Phloretin ameliorates hepatic steatosis through regulation of lipogenesis and Sirt1/AMPK signaling in obese mice

Abstract

Background Phloretin is isolated from apple trees and could increase lipolysis in 3T3-L1 adipocytes. Previous studies have found that phloretin could prevent obesity in mice. In this study, we investigated whether phloretin ameliorates non-alcoholic fatty liver disease (NAFLD) in high-fat diet (HFD)-induced obese mice, and evaluated the regulation of lipid metabolism in hepatocytes. Methods HepG2 cells were treated with 0.5 mM oleic acid to induce lipid accumulation, and then treated with phloretin to evaluate the molecular mechanism of lipogenesis. In another experiment, male C57BL/6 mice were fed normal diet or HFD (60% fat, w/w) for 16 weeks. After the fourth week, mice were treated with or without phloretin by intraperitoneal injection for 12 weeks. Results Phloretin significantly reduced excessive lipid accumulation and decreased sterol regulatory element-binding protein 1c, blocking the expression of fatty acid synthase in oleic acid-induced HepG2 cells. Phloretin increased Sirt1, and phosphorylation of AMP activated protein kinase to suppress acetyl-CoA carboxylase expression, reducing fatty acid synthesis in hepatocytes. Phloretin also reduced body weight and fat weight compared to untreated HFD-fed mice. Phloretin also reduced liver weight and liver lipid accumulation and improved hepatocyte steatosis in obese mice. In liver tissue from obese mice, phloretin suppressed transcription factors of lipogenesis and fatty acid synthase, and increased lipolysis and fatty acid β-oxidation. Furthermore, phloretin regulated serum leptin, adiponectin, triglyceride, low-density lipoprotein, and free fatty acid levels in obese mice. Conclusions These findings suggest that phloretin improves hepatic steatosis by regulating lipogenesis and the Sirt-1/AMPK pathway in the liver.

Flavonoid Phloretin Inhibits Adipogenesis and Increases OPG Expression in Adipocytes Derived from Human Bone-Marrow Mesenchymal Stromal-Cells

“…In the liver of these animals, phloretin inhibited lipogenesis and promoted lipolysis. Furthermore, in HepG2 cells (a human liver cancer cell line) induced with oleic acid to accumulate fat, treatment with phloretin decreased the accumulation of lipid droplets and inhibited the expression of lipogenesis-related transcription factors [37]. Similar results have also been obtained in a study with mice treated with a high-fat diet supplemented or not with phloretin.…”

“…Therefore, phloretin could act mainly in stages of adipogenesis with higher metabolic activity, favoring in part lipolysis. This has been observed in experimental models using such flavonoids, like the liver of obese mice [37] and in 3T3-L1 cells differentiated into adipocytes [35]. In addition, activation of the Wnt/β-catenin pathway has also been associated with increased lipolysis [73].…”

“…However, there are contradictory results in relation to adipogenesis. Thus, while some reports indicate that phloretin promotes adipogenesis [31][32][33][34], others indicate the opposite [35][36][37]. These studies have been conducted mainly in mouse cell models such as 3T3-L1 and ST2 preadipocytes, and porcine primary adipocytes.…”

Maternal obesity accelerated non‑alcoholic fatty liver disease in offspring mice by reducing autophagy

“…Some studies have suggested that maternal obesity is related to the onset of NAFLD in the offspring and the oxidation of their lipids ( 6 , 7 ). Previous articles have commonly used male rats that were fed a high-fat diet to establish NAFLD models ( 8 , 9 ). Borengasser et al ( 10 ) induced obesity in female Spring Dawley rats (SD) via a high fat diet.…”

Nicotinamide Riboside Enhances Endothelial Precursor Cell Function to Promote Refractory Wound Healing Through Mediating the Sirt1/AMPK Pathway

“…It has been reported that Sirt1 upregulates the expression of phosphorylated AMPK under exposure to diabetic conditions ( Karbasforooshan and Karimi, 2018 ). The Sirt1/AMPK pathway can participate in hepatic steatosis in obese mice ( Liou et al, 2020 ). Our results indicate that treatment of the NAD substrate with NR increased the expression of phosphorylated AMPK in diabetic EPCs.…”