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

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

Published In Dig Liver Dis, (2018 Oct)

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 (FXRhep-/-) 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. FXRhep-/- 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 FXRhep-/- 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 FXRhep-/- mice, there were no significant differences in the severity of steatosis, inflammation, or fibrosis between WT and FXRhep-/- 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.

PubMed ID: 29730159

MeSH Terms: Animals; Bile Acids and Salts/metabolism; Disease Models, Animal; Ethanol/toxicity; Hepatocytes/drug effects*; Liver Diseases, Alcoholic/genetics*; Liver Diseases, Alcoholic/physiopathology*; Liver/pathology*; Male; Mice; Mice, Knockout; RNA-Binding Proteins/genetics*