Autophagy Deficiency by Hepatic FIP200 Deletion Uncouples Steatosis From Liver Injury in NAFLD

The Endocrine Society - Tập 27 Số 10 - Trang 1643-1654 - 2013
Di Ma1, Matthew M. Molusky1, Jianrui Song1, Chun-Rui Hu2, Fang Fang3, Crystal Rui1, Anna V. Mathew4, Subramaniam Pennathur4, Fei Liu3, Ji‐Xin Cheng5, Jun‐Lin Guan6, Jiandie D. Lin1
1Life Sciences Institute and Department of Cell and Developmental Biology (D.M., M.M.M., J.S., C.R., J.D.L.), University of Michigan
2Hefei National Laboratory for Physical Sciences at Microscale (C.-R.H.), School of Life Science, University of Science and Technology of Science, Hefei 230027, People's Republic of China
3Department of Biologic and Materials Sciences (F.F., F.L.), University of Michigan, Ann Arbor, Michigan 48109
4Departments of Internal Medicine and Cell and Developmental Biology, Division of Nephrology (A.V.M., S.P.), Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109
5Weldon School of Biomedical Engineering and Department of Chemistry (J.-X.C.), Purdue University, West Lafayette, Indiana 47907
6School of Dentistry, Division of Molecular Medicine and Genetics (J.-L.G.), University of Michigan, Ann Arbor, Michigan 48109

Tóm tắt

Nonalcoholic fatty liver disease is a metabolic disorder commonly associated with obesity. A subset of nonalcoholic fatty liver disease patients further develops nonalcoholic steatohepatitis that is characterized by chronic liver injury, inflammation, and fibrosis. Recent work has implicated the autophagy pathway in the mobilization and oxidation of triglycerides from lipid droplets. However, whether impaired autophagy in hepatocytes drives excess fat accumulation in the liver remains controversial. In addition, the role of autophagy in protecting the liver from gut endotoxin-induced injury has not been elucidated. Here we generated mice with liver-specific autophagy deficiency by the conditional deletion of focal adhesion kinase family kinase-interacting protein of 200 kDa (also called Rb1cc1), a core subunit of the mammalian autophagy related 1 complex. To our surprise, mice lacking FIP200 in hepatocytes were protected from starvation- and high-fat diet-induced fat accumulation in the liver and had decreased expression of genes involved in lipid metabolism. Activation of the de novo lipogenic program by liver X receptor was impaired in FIP200-deficient livers. Furthermore, liver autophagy was stimulated by exposure to low doses of lipopolysaccharides and its deficiency-sensitized mice to endotoxin-induced liver injury. Together these studies demonstrate that hepatocyte-specific autophagy deficiency per se does not exacerbate hepatic steatosis. Instead, autophagy may play a protective role in the liver after exposure to gut-derived endotoxins and its blockade may accelerate nonalcoholic steatohepatitis progression.

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The Endocrine Society

Tập 27 Số 10

1643-1654

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