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

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

Research output: Contribution to journalArticle

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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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Transcription Factor CHOP
Macrophages
Fatty Liver
Liver
Apoptosis
Endoplasmic Reticulum Stress
Palmitic Acid
Wounds and Injuries
Choline
Inflammation
Methionine
Fibrosis
Diet
Nutrition
Macrophage Activation
Peritoneal Macrophages
Bone
Nonesterified Fatty Acids
Knockout Mice
Liver Diseases

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Malhi, H. M., Kropp, E. M., Clavo, V. F., Kobrossi, C. R., Han, J., Mauer, A. S., ... 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

C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis. / Malhi, Harmeet M; Kropp, Erin M.; Clavo, Vinna F.; Kobrossi, Christina R.; Han, JaeSeok; Mauer, Amy S.; Yong, Jing; Kaufman, Randal J.

In: Journal of Biological Chemistry, Vol. 288, No. 26, 28.06.2013, p. 18624-18642.

Research output: Contribution to journalArticle

Malhi, HM, Kropp, EM, Clavo, VF, Kobrossi, CR, Han, J, Mauer, AS, Yong, J & Kaufman, RJ 2013, 'C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis', Journal of Biological Chemistry, vol. 288, no. 26, pp. 18624-18642. https://doi.org/10.1074/jbc.M112.442954
Malhi, Harmeet M ; Kropp, Erin M. ; Clavo, Vinna F. ; Kobrossi, Christina R. ; Han, JaeSeok ; Mauer, Amy S. ; Yong, Jing ; Kaufman, Randal J. / C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 26. pp. 18624-18642.
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