Journal Article

Dihydromyricetin ameliorates hepatic steatosis and insulin resistance via AMPK/PGC-1α and PPARα-mediated autophagy pathway

Yang, Yan, Ren, Xuan, Xiao, Jiyuan, Sun, Jie, Jiang, Luxia, Qiu, Wen

2024

Overview

Background Dihydromyricetin (DHM), a flavonoid compound of natural origin, has been identified in high concentrations in ampelopsis grossedentata and has a broad spectrum of biological and pharmacological functions, particularly in regulating glucose and lipid metabolism. The objective of this research was to examine how DHM affected nonalcoholic fatty liver disease (NAFLD) and its underlying mechanisms involved in the progression of NAFLD in a rat model subjected to a high-fat diet (HFD). Additionally, the study examines the underlying mechanisms in a cellular model of steatohepatitis using palmitic acid (PA)-treated HepG2 cells, with a focus on the potential correlation between autophagy and hepatic insulin resistance (IR) in the progress of NAFLD. Methods SD rats were exposed to a HFD for a period of eight weeks, followed by a treatment with DHM (at doses of 50, 100, and 200 mg·kg −1 ·d −1 ) for additional six weeks. The HepG2 cells received a 0.5 mM PA treatment for 24 h, either alone or in conjunction with DHM (10 µM). The histopathological alterations were assessed by the use of Hematoxylin–eosin (H&E) staining. The quantification of glycogen content and lipid buildup in the liver was conducted by the use of PAS and Oil Red O staining techniques. Serum lipid and liver enzyme levels were also measured. Autophagic vesicle and autolysosome morphology was studied using electron microscopy. RT-qPCR and/or western blotting techniques were used to measure IR- and autophagy-related factors levels. Results The administration of DHM demonstrated efficacy in ameliorating hepatic steatosis, as seen in both in vivo and in vitro experimental models. Moreover, DHM administration significantly increased GLUT2 expression, decreased G6Pase and PEPCK expression, and improved IR in the hepatic tissue of rats fed a HFD and in cells exhibiting steatosis. DHM treatment elevated Beclin 1, ATG 5, and LC3-II levels in hepatic steatosis models, correlating with autolysosome formation. The expression of AMPK levels and its downstream target PGC-1α, and PPARα were decreased in HFD-fed rats and PA-treated hepatocytes, which were reversed through DHM treatment. AMPK/ PGC-1α and PPARα knockdown reduced the impact of DHM on hepatic autophagy, IR and accumulation of hepatic lipid. Conclusions Our findings revealed that AMPK/ PGC-1α, PPARα-dependent autophagy pathways in the pathophysiology of IR and hepatic steatosis has been shown, suggesting that DHM might potentially serve as a promising treatment option for addressing this disease. Graphical Abstract

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: AMP-Activated Protein Kinases - metabolism / Animals / Autophagy / Biomedical and Life Sciences / Biomedicine / Cholesterol / Diet / Diet, High-Fat / Dihydromyricetin / Drug dosages / Electron microscopy / Fatty liver / Flavonoids / Flavonols / Glucose / Glucose metabolism / Glucose transporter / Glycogen / Hepatocytes / High fat diet / Homeostasis / Insulin resistance / Insulin Resistance - physiology / Lipid Metabolism / Liver / Liver - pathology / Liver diseases / Liver steatosis / Medicine/Public Health / Mice / Mice, Inbred C57BL / Non-alcoholic Fatty Liver Disease - pathology / Nutrition & metabolism / Palmitic acid / Palmitic Acid - metabolism / Palmitic Acid - pharmacology / Palmitic Acid - therapeutic use / PPAR alpha - metabolism / Rats / Rats, Sprague-Dawley / Sample size / Steatosis / Western blotting