Scopoletin ameliorates hyperlipidemia and hepatic steatosis via AMPK, Nrf2/HO-1 and NF-κB signaling pathways

Jianxiu Zhang; Yilin Yuan; Xiaoyan Gao; Hui Li; Fengxia Yuan; Di Wu; Qinglong Cui; Guangchun Piao; Haidan Yuan

doi:10.1016/j.bcp.2024.116639

Scopoletin ameliorates hyperlipidemia and hepatic steatosis via AMPK, Nrf2/HO-1 and NF-κB signaling pathways

Biochem Pharmacol. 2024 Nov 19:116639. doi: 10.1016/j.bcp.2024.116639. Online ahead of print.

Authors

Jianxiu Zhang¹, Yilin Yuan¹, Xiaoyan Gao¹, Hui Li¹, Fengxia Yuan¹, Di Wu¹, Qinglong Cui¹, Guangchun Piao², Haidan Yuan³

Affiliations

¹ Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China.
² Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China. Electronic address: gcpiao@ybu.edu.cn.
³ Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China. Electronic address: hdyuan@ybu.edu.cn.

PMID: 39571916
DOI: 10.1016/j.bcp.2024.116639

Abstract

Scopoletin (SC) is one of the important phenolic coumarin constituents derived from many edible plants and fruits, and exerts a wide range of biological activities. In the present study, we investigated the effects of SC on tyloxapol (TY)-induced hyperlipidemia and hepatic steatosis in C57BL/6j mice and free fatty acid (FFA) 0.5 mM-stimulated lipid accumulation in human L02 cells. Our results showed that TY injection significantly increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL-C) as well as malondialdehyde (MDA) in the livers of the mice (p < 0.001, respectively), and decreased serum levels of high density lipoprotein (HDL-C), IL-10 levels as well as superoxide dismutase (SOD) in the livers (p < 0.001, respectively). On the other hand, SC pretreatment reversed these changes. SC obviously alleviated TY-induced liver steatosis by upregulating the AMP-activated kinase (AMPK), acetyl-CoA carboxylase (ACC) phosphorylation, and significantly downregulated sterol regulatory element binding protein (SREBP)1c and fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1), Lipin 1, phospho-hormone-sensitive triglyceride lipase (p-HSL) proteins and SREBP-2, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) mRNA expressions. In the meantime, SC upregulated the expressions of the lipolysis-associated genes LDL receptor (LDLR), adipose triglyceride lipase (ATGL), and HSL. In addition, SC significantly inhibited TNF-α, F4/80, caspase-1 (cas-1), cas-1p10, IL-1β, Kelch-like ECH-associated protein 1 (Keap1) expressions, nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) translocation, and increased heme oxygenase 1 (HO-1) expressions in TY-induced hyperlipidemia and hepatic steatosis mice. The in vivo results were similar to that those in the in vitro experiment, for example, SC markedly lowered TG and TC levels and protected lipid accumulation via AMPK, NF-κB, and Nrf2/HO-1 signaling pathway in FFA-induced L02 cells. These results indicate that SC has protective potential against hyperlipidemia and hepatic steatosis, and the underlying mechanism may be closely associated with AMPK activation and Nrf2/HO-1 and NF-κB inhibition.

Keywords: Hyperlipidemia; Inflammation; Non-alcoholic fatty liver disease (NAFLD); Scopoletin; Tyloxapol.