C/EBP Homologous Protein-induced Macrophage Apoptosis Protects Mice from Steatohepatitis |
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Authors: | Harmeet Malhi Erin M Kropp Vinna F Clavo Christina R Kobrossi JaeSeok Han Amy S Mauer Jing Yong Randal J Kaufman |
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Institution: | From the ‡Department of Biological Chemistry and ;¶Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109.;the §Center for Neuroscience, Aging, and Stem Cell Research, Sanford Burnham Medical Research Institute, La Jolla, California 92037, and ;the ‖Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 |
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Abstract: | Nonalcoholic fatty liver disease is a heterogeneous disorder characterized by liver steatosis; inflammation and fibrosis are features of the progressive form nonalcoholic steatohepatitis. The endoplasmic reticulum stress response is postulated to play a role in the pathogenesis of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. In particular, C/EBP homologous protein (CHOP) is undetectable under normal conditions but is induced by cellular stress, including endoplasmic reticulum stress. Chop wild type (Chop+/+) and knock-out (Chop−/−) mice were used in these studies to elucidate the role of CHOP in the pathogenesis of fatty liver disease. Paradoxically, Chop−/− mice developed greater liver injury, inflammation, and fibrosis than Chop+/+ mice, with greater macrophage activation. Primary, bone marrow-derived, and peritoneal macrophages from Chop+/+ and Chop−/− were challenged with palmitic acid, an abundant saturated free fatty acid in plasma and liver lipids. Where palmitic acid treatment activated Chop+/+ and Chop−/− macrophages, Chop−/− macrophages were resistant to its lipotoxicity. Chop−/− mice were sensitized to liver injury in a second model of dietary steatohepatitis using the methionine-choline-deficient diet. Analysis of bone marrow chimeras between Chop−/− and Chop+/+ mice demonstrated that Chop in macrophages protects from liver injury and inflammation when fed the methionine-choline-deficient diet. We conclude that Chop deletion has a proinflammatory effect in fatty liver injury apparently due to decreased cell death of activated macrophages, resulting in their net accumulation in the liver. Thus, macrophage CHOP plays a key role in protecting the liver from steatohepatitis likely by limiting macrophage survival during lipotoxicity. |
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Keywords: | Apoptosis Endoplasmic Reticulum Stress Inflammation Liver Injury Macrophages Fatty Liver |
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