TY - JOUR
T1 - FXR deletion in hepatocytes does not affect the severity of alcoholic liver disease in mice
AU - Zhang, Min
AU - Kong, Bo
AU - Huang, Mingxing
AU - Wan, Ruixuan
AU - Armstrong, Laura E.
AU - Schumacher, Justin D.
AU - Rizzolo, Daniel
AU - Chow, Monica D.
AU - Lee, Yi Horng
AU - Guo, Grace L.
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
KW - Alcoholic liver disease
KW - Bile acid metabolism
KW - Ethanol toxicity
KW - FXR
KW - Lipid metabolism
KW - Tissue specific knockout
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U2 - 10.1016/j.dld.2018.04.009
DO - 10.1016/j.dld.2018.04.009
M3 - Article
C2 - 29730159
AN - SCOPUS:85046756296
VL - 50
SP - 1068
EP - 1075
JO - Digestive and Liver Disease
JF - Digestive and Liver Disease
SN - 1590-8658
IS - 10
ER -