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

• Published in: Scientific reports Vol. 13; no. 1; p. 18983
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03-11-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 692/308/2778; 692/4017; Acids; Adipose tissue; Bacteria; Diabetes mellitus; Extracellular matrix; Fatty liver; Fibrosis; Gene expression; Genes; High fat diet; Histology; Humanities and Social Sciences; Inflammation; Insulin resistance; Intestinal microflora; Lactic acid bacteria; Linoleic acid; Liver; Liver diseases; Metabolites; Microbiota; multidisciplinary; Phosphorylation; Pioglitazone; Science; Science (multidisciplinary); Smad3 protein; Steatosis; Stellate cells; Transforming growth factor-b
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-46404-5

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.