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A gut microbial metabolite of linoleic acid ameliorates liver fibrosis by inhibiting TGF-β signaling in hepatic stellate cells

Kasahara, Nanaho Imi, Yukiko Amano, Reina Shinohara, Masakazu Okada, Kumiko Hosokawa, Yusei Imamori, Makoto Tomimoto, Chiaki Kunisawa, Jun Kishino, Shigenobu Ogawa, Jun Ogawa, Wataru Hosooka, Tetsuya 神戸大学

2023.11.03

概要

The antidiabetic drug pioglitazone ameliorates insulin resistance by activating the transcription factor PPARγ. In addition to its blood glucose–lowering action, pioglitazone exerts pleiotropic effects including amelioration of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). The mechanism by which pioglitazone achieves this latter effect has remained unclear, however. We here show that pioglitazone administration increases the amount of linoleic acid (LA) metabolites in adipose tissue of KK-Ay mice. These metabolites are produced by lactic acid bacteria in the gut, and pioglitazone also increased the fraction of Lactobacillus in the gut microbiota. Administration of the LA metabolite HYA (10-hydroxy-cis-12-octadecenoic acid) to C57BL/6 J mice fed a high-fat diet improved liver histology including steatosis, inflammatory cell infiltration, and fibrosis. Gene ontology analysis of RNA-sequencing data for the liver revealed that the top category for genes downregulated by HYA treatment was related to extracellular matrix, and the expression of individual genes related to fibrosis was confirmed to be attenuated by HYA treatment. Mechanistically, HYA suppressed TGF-β–induced Smad3 phosphorylation and fibrosis-related gene expression in human hepatic stellate cells (LX-2). Our results implicate LA metabolites in the mechanism by which pioglitazone ameliorates liver fibrosis, and they suggest that HYA is a potential therapeutic for NAFLD/NASH.

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Acknowledgements

This work was supported, in part, by Japan Society for the Promotion of Science KAKENHI grants (21H03355

to TH). We thank C. Aoki (Kobe University) and K. Sato (University of Shizuoka) for assistance with mouse

experiments.

Author contributions

T.H. designed research; N.K., Y.I., R.A., M.S., K.O., Y.H., M.I., C.T., J.K., S.K., J.O., W.O., and T.H. performed

research; N.K., Y.I., R.A., M.S., K.O., Y.H., M.I., C.T., J.K., S.K., J.O., W.O., and T.H. analyzed data; Y.I., and T.H.

wrote the paper.

Competing interests The authors declare no competing interests.

Additional information

Supplementary Information The online version contains supplementary material available at https://​doi.​org/​

10.​1038/​s41598-​023-​46404-5.

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