Abstract: To explore the effects and mechanisms of hydroxy-α-sanshool (HAS) on the redox state in insulin-resistant cells, a cell model of insulin resistance (IR) was constructed using glucose combined with free fatty acid as the inducer. After HAS intervention, intracellular total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), malondialdehyde (MDA), and superoxide dismutase (SOD) levels were measured, and the relative mRNA and protein expression of key genes associated with lipid metabolism, oxidative stress and endoplasmic reticulum stress were detected by quantitative real-time polymerase chain reaction (real-time PCR) and Western blotting. The results showed that HAS significantly up-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and its downstream antioxidant genes such as heme oxygenase 1 (HO-1), glutamate cysteine ligase modifier subunit (GCLM) and NAD(P)H quinone oxidoreductase 1 (NQO1) in HepG2 cells. HAS also induced the expression of endoplasmic reticulum stress-related proteins such as binding immunoglobulin protein (Bip), C/EBP homologous protein (CHOP), inositol-requiring enzyme (IRE), and X-box binding protein 1 (XBP1), and down-regulated the expression of key genes related to the de novo synthesis of fatty acids acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN). It was shown that HAS reduced the rate of de novo fatty acid synthesis in insulin-resistant cells and activated the Nrf2/HO-1 and protein kinase R-like endoplasmic reticulum kinase (PERK)/CHOP signaling pathways to ameliorate the imbalance of redox homeostasis.

Key words: hydroxy-α-sanshool; insulin resistance; HepG2 cells; redox homeostasis