α,β-Amyrin prevents steatosis and insulin resistance in a high-fat diet-induced mouse model of NAFLD via the AMPK-mTORC1-SREBP1 signaling mechanism

Abstract

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatosteatosis and steatohepatitis, is intrinsically related to obesity. Our previous study reported on the anti-obese activity of a,b-amyrin (AMY), a pentacyclic triterpene isolated from Protium heptaphyllum. This study investigated its ability to prevent fatty liver and the underlying mechanism using the mouse model of NAFLD. NAFLD was induced in male Swiss mice fed a high fat diet (HFD) for 15 weeks. The controls were fed a normal chow diet (ND). The mice were simultaneously treated with AMY at 10 and 20 mg/kg or fenofibrate at 50 mg/kg. Lipid levels along with metabolic and inflammatory parameters were assessed in liver and serum. The liver sections were histologically examined using H&E staining. RT-qPCR and western blotting assays were performed to analyze signaling mechanisms. Mice fed HFD developed severe hepatic steatosis with elevated triglycerides and lipid droplets compared with ND controls. This was associated with a decrease in AMP-activated protein kinase (AMPK) activity, an increase of mechanistic target of rapamycin complex 1 (mTORC1) signaling, and enhanced sterol regulatory element binding protein 1 (SREBP1) expression, which have roles in lipogenesis, inhibition of lipolysis, and inflammatory response. AMY treatment reversed these signaling activities and decreased the severity of hepatic steatosis and inflammatory response, evidenced by serum and liver parameters as well as histological findings. AMY-induced reduction in hepatic steatosis seemed to involve AMPK-mTORC1-SREBP1 signaling pathways, which supported its beneficial role in the prevention and treatment of NAFLD.

The Focus on Core Genetic Factors That Regulate Hepatic Injury in Cattle Seems to Be Important for the Dairy Sector’s Long-Term Development

“…Some of these symptoms closely reflect periparturient-period reactions that we and others have seen, as well as reactions to endotoxin treatment [89,90]. Since proinflammatory and signaling genes are upregulated in the liver of mice that have been induced to develop fatty liver and insulin resistance by high-fat diets, TNFA upregulation in liver macrophages may act in a paracrine manner and cause potent upregulation of SAA1 in hepatocytes [91,92]. Increased inflammation during the formation of fatty livers in transition dairy cows may be caused by NF-B-mediated proinflammatory signals [93].…”

Reducing VEGFB accelerates NAFLD and insulin resistance in mice via inhibiting AMPK signaling pathway

“…Studies have shown that exercise and diet intervention participated in the circulation through AMPK dependent pathway to promote fat phagocytosis of the liver and improve the aging process of the liver, which has become the therapeutic target of NAFLD [ 22 ]. Lima et al found that activating AMPK for phosphorylation can inhibit adipogenesis, promote lipolysis and prevent the development of NAFLD [ 23 ].…”

AMPK/mTOR pathway significance in healthy liver and non‐alcoholic fatty liver disease and its progression

“…7 Excessive deposition of free fatty acids, triacylglycerol, and cholesterol in the liver leads to a positive energy balance triggering a series of toxic effects on the liver, such as hepatic steatosis, inflammation, endoplasmic reticulum (ER) stress, autophagy, and apoptosis. 8 Liver lipids accumulation is the most influential factor in the development and progression of NAFLD. The evolution from simple hepatic steatosis to more severe liver diseases is accompanied by cellular damage in hepatocytes and inflammation.…”