Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis

Abstract

Although simple steatosis was originally thought to be a pathologically inert histological change, fat accumulation in the liver may play a critical role not only in disease initiation, but also in the progression to nonalcoholic steatohepatitis and cirrhosis. Therefore, prevention of fat accumulation in the liver may be an effective therapy for multiple stages of nonalcoholic fatty liver disease (NAFLD). Promising beneficial effects of betaine supplementation on human NAFLD have been reported in some pilot clinical studies; however, data related to betaine therapy in NAFLD are limited. In this study, we examined the effects of betaine on fat accumulation in the liver induced by high-sucrose diet and evaluated mechanisms by which betaine could attenuate or prevent hepatic steatosis in this model. Male C57BL/6 mice weighing 20 +/- 0.5 g (means +/- SE) were divided into four groups (8 mice per group) and started on one of four treatments: standard diet (SD), SD+betaine, high-sucrose diet (HS), and HS + betaine. Betaine was supplemented in the drinking water at a concentration of 1% (wt/vol) (anhydrous). Long-term feeding of high-sucrose diet to mice caused significant hepatic steatosis accompanied by markedly increased lipogenic activity. Betaine significantly attenuated hepatic steatosis in this animal model, and this change was associated with increased activation of hepatic AMP-activated protein kinase (AMPK) and attenuated lipogenic capability (enzyme activities and gene expression) in the liver. Our findings are the first to suggest that betaine might serve as a therapeutic tool to attenuate hepatic steatosis by targeting the hepatic AMPK system.

Long-term baicalin administration ameliorates metabolic disorders and hepatic steatosis in rats given a high-fat diet

“…As the activity of AMPK correlates strongly with phosphorylation at Thr172 (p-AMPKα), we assessed the activation of AMPK by determining the phosphorylation status of AMPKα and its primary downstream target, acetyl-CoA carboxylase (ACC), using immunoblots with phospho-specific antibodies. As expected [13] , the HFD suppressed hepatic AMPKα phosphorylation (activation) and ACC phosphorylation (inactivation) ( Figure 3A and 3B). Interestingly, baicalin induced a significant recovery of phosphorylation of AMPKα and ACC in liver depressed by the HFD (Figure 3A and 3B).…”

“…Recently, polyphenols have been reported to reduce hyperlipidemia and hyperglycemia, and their effects on lipogenesis have been suggested to be mediated via activation of the AMP-activated protein kinase (AMPK) [9][10][11] . In this relation, AMPK has emerged as an important regulator of lipid metabolism at the cellular and systemic levels, and dysfunction of hepatic AMPK represents a key mechanism for hepatic lipid accumulation and hyperlipidemia with hepatic steatosis in genetically obese rodents [12,13] and in high-fat-fed mice [13] and rats [9,14] . Consistent with this observation, transgenic mice expressing constitutively active Long-term baicalin administration ameliorates metabolic disorders and hepatic steatosis in rats given a high-fat diet 1506 www.nature.com/aps Guo HX et al Acta Pharmacologica Sinica npg (CA)-AMPKα 1 in liver had reduced levels of white fat and were resistant to high-fat diet-induced obesity [15] .…”

Phosphatidylcholine functional foods and nutraceuticals: A potential approach to prevent non‐alcoholic fatty liver disease

“…Interestingly, a choline-supplemented diet decreased percentage of body fat in guinea pigs [36]. In a recent study conducted by Song et al, mice were fed high-sucrose diets with and without betaine for 16 weeks [37]. The high-sucrose only diets induced extraordinary hepatic steatosis, whereas the mice also supplemented with betaine in their drinking water had significantly reduced steatosis.…”

Mechanisms Linking Obesity, Chronic Kidney Disease, and Fatty Liver Disease

“…70,71 Rats fed high sucrose develop NAFLD in association with reduced AMPK. 72 Activation of AMPK in the liver leads to fatty acid oxidation, inhibition of glucose production, and inhibition of lipogenesis and protein synthesis. Mice with genetically engineered chronic liver disease and AMPK activation are resistant to weight gain and accumulation of liver fat when fed high-fat diets.…”