Honokiol Acts as a Potent Anti-Fibrotic Agent in the Liver through Inhibition of TGF-beta 1/SMAD Signaling and Autophagy in Hepatic Stellate Cells

• Type of Material: Article
• Authors: Seita Kataoka, Kyoto Prefectural University of Medicine; Atsushi Umemura, Kyoto Prefectural University of Medicine; Keiichiro Okuda, Kyoto Prefectural University of Medicine; Hiroyoshi Taketani, Kyoto Prefectural University of Medicine; Yuya Seko, Kyoto Prefectural University of Medicine; Taichiro Nishikawa, Kyoto Prefectural University of Medicine; Kanji Yamaguchi, Kyoto Prefectural University of Medicine; Michihisa Moriguchi, Kyoto Prefectural University of Medicine; Yoshihiro Kanbara, Saiseikai Suita Hospital; Jack Arbiser, Emory University; Toshihide Shima, Saiseikai Suita Hospital; Takeshi Okanoue, Saiseikai Suita Hospital; Yoshito Itoh, Kyoto Prefectural University of Medicine
• Language: English
• Date: 2021-12-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/ijms222413354
• Title of Journal or Parent Work: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• Volume: 22
• Issue: 24
• Grant/Funding Information: This research was supported by research grants from JSPS KAKENHI #19K08377 (A.U.), AMED #JP19fk0210059 (A.U.), #JP18fk0210027 (K.Y. and Y.I.), #JP19fk0210040 (T.O.), #JP18fk0210040 (Y.I.).
• Keywords: Biochemistry & Molecular Biology; IN-VITRO; Chemistry; autophagy; PATHWAY; FIBROSIS; Life Sciences & Biomedicine; Science & Technology; Chemistry, Multidisciplinary; honokiol; ACTIVATION; Physical Sciences; APOPTOSIS; stellate cell; hepatic fibrosis; VIVO; DEATH; INDUCTION; GROWTH-FACTOR-BETA
• Research Categories: Health Sciences, Pharmacology

Abstract

Chronic liver injury may result in hepatic fibrosis, which can progress to cirrhosis and eventually liver failure. There are no drugs that are specifically approved for treating hepatic fibrosis. The natural product honokiol (HNK), a bioactive compound extracted from Magnolia grandiflora, represents a potential tool in the management of hepatic fibrosis. Though HNK has been reported to exhibit suppressive effects in a rat fibrosis model, the mechanisms accounting for this suppression remain unclear. In the present study, the anti-fibrotic effects of HNK on the liver were evaluated in vivo and in vitro. In vivo studies utilized a murine liver fibrosis model, in which fibrosis is induced by treatment with carbon tetrachloride (CCl4 ). For in vitro studies, LX-2 human hepatic stellate cells (HSCs) were treated with HNK, and expression of markers of fibrosis, cell viability, the transforming growth factor-β (TGF-β1)/SMAD signaling pathway, and autophagy were analyzed. HNK was well tolerated and significantly attenuated CCl4-induced liver fibrosis in vivo. Moreover, HNK decreased HSC activation and collagen expression by downregulating the TGF-β1/SMAD signaling pathway and autophagy. These results suggest that HNK is a new potential candidate for the treatment of hepatic fibrosis through suppressing both TGF-β1/SMAD signaling and autophagy in HSCs.