These two authors contributed equally to this work.
Steatohepatitis/Metabolic Liver Disease
Role of adipose triglyceride lipase (PNPLA2) in protection from hepatic inflammation in mouse models of steatohepatitis and endotoxemia
Article first published online: 28 JAN 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 3, pages 858–869, March 2014
How to Cite
Jha, P., Claudel, T., Baghdasaryan, A., Mueller, M., Halilbasic, E., Das, S. K., Lass, A., Zimmermann, R., Zechner, R., Hoefler, G. and Trauner, M. (2014), Role of adipose triglyceride lipase (PNPLA2) in protection from hepatic inflammation in mouse models of steatohepatitis and endotoxemia. Hepatology, 59: 858–869. doi: 10.1002/hep.26732
Potential conflict of interest: Prof. Trauner consults for, is on the speakers' bureau for, and received grants from Falk. He is on the speakers' bureau for and received grants from MSD. He consults for Phenex. He is on the speakers' bureau for Gilead and Roche. He received grants from Intercept.
Supported by grants F3008 (to MT) and F3002 (R. Zechner) from the Austrian Science Foundation and European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement HEALTH-F2-2009-241762 for the project FLIP (to MT). P. Jha was also supported by the PhD program of the Medical University of Graz.
- Issue published online: 25 FEB 2014
- Article first published online: 28 JAN 2014
- Accepted manuscript online: 3 SEP 2013 11:45AM EST
- Manuscript Accepted: 29 AUG 2013
- Manuscript Received: 7 MAR 2013
Hepatic inflammation is a key feature of progressive liver disease. Alterations of fatty acid (FA) metabolism and signaling may play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). Moreover, FAs activate peroxisome proliferator-activated receptor α (PPARα) as a key transcriptional regulator of hepatic FA metabolism and inflammation. Since adipose triglyceride lipase (ATGL/PNPLA2) is the key enzyme for intracellular hydrolysis of stored triglycerides and determines FA signaling through PPARα, we explored the role of ATGL in hepatic inflammation in mouse models of NASH and endotoxemia. Mice lacking ATGL or hormone-sensitive lipase (HSL) were challenged with a methionine-choline-deficient (MCD) diet as a nutritional model of NASH or lipopolysaccharide (LPS) as a model of acute hepatic inflammation. We further tested whether a PPARα agonist (fenofibrate) treatment improves the hepatic phenotype in MCD- or LPS-challenged ATGL-knockout (KO) mice. MCD-fed ATGL-KO mice, although partially protected from peripheral lipolysis, showed exacerbated hepatic steatosis and inflammation. Moreover, ATGL-KO mice challenged by LPS showed enhanced hepatic inflammation, increased mortality, and torpor, findings which were attributed to impaired PPARα DNA binding activity due to reduced FABP1 protein levels, resulting in impaired nuclear FA import. Notably, liganding PPARα through fenofibrate attenuated hepatic inflammation in both MCD-fed and LPS-treated ATGL-KO mice. In contrast, mice lacking HSL had a phenotype similar to the WT mice on MCD and LPS challenge. Conclusion: These findings unravel a novel protective role of ATGL against hepatic inflammation which could have important implications for metabolic and inflammatory liver diseases. (Hepatology 2014;59:858–869)