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 language | English (US) |
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Pages (from-to) | 1068-1075 |
Number of pages | 8 |
Journal | Digestive and Liver Disease |
Volume | 50 |
Issue number | 10 |
DOIs | |
State | Published - 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