C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis

Harmeet Malhi, Erin M. Kropp, Vinna F. Clavo, Christina R. Kobrossi, Jae Seok Han, Amy S. Mauer, Jing Yong, Randal J. Kaufman

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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.

Original languageEnglish (US)
Pages (from-to)18624-18642
Number of pages19
JournalJournal of Biological Chemistry
Volume288
Issue number26
DOIs
StatePublished - Jun 28 2013

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Malhi, H., Kropp, E. M., Clavo, V. F., Kobrossi, C. R., Han, J. S., Mauer, A. S., Yong, J., & Kaufman, R. J. (2013). C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis. Journal of Biological Chemistry, 288(26), 18624-18642. https://doi.org/10.1074/jbc.M112.442954