Natural small molecule hinokitone mitigates NASH fibrosis by targeting regulation of FXR-mediated hepatocyte apoptosis.

Autor:	Ma ZJ; Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing 100191, China; Department of Physiology, School of Basic Medical Sciences, Xinjiang Second Medical College, Karamay, China., Qiu YK; Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China., Yu ZW; Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, China; Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China., Song TT; Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing 100191, China., Hu YT; Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing 100191, China., Peng AK; Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing 100191, China; Department of Cardiology, Pu'er People's Hospital, Yunnan, China., Qi R; Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing 100191, China. Electronic address: ronaqi@bjmu.edu.cn.
Jazyk:	angličtina
Zdroj:	Journal of advanced research [J Adv Res] 2024 Dec 13. Date of Electronic Publication: 2024 Dec 13.
DOI:	10.1016/j.jare.2024.12.016
Abstrakt:	Introduction: Liver fibrosis is the common fate of NASH and poses a major health threat with very limited pharmacological treatments. Objectives: This study aims to investigate the preventive effect of hinokitone (HO), an isolated compound from Agathis dammara, on NASH fibrosis and its underlying mechanism. Methods: To investigate the effect of HO on NASH fibrosis, C57BL/6 mice were either fed a high-fat diet (HFD) in conjunction with intraperitoneal injection of CCl 4 for 8 weeks or single CCl 4 for 14 days to establish mouse liver fibrosis model, and HO was administered by gavage simultaneously. To elucidate the underlying mechanisms, HepG2 cells were stimulated by palmitic acid (PA) or tumor necrosis factor α plus actinomycin-D (Act-D + TNFα) to induce hepatocyte apoptosis model. Furthermore, hepatocyte Farnesoid-X-receptor (FXR) specifically knocked out mice were established by the albumin-Cre-loxP recombination enzyme system to ascertain the role of FXR in the anti-NASH fibrosis effects of HO. Results: The results showed that HO presented dose-dependent anti-liver fibrosis efficacy in NASH mice induced by HFD + CCl 4 and CCl 4 -induced mouse liver fibrosis. Cellularly, HO significantly inhibited PA-induced lipotoxic apoptosis and Act-D + TNFα-induced exogenous apoptosis in hepatocytes, which in turn prevented HSC activation. Mechanistically, bioinformatics analysis and surface plasmon resonance assay had identified hepatocyte FXR as a target of HO. Specifically, HO directly bound to FXR and upregulated its protein level by inhibiting proteasomal degradation. In turn, HO attenuated hepatocyte lipid deposition through upregulating the FXR's downstream target genes SHP and CES1, and reduced cleaved-CASP8 level, thereby inhibiting hepatocyte apoptosis. Furthermore, HO lost its function in the inhibition of hepatocyte apoptosis and liver fibrosis when knockout hepatocyte FXR. Conclusion: In conclusion, HO has an inhibitory effect on NASH fibrosis. This effect is mediated by targeting upregulation of hepatocyte FXR, which in turn attenuates hepatocyte apoptosis and thus indirectly inhibits the activation of HSCs. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Published by Elsevier B.V.)
Databáze:	MEDLINE
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