Systemic Inflammation Induces Cholestasis via Upregulating a Short Variant of FTO to Remove the m6A Methylation in the 3’-UTR of Cyp7b1 mRNAs in liver

ABSTRACT: The cholestasis frequently occurs in patients with inflammatory processes. However, the mechanisms of inflammation in inducing cholestasis are still unclear. Here, by using lipopolysaccharide (LPS)-induced cholestasis mouse models, we found that most genes encoding enzymes responsible for bile acid biosynthesis were downregulated in the hepatic tissues. Notably, among these genes, only Cyp7b1 was directly reduced by LPS in hepatocytes. The content of UDCA was decreased in the liver of inflammation-model mice which might be caused by the downregulation of Cyp7b1, and UDCA supplementation could alleviate the cholestasis and liver injury caused by LPS. Mechanistically, we observed that the level of m6A methylation in the 3’-UTR of Cyp7b1 mRNA was decreased, and inhibition of m6A methylation could reduce the expression of Cyp7b1 in Hep1-6 cells. Finally, a novel short variant FTO was identified to be upregulated in the liver of mice with LPS, and knockdown of the short variant FTO could rescue the expression of Cyp7b1 by improving the m6A modification in its mRNA, and then mitigate the cholestasis and liver injury in mice with LPS treatment. Collectively, our study uncovers that LPS-induced inflammation results in cholestasis by upregulating the expression of a short variant FTO, which subsequently leads to the reduction of Cyp7b1 mRNA by removing its m6A modification at the 3’-UTR region.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse phase

PROVIDER: MTBLS10713 | MetaboLights | 2025-11-07

REPOSITORIES: MetaboLights