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

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.

SUBMITTER: Zhang M

PROVIDER: S-EPMC6168334 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Zhang Min M Kong Bo B Huang Mingxing M Wan Ruixuan R Armstrong Laura E LE Schumacher Justin D JD Rizzolo Daniel D Chow Monica D MD Lee Yi-Horng YH Guo Grace L GL

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 20180423 10

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<sup>-/-</sup> mice is due to deficiency of hepatic FXR or increased toxicity secondary to increased bile acid (BA) levels. Hepatocyte-specific FXR knockout mice (FXR<sup>hep-/-</sup>) present similar BA levels compared to wild-type mice, ...[more]

PMID: 29730159

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Project description:Background & aimsSirtuin (SIRT1) is a nicotinamide adenine dinucleotide-dependent protein deacetylase that regulates hepatic lipid metabolism by modifying histones and transcription factors. Ethanol exposure disrupts SIRT1 activity and contributes to alcoholic liver disease in rodents, but the exact pathogenic mechanism is not clear. We compared mice with liver-specific deletion of Sirt1 (Sirt1LKO) mice with their LOX littermates (controls).MethodsWe induced alcoholic liver injury in male Sirt1LKO and control mice, placing them on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5 g/kg body weight) via gavage. Liver and serum samples were collected. We also measured messenger RNA levels of SIRT1, SFRS10, and lipin-1β and lipin-1α in liver samples from patients with alcoholic hepatitis and individuals without alcoholic hepatitis (controls).ResultsOn the ethanol-containing diet, livers of Sirt1LKO mice accumulated larger amounts of hepatic lipid and expressed higher levels of inflammatory cytokines than control mice; serum of Sirt1LKO mice had increased levels of alanine aminotransferase and aspartate aminotransferase. Hepatic deletion of SIRT1 exacerbated ethanol-mediated defects in lipid metabolism, mainly by altering the function of lipin-1, a transcriptional regulator of lipid metabolism. In cultured mouse AML-12 hepatocytes, transgenic expression of SIRT1 prevented fat accumulation in response to ethanol exposure, largely by reversing the aberrations in lipin-1 signaling induced by ethanol. Liver samples from patients with alcoholic hepatitis had reduced levels of SIRT1 and a higher ratio of Lpin1β/α messenger RNAs than controls.ConclusionsIn mice, hepatic deletion of Sirt1 promotes steatosis, inflammation, and fibrosis in response to ethanol challenge. Ethanol-mediated impairment of hepatic SIRT1 signaling via lipin-1 contributes to development of alcoholic steatosis and inflammation. Reagents designed to increase SIRT1 regulation of lipin-1 can be developed to treat patients with alcoholic fatty liver disease.

Project description:Background/aimsSome studies showed that probiotics could improve the composition and structure of gut microbiota. Changes in the gut microbiota may alter bile acid (BAs) composition and kinetics, improving non-alcoholic fatty liver disease (NAFLD). However, it still needs to be clarified how probiotics improve both the metabolism of BAs and NAFLD. This study aimed to reveal the regulatory mechanisms of cholesterol-lowering (CL) probiotics on NAFLD from aspects involved in BA metabolism in FXR gene knockout (FXR-/-) mice.MethodsFXR-/- male mice were randomly divided into three groups based on different interventions for 16 weeks, including normal diet (ND), high-fat diet (HFD), and probiotic intervention in the HFD (HFD+P) group. 16s rDNA sequencing and ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) were utilized to analyze the changes in gut microbiota and fecal bile acids in mice.ResultsWe found that the intervention of the CL probiotics improved liver lipid deposition and function in HFD-induced NAFLD mice by decreasing the levels of total cholesterol (TC; p = 0.002) and triglyceride (TG; p = 0.001) in serum, as well as suppressing liver inflammation, such as interleukin-1 beta (IL-1β; p = 0.002) and tumor necrosis factor-alpha (TNF-α; p < 0.0001). 16S rDNA sequencing and metabolomic analyses showed that probiotics effectively reduced the abundance of harmful gut microbiota, such as Firmicutes (p = 0.005), while concomitantly increasing the abundance of beneficial gut microbiota in NAFLD mice, such as Actinobacteriota (p = 0.378), to improve NAFLD. Compared with the ND group, consuming an HFD elevated the levels of total BAs (p = 0.0002), primary BAs (p = 0.017), and secondary BAs (p = 0.0001) in mice feces, while the intervention with probiotics significantly reduced the increase in the levels of fecal total bile acids (p = 0.013) and secondary bile acids (p = 0.017) induced by HFD.ConclusionThe CL probiotics were found to improve liver function, restore microbiota balance, correct an abnormal change in the composition and content of fecal bile acids, and repair the damaged intestinal mucosal barrier in mice with NAFLD, ultimately ameliorating the condition. These results suggested that CL probiotics may be a promising and health-friendly treatment option for NAFLD.

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

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

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