Naringenin ameliorates MASH fibrosis via regulating TAK1/MAPK/FoxO3a-mediated apoptosis in the activated hepatic stellate cells.

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. Electronic address: 18811331959@163.com., Yue SS; 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; School of Basic Medical Science, Shihezi University, Shihezi, 83200, Xinjiang, China. Electronic address: yueshanshan@bjmu.edu.cn., Qin BY; 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: 603779536@qq.com., 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. Electronic address: 2010122417@stu.pku.edu.cn., 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. Electronic address: pengak@126.com., Wang QY; 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: wangqinyu808@163.com., 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; School of Basic Medical Science, Shihezi University, Shihezi, 83200, Xinjiang, China. Electronic address: ronaqi@bjmu.edu.cn.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 Nov 19; Vol. 734, pp. 150732. Date of Electronic Publication: 2024 Sep 21.
DOI: 10.1016/j.bbrc.2024.150732
Abstrakt: This study aims to explore the regulating effect and mechanism of naringenin (NGN) on the hepatic stellate cells (HSCs) apoptosis and its preventive effects on MASH fibrosis. C57BL/6 mice were subjected to either high-fat diet (HFD) plus carbon tetrachloride (CCl 4 ) injection (HFD + CCl 4 ) for 8 weeks to induce a MASH fibrosis model or bile duct ligation (BDL) to establish a liver fibrosis model, NGN was administered by gavage. LX2 cells were stimulated by oleic acid (OA) and lipopolysaccharide (LPS) (OA + LPS) to study the effects of NGN on activated hepatic stellate cell (HSC). Additionally, LO2 cells stimulated with OA + LPS were used to assess the protective effects of NGN on lipotoxicity of hepatocytes. Our in vivo results showed that NGN administration effectively inhibited mouse liver fibrosis in both of the MASH model and BDL model. The in vitro results indicate that NGN directly inhibited HSCs activation and promoted apoptosis of the activated HSCs, while it suppressed the apoptosis of LO2 cells induced by OA + LPS. The underlying mechanisms were mainly elucidated through the reduction of TAK1 phosphorylation, leading to the downregulation of p-JNK and p-ERK expression. This in turn, inhibited the phosphorylation of FoxO3a and promoted the nuclear localization of FoxO3a. Consequently, this may enhance the transcription of apoptosis-related genes, resulting in the apoptosis of activated HSCs. In conclusion, NGN ameliorates MASH fibrosis by enhancing apoptosis of the activated HSCs. The inhibitory effects of NGN on the TAK1/MAPK/FoxO3a pathway were demonstrated as its preventive mechanisms against MASH fibrosis.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rong Qi reports was provided by National Natural Science Foundation of China. If there are other authors, they 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 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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