Yangonin protects against non-alcoholic fatty liver disease through farnesoid X receptor

• Published in: Phytomedicine (Stuttgart) 2019-02, Vol.53, p.134-142
• Main Authors: Dong, Renchao, Yang, Xiaobo, Wang, Changyuan, Liu, Kexin, Liu, Zhihao, Ma, Xiaodong, Sun, Huijun, Huo, Xiaokui, Fu, Ting, Meng, Qiang
• Format: Article
• Language: English
• Subjects: Animals; Diet, High-Fat - adverse effects; FXR; Gluconeogenesis - drug effects; Glucose - metabolism; Glucose homeostasis; Glycogen - metabolism; Insulin - metabolism; Insulin Resistance; Lipid homeostasis; Lipid Metabolism - drug effects; Lipid Metabolism - genetics; Lipogenesis - drug effects; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice, Inbred C57BL; NAFLD; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - prevention & control; Protective Agents - pharmacology; Pyrones - pharmacology; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Triglycerides - blood; Triglycerides - metabolism; Yangonin
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2018.09.006

Non-alcoholic fatty liver disease (NAFLD) is currently evolving as the most common liver disease worldwide. Dyslipidemia, pathoglycemia and insulin resistance are the major risk factors for the development of NAFLD. To date, no effective drug therapies for this condition have been approved. The present study was to investigate the protective effects of yangonin, a kavalactone isolated from Kava, against NAFLD and further elucidate the mechanisms in vivo and in vitro. A high-fat diet (HFD) induced mouse NAFLD model was used with or without yangonin treatment. The body weight, relative liver weight and serum biochemical indicators were measured. H&E and Oil Red O staining were used to identify the amelioration of the liver histopathological changes. Serum and hepatic triglyceride, free fatty acids and total cholesterol were analyzed. siRNA, quantitative real-time PCR and Western blot assay were used to clarify the mechanisms underlying yangonin protection. Yangonin had obvious protective effects against NAFLD via farnesoid X receptor (FXR) activation. Through FXR activation, yangonin attenuated lipid accumulation in the liver via inhibition of hepatic lipogenesis-related protein including sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthetase (FAS), acetyl-CoA carboxylase 1 (ACC1) and stearoyl-CoA desaturase 1 (SCD1). Besides, yangonin promoted lipid metabolism through an induction in genes required for lipoprotein lipolysis and fatty acid β-oxidation. Furthermore, yangonin modulated blood glucose homeostasis through regulation of gluconeogenesis-related gene phosphoenol pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), and glycogen synthesis-related gene glycogen synthase kinase 3β (GSK3β) and pyruvate dehydrogenase (PDase). Also, yangonin increased insulin sensitivity through upregulating phosphorylation of insulin responsive substrate 1, 2 (IRS-1 and IRS-2). Then, in vivo and in vitro evidence further demonstrated the involvement of FXR activation in yangonin hepatoprotection. Yangonin protects against NAFLD due to its activation of FXR signalling to inhibit hepatic lipogenesis and gluconeogenesis, and to promote lipid metabolism and glycogen synthesis, as well as insulin sensitivity. [Display omitted]