Enhanced alcoholic liver disease in mice with intestine-specific farnesoid X receptor deficiency

Mingxing Huang, Bo Kong, Min Zhang, Daniel Rizzolo, Laura E. Armstrong, Justin D. Schumacher, Monica D. Chow, Yi Horng Lee, Laurie B. Joseph, Mary Stofan, Lanjing Zhang, Grace L. Guo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Alcoholic fatty liver disease (AFLD) is one of the major causes of liver morbidity and mortality worldwide. We have previously shown that whole-body, but not hepatocyte-specific, deficiency of farnesoid X receptor (FXR) in mice worsens AFLD, suggesting that extrahepatic FXR deficiency is critical for AFLD development. Intestinal FXR is critical in suppressing hepatic bile acid (BA) synthesis by inducing fibroblast growth factor 15 (FGF15) in mice and FGF19 in humans. We hypothesized that intestinal FXR is critical for reducing AFLD development in mice. To test this hypothesis, we compared the AFLD severity in wild type (WT) and intestine-specific Fxr knockout (FXRInt−/−) mice following treatment with control or ethanol-containing diet. We found that FXRInt−/− mice were more susceptible to ethanol-induced liver steatosis and inflammation, compared with WT mice. Ethanol treatment altered the expression of hepatic genes involved in lipid and BA homeostasis, and ethanol detoxification. Gut FXR deficiency increased intestinal permeability, likely due to reduced mucosal integrity, as revealed by decreased secretion of Mucin 2 protein and lower levels of E-cadherin protein. In summary, intestinal FXR may protect AFLD development by maintaining gut integrity.

Original languageEnglish (US)
Pages (from-to)1158-1168
Number of pages11
JournalLaboratory Investigation
Volume100
Issue number9
DOIs
StatePublished - Sep 1 2020

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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