Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet

Xiaoying Liu*, Anne S. Henkel, Brian E. LeCuyer, Matthew J. Schipma, Kristy A. Anderson, Richard M. Green

*Corresponding author for this work

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Fatty liver is associated with endoplasmic reticulum stress and activation of the hepatic unfolded protein response (UPR). Reduced hepatic expression of the UPR regulator X-box binding protein 1 spliced (XBP1s) is associated with human nonalcoholic steatohepatitis (NASH), and feeding mice a high-fat diet with fructose/sucrose causes progressive, fibrosing steatohepatitis. This study examines the role of XBP1 in nonalcoholic fatty liver injury and fatty acid-induced cell injury. Hepatocytespecific Xbp1-deficient (Xbp1-/-) mice were fed a high-fat/sugar (HFS) diet for up to 16 wk. HFS-fed Xbp1-/- mice exhibited higher serum alanine aminotransferase levels compared with Xbp1fl/fl controls. RNA sequencing and Gene Ontogeny pathway analysis of hepatic mRNA revealed that apoptotic process, inflammatory response, and extracellular matrix structural constituent pathways had enhanced activation in HFS-fed Xbp1-/- mice. Liver histology demonstrated enhanced injury and fibrosis but less steatosis in the HFSfed Xbp1-/- mice. Hepatic Col1a1 and Tgf-1 gene expression, as well as Chop and phosphorylated JNK (p-JNK), were increased in Xbp1-/- compared with Xbp1fl/fl mice after HFS feeding. In vitro, stable XBP1-knockdown Huh7 cells (Huh7-KD) and scramble control cells (Huh7-SCR) were generated and treated with palmitic acid (PA) for 24 h. PA-treated Huh7-KD cells had increased cytotoxicity measured by lactate dehydrogenase release, apoptotic nuclei, and caspase3/7 activity assays compared with Huh7-SCR cells. CHOP and p-JNK expression was also increased in Huh7-KD cells following PA treatment. In conclusion, loss of XBP1 enhances injury in both in vivo and in vitro models of fatty liver injury. We speculate that hepatic XBP1 plays an important protective role in pathogenesis of NASH.

Original languageEnglish (US)
Pages (from-to)G965-G974
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume309
Issue number12
DOIs
StatePublished - 2015

Keywords

  • Endoplasmic reticulum stress
  • Fatty liver
  • Nonalcoholic steatohepatitis
  • Steatosis
  • Unfolded protein response

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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