Hepatocyte toll-like receptor 4 deficiency protects against alcohol-induced fatty liver disease

Lin Jia, Xiuli Chang, Shuwen Qian, Chen Liu, Caleb C. Lord, Newaz Ahmed, Charlotte E. Lee, Syann Lee, Laurent Gautron, Mack C. Mitchell, Jay D. Horton, Philipp E. Scherer, Joel K. Elmquist

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Objective: Recent studies have suggested a critical role for toll-like receptor 4 (TLR4) in the development of alcoholic liver disease. As TLR4 is widely expressed throughout the body, it is unclear which TLR4-expressing cell types contribute to alcohol-induced liver damage. Methods: We selectively ablated TLR4 in hepatocytes and myeloid cells. Male mice were fed a liquid diet containing either 5% alcohol or pair-fed a control diet for 4 weeks to examine chronic alcohol intake-induced liver damage and inflammation. In addition, mice were administered a single oral gavage of alcohol to investigate acute alcohol drinking-associated liver injury. Results: We found that selective hepatocyte TLR4 deletion protected mice from chronic alcohol-induced liver injury and fatty liver. This result was in part due to decreased expression of endogenous lipogenic genes and enhanced expression of genes involved in fatty acid oxidation. In addition, mice lacking hepatocyte TLR4 exhibited reduced mRNA expression of inflammatory genes in white adipose tissue. Furthermore, in an acute alcohol binge model, hepatocyte TLR4 deficient mice had significantly decreased plasma alanine transaminase (ALT) levels and attenuated hepatic triglyceride content compared to their alcohol-gavaged control mice. In contrast, deleting TLR4 in myeloid cells did not affect the development of chronic-alcohol induced fatty liver, despite the finding that mice lacking myeloid cell TLR4 had significantly reduced circulating ALT concentrations. Conclusions: These findings suggest that hepatocyte TLR4 plays an important role in regulating alcohol-induced liver damage and fatty liver disease.

Original languageEnglish (US)
Pages (from-to)121-129
Number of pages9
JournalMolecular Metabolism
Volume14
DOIs
StatePublished - Aug 1 2018

Keywords

  • Alcoholic fatty liver disease
  • Hepatocyte
  • Inflammation
  • Liver injury
  • Myeloid cell
  • Toll-like receptor 4

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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