrosis and cancer. Moreover, we will explore the role of BAs as potential theraoeutic modulators of metabolic lipases potentially counteracting hepatic lipotoxicity.
Methods & Techniques
Phenotypic and molecular characterization of trangenic mouse models for bile acid transport and signaling; knockout mouse models for metabolic lipases; mouse models for NAFLD and cholestatic disorders; cell culture; bile acid, lipid and molecular analysis; lipase assays in isolated cells and tissues
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Chennamsetty I, Claudel T, Kostner KM, Baghdasaryan A, Kratky D, Levak-Frank S, Frank S, Gonzalez FJ, Trauner M, Kostner GM. Farnesoid X receptor represses hepatic human APOA gene expression. J Clin Invest 121: 3724-3734, 2011
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Das SK, Eder S, Schauer S, Diwoky C, Temmel H, Guertl B, Gorkiewicz G, Tamilarasan KP, Kumari P, Trauner M, Zimmermann R, Vesely P, Haemmerle G, Zechner R, Hoefler G. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333: 233-238, 2011
Trauner M, Halilbasic E. Nuclear receptors as new perspective for the management of liver diseases. Gastroenterology 140: 1120-1125, 2011
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Trauner M, Arrese M, Wagner M. Fatty liver and lipotoxicity. Biochim Biophys Acta 1801: 299-310, 2010