Dataset Information

FXR deficiency alters bile acid pool composition and exacerbates chronic alcohol induced liver injury.

ABSTRACT: Recent studies have investigated the roles of FXR deficiency in the pathogenesis of alcoholic liver disease (ALD). However, the underlying molecular mechanisms remain unclear. In this study, FXR knockout (FXR-/-) and wild-type (WT) mice were subjected to chronic-plus-binge alcohol feeding to study the effect of FXR deficiency on ALD development. The degree of liver injury was greater in FXR-/- mice compared to WT mice. Ethanol feeding enhanced hepatic steatosis in FXR-/- mice, accompanied by decreased mRNA levels of Ppar? and Srebp-1c. The expression of Lcn2 was increased by ethanol treatment, despite unchanged expression of pro-inflammatory cytokines Tnf?, Il6 and Il-1?. Furthermore, ethanol treatment altered bile acid (BA) homeostasis to a greater extent in FXR-/- mice, as well as serum and hepatic BA pool composition. The mRNA levels of hepatic Cyp7a1 and Shp, as well as intestinal Fgf15, were decreased in WT mice with ethanol feeding, which were further reduced in FXR-/- mice. Levels of both primary and secondary BAs were markedly elevated in FXR-/- mice, which were further increased after ethanol treatment. Moreover, hepatic MAPK signaling pathways were disturbed presumably by increased hepatic BA levels. In summary, FXR deficiency increased hepatic steatosis and altered BA pool composition, contributing to worsened liver toxicity.

SUBMITTER: Kong B

PROVIDER: S-EPMC6451669 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

FXR deficiency alters bile acid pool composition and exacerbates chronic alcohol induced liver injury.

Kong Bo B Zhang Min M Huang Mingxing M Rizzolo Dan D Armstrong Laura E LE Schumacher Justin D JD 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 20190129 4

Recent studies have investigated the roles of FXR deficiency in the pathogenesis of alcoholic liver disease (ALD). However, the underlying molecular mechanisms remain unclear. In this study, FXR knockout (FXR-/-) and wild-type (WT) mice were subjected to chronic-plus-binge alcohol feeding to study the effect of FXR deficiency on ALD development. The degree of liver injury was greater in FXR-/- mice compared to WT mice. Ethanol feeding enhanced hepatic steatosis in FXR- ...[more]

PMID: 30803859

Similar Datasets

Project description:Background & aimsBile-acid metabolism and the intestinal microbiota are impaired in alcohol-related liver disease. Activation of the bile-acid receptor TGR5 (or GPBAR1) controls both biliary homeostasis and inflammatory processes. We examined the role of TGR5 in alcohol-induced liver injury in mice.MethodsWe used TGR5-deficient (TGR5-KO) and wild-type (WT) female mice, fed alcohol or not, to study the involvement of liver macrophages, the intestinal microbiota (16S sequencing), and bile-acid profiles (high-performance liquid chromatography coupled to tandem mass spectrometry). Hepatic triglyceride accumulation and inflammatory processes were assessed in parallel.ResultsTGR5 deficiency worsened liver injury, as shown by greater steatosis and inflammation than in WT mice. Isolation of liver macrophages from WT and TGR5-KO alcohol-fed mice showed that TGR5 deficiency did not increase the pro-inflammatory phenotype of liver macrophages but increased their recruitment to the liver. TGR5 deficiency induced dysbiosis, independently of alcohol intake, and transplantation of the TGR5-KO intestinal microbiota to WT mice was sufficient to worsen alcohol-induced liver inflammation. Secondary bile-acid levels were markedly lower in alcohol-fed TGR5-KO than normally fed WT and TGR5-KO mice. Consistent with these results, predictive analysis showed the abundance of bacterial genes involved in bile-acid transformation to be lower in alcohol-fed TGR5-KO than WT mice. This altered bile-acid profile may explain, in particular, why bile-acid synthesis was not repressed and inflammatory processes were exacerbated.ConclusionsA lack of TGR5 was associated with worsening of alcohol-induced liver injury, a phenotype mainly related to intestinal microbiota dysbiosis and an altered bile-acid profile, following the consumption of alcohol.Lay summaryExcessive chronic alcohol intake can induce liver disease. Bile acids are molecules produced by the liver and can modulate disease severity. We addressed the specific role of TGR5, a bile-acid receptor. We found that TGR5 deficiency worsened alcohol-induced liver injury and induced both intestinal microbiota dysbiosis and bile-acid pool remodelling. Our data suggest that both the intestinal microbiota and TGR5 may be targeted in the context of human alcohol-induced liver injury.

Dataset Information

FXR deficiency alters bile acid pool composition and exacerbates chronic alcohol induced liver injury.

Publications

FXR deficiency alters bile acid pool composition and exacerbates chronic alcohol induced liver injury.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets