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

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.