Title: Enhanced alcoholic liver disease in mice with intestine-specific farnesoid X receptor deficiency.
Authors: Huang, Mingxing; Kong, Bo; Zhang, Min; Rizzolo, Daniel; Armstrong, Laura E; Schumacher, Justin D; Chow, Monica D; Lee, Yi-Horng; Joseph, Laurie B; Stofan, Mary; Zhang, Lanjing; Guo, Grace L
Published In Lab Invest, (2020 Sep)
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.
PubMed ID: 32404932
MeSH Terms: Animals; Bile Acids and Salts; Ethanol/administration & dosage; Ethanol/pharmacology*; Fatty Liver/genetics; Fatty Liver/metabolism; Fatty Liver/pathology; Fibroblast Growth Factors/genetics; Fibroblast Growth Factors/metabolism; Gene Expression/drug effects; Intestinal Mucosa/metabolism*; Liver Diseases, Alcoholic/genetics*; Liver Diseases, Alcoholic/metabolism; Liver Diseases, Alcoholic/pathology; Liver/drug effects; Liver/metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Receptors, Cytoplasmic and Nuclear/deficiency; Receptors, Cytoplasmic and Nuclear/genetics*