FXR deletion in hepatocytes does not affect the severity of alcoholic liver disease in mice

Min Zhang, Bo Kong, Mingxing Huang, Ruixuan Wan, Laura E. Armstrong, Justin D. Schumacher, Daniel Rizzolo, Monica D. Chow, Yi Horng Lee, Grace L. Guo

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Emerging evidence has shown that FXR activation ameliorates the development of alcoholic liver diseases (ALD) while whole-body deficiency of FXR in mice leads to more severe ALD. However, it's unknown whether the enhanced susceptibility to ALD development in FXR −/− mice is due to deficiency of hepatic FXR or increased toxicity secondary to increased bile acid (BA) levels. Hepatocyte-specific FXR knockout mice (FXR hep−/− ) present similar BA levels compared to wild-type mice, and are therefore a useful model to study a direct role of hepatic FXR in ALD development. FXR hep−/− mice were subject to an ALD model with chronic plus binge drinking of alcohol to determine the effects of hepatic FXR deficiency on ALD development. The FXR hep−/− mice showed an altered expression of genes involved in BA and lipid homeostasis with alcohol treatment. Despite a slightly increased trend in hepatic lipid deposition and collagen accumulation in FXR hep−/− mice, there were no significant differences in the severity of steatosis, inflammation, or fibrosis between WT and FXR hep−/− mice. Therefore, these findings indicate that FXR deficiency in hepatocytes might only play a minor role in ALD development. Deficiency of FXR in other non-hepatic tissues and/or increased BA levels resultant from whole-body FXR deficiency might be responsible for more severe ALD development.

Original languageEnglish (US)
Pages (from-to)1068-1075
Number of pages8
JournalDigestive and Liver Disease
Volume50
Issue number10
DOIs
StatePublished - Oct 2018

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Keywords

  • Alcoholic liver disease
  • Bile acid metabolism
  • Ethanol toxicity
  • FXR
  • Lipid metabolism
  • Tissue specific knockout

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