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Deletion of IFN? enhances hepatocarcinogenesis in FXR knockout mice.

ABSTRACT: Liver tumor, especially hepatocellular carcinoma (HCC), is closely associated with chronic inflammation. We previously showed that farnesoid X receptor knockout (FXR(-)(/)(-)) mice displayed chronic inflammation and developed spontaneous liver tumors when they aged. However, the mechanism by which inflammation leads to HCC in the absence of FXR is unclear. Because IFN? is one of the most upregulated pro-inflammatory cytokines in FXR(-)(/)(-) livers, we generated IFN?(-)(/)(-)FXR(-)(/)(-) double knockout mice to determine IFN?'s roles in hepatocarcinogenesis.IFN?(-)(/)(-) mice were crossed with an FXR(-)(/)(-) C57BL/6 background or injected i.p. with the hepatocarcinogen diethylnitrosamine (DEN). Hepatocarcinogenesis was analyzed with biochemical and histological methods.IFN? deletion accelerated spontaneous hepatocarcinogenesis in FXR(-)(/)(-) mice and increased the susceptibility to DEN-induced hepatocarcinogenesis. IFN? deletion enhanced activation of HCC promoters STAT3 and JNK/c-Jun, but abolished induction of p53 in IFN?(-)(/)(-) livers after acute DEN-induced injury. Furthermore, hepatic p53 expression increased in aged wild type mice but not in aged IFN?(-)(/)(-) and IFN?(-)(/)(-)FXR(-)(/)(-) mice, while activation of STAT3 and JNK/c-Jun was enhanced in aged IFN?(-)(/)(-) and IFN?(-)(/)(-)FXR(-)(/)(-) mice. In addition, IFN? inhibited liver cancer xenograft growth and impaired IL-6-induced STAT3 phosphorylation by inducing SOCS1/3 expression.Increased IFN? expression in FXR(-)(/)(-) livers represents a protective response of the liver against chronic injury and tumorigenesis. IFN? suppresses hepatocarcinogenesis by inducing p53 expression and preventing STAT3 activation.

SUBMITTER: Meng Z

PROVIDER: S-EPMC3477276 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice.

Meng Zhipeng Z Wang Xiaoqiong X Gan Yichao Y Zhang Yunfeng Y Zhou Hong H Ness Carl Van CV Wu Jun J Lou Guiyu G Yu Hua H He Chao C Xu Rongzhen R Huang Wendong W

Journal of hepatology 20120621 5

<h4>Background & aims</h4>Liver tumor, especially hepatocellular carcinoma (HCC), is closely associated with chronic inflammation. We previously showed that farnesoid X receptor knockout (FXR(-)(/)(-)) mice displayed chronic inflammation and developed spontaneous liver tumors when they aged. However, the mechanism by which inflammation leads to HCC in the absence of FXR is unclear. Because IFNγ is one of the most upregulated pro-inflammatory cytokines in FXR(-)(/)(-) livers, we generated IFNγ(-) ...[more]

PMID: 22728874

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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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Deletion of IFN? enhances hepatocarcinogenesis in FXR knockout mice.

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Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice.

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