Oxymatrine reduces hepatic lipid synthesis in rat models of nonalcoholic steatohepatitis by regulating Sirt1/AMPK and LXR/Plin2/SREBP-1c pathways

Jingfang Xiong; Gaofeng Chen; Ying He; Changqing Zhao; Dongya Chen; Yihui Liu; Zhaolin Zhang; Yijun Wu; Hong Xu

doi:10.1016/j.cbi.2024.111370

Oxymatrine reduces hepatic lipid synthesis in rat models of nonalcoholic steatohepatitis by regulating Sirt1/AMPK and LXR/Plin2/SREBP-1c pathways

Chem Biol Interact. 2024 Dec 31:111370. doi: 10.1016/j.cbi.2024.111370. Online ahead of print.

Authors

Jingfang Xiong¹, Gaofeng Chen², Ying He³, Changqing Zhao⁴, Dongya Chen⁵, Yihui Liu⁵, Zhaolin Zhang⁵, Yijun Wu⁶, Hong Xu⁷

Affiliations

¹ Department of Geriatrics, Hangzhou Red Cross Hospital, Hangzhou, China, 310003.
² Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China, 201203.
³ Department of Pharmacy, Hangzhou Red Cross Hospital, Hangzhou, China, 310003.
⁴ Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China, 201203; Department of Hepatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China, 201203.
⁵ Department of Gastroenterology and Hepatology, Hangzhou Red Cross Hospital, Hangzhou, China, 310003.
⁶ The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China, 310053.
⁷ Department of Gastroenterology and Hepatology, Hangzhou Red Cross Hospital, Hangzhou, China, 310003. Electronic address: [email protected].

PMID: 39746502
DOI: 10.1016/j.cbi.2024.111370

Abstract

Nonalcoholic Steatohepatitis (NASH) is a common liver disease with limited treatment options. Oxymatrine (OMT) has been reported to treat liver diseases effectively. This study aims to explore the mechanisms of OMT in NASH. Male Sprague-Dawley rats were fed a high-fat and high-sucrose diet and hepatocytes were stimulated with oleic acid (OA) to establish NASH models, then, NASH models were intervened with OMT. In vivo, liver injury and lipid accumulation extents were evaluated by serum and liver biochemical indexes, and histological analysis. In vitro, cell viability and lipid accumulation degrees were measured. Additionally, the relationships between perilipin 2 (Plin2) and liver X-activated receptor alpha (LXRa) as well as Plin2 and sterol regulatory element binding protein-1c (SREBP-1c), sirtuin 1 (Sirt1)/adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway-, liver X-activated receptor (LXR)/Plin2/SREBP-1c pathway- and lipid synthesis-related proteins were detected both in vivo and in vitro. Finally, Sirt1 was knocked down in hepatocytes. OMT not only reduced serum alanine aminotransferase activity and triglyceride content, liver triglyceride and free fatty acid levels in NASH rats, but also improved hepatic injury and lipid accumulation. In vitro, OMT enhanced viability, and downregulated lipid accumulation in OA-induced hepatocytes. Both in vivo and in vitro results revealed Plin2 directly interacted with LXRa and SREBP-1c, and OMT activated Sirt1/AMPK pathway but inhibited the expressions of LXR/Plin2/SREBP-1c pathway and lipid synthesis (acetyl-CoA carboxylase, fatty acid synthase, stearoyl-Coenzyme A desaturase 1) related proteins in NASH models. Importantly, Sirt1 knockdown reversed the protective effects of OMT in OA-stimulated hepatocytes. OMT may reduce hepatic lipid synthesis in NASH by activating the Sirt1/AMPK pathway and inhibiting the LXR/Plin2/SREBP-1c pathway, suggesting that OMT may be a promising strategy for treating NASH.

Keywords: Oxymatrine; hepatic lipid synthesis; liver X-activated receptor/perilipin 2/sterol regulatory element binding protein-1c pathway; non-alcoholic fatty liver disease; sirtuin 1/adenosine 5‘-monophosphate-activated protein kinase pathway.