Tangeretin Unravels Metabolic Dysfunction-Associated Fatty Liver Disease in Rats by Enhancing the IRS/Akt Pathway

Excessive high-fat diet (HFD) intake can precipitate metabolic dysfunction-associated fatty liver disease (MAFLD). Tangeretin is a citrus flavonoid possessing many biological properties. We examined the impact of tangeretin on MAFLD and its underlying mechanism. Rats were given HFD plus 15% fructose solution for four months to produce metabolic syndrome. Metabolic syndrome rats were administered 100 mg/kg of metformin or 25 mg/kg of tangeretin for the last four weeks. HFD-induced increased body weight, liver weight, adipose tissue weight, fasting blood glucose, serum insulin, total triglyceride, total cholesterol, and free fatty acids and reduced adiponectin and high-density lipoprotein cholesterol levels in metabolic syndrome, which were alleviated by tangeretin (p < 0.05). Tangeretin stabilized alanine transaminase activity, liver catalase, and inflammatory and oxidative stress markers in HFD rats compared to untreated HFD rats (p < 0.05). Tangeretin reduced hepatic steatosis induced by HFD. Downregulation of hepatic insulin receptor substrate-1 (IRS-1) and protein kinase B (Akt) protein expression in metabolic syndrome rats was recovered by tangeretin (p < 0.05). Metformin, an antihyperglycemic drug, produced comparable effects to tangeretin. In conclusion, tangeretin attenuates metabolic disorders and fatty liver induced by HFD in rats. The underlying mechanisms involve reducing oxidative stress, and inflammation and enhancing insulin sensitivity.