title: C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis.
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.
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
authors.forename: Harmeet
authors.initials: H
authors.lastname: Malhi
authors.forename: Erin M
authors.initials: EM
authors.lastname: Kropp
authors.forename: Vinna F
authors.initials: VF
authors.lastname: Clavo
authors.forename: Christina R
authors.initials: CR
authors.lastname: Kobrossi
authors.forename: JaeSeok
authors.initials: J
authors.lastname: Han
authors.forename: Amy S
authors.initials: AS
authors.lastname: Mauer
authors.forename: Jing
authors.initials: J
authors.lastname: Yong
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005234:Fatty Liver / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005355:Fibrosis / Q000378:metabolism; D007249:Inflammation; D008099:Liver / Q000293:injuries / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity; D047495:PPAR gamma / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; C497250:Ddit3 protein, mouse; D047495:PPAR gamma; D051742:Transcription Factor CHOP
keywords: Apoptosis; Endoplasmic Reticulum Stress; Fatty Liver; Inflammation; Liver Injury; Macrophages