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

Autor: Kasahara N; Laboratory of Nutritional Physiology, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka, 422-8526, Japan., Imi Y; Laboratory of Nutritional Physiology, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka, 422-8526, Japan., Amano R; Laboratory of Nutritional Physiology, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka, 422-8526, Japan., Shinohara M; Division of Molecular Epidemiology, Department of Future Medicine Sciences, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan.; The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan., Okada K; Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan., Hosokawa Y; Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan., Imamori M; Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan., Tomimoto C; Noster Inc., Muko-Shi, Kyoto, 617-0006, Japan., Kunisawa J; Laboratory of Vaccine Materials and Laboratory of Gut Environmental System, Microbial Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBIOHN), Osaka, 567-0085, Japan., Kishino S; Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-Ku, Kyoto, 606-8502, Japan., Ogawa J; Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-Ku, Kyoto, 606-8502, Japan., Ogawa W; Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan., Hosooka T; Laboratory of Nutritional Physiology, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka, 422-8526, Japan. thosooka@u-shizuoka-ken.ac.jp.; Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan. thosooka@u-shizuoka-ken.ac.jp.; Laboratory of Vaccine Materials and Laboratory of Gut Environmental System, Microbial Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBIOHN), Osaka, 567-0085, Japan. thosooka@u-shizuoka-ken.ac.jp.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Nov 03; Vol. 13 (1), pp. 18983. Date of Electronic Publication: 2023 Nov 03.
DOI: 10.1038/s41598-023-46404-5
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje