| Summary: | 博士 === 臺北醫學大學 === 醫學科學研究所 === 100 === Obesity and diseases associated with obesity such as dyslipidemia, fatty liver, non-alcoholic steatotic hepatitis, and metabolic syndrome are increasingly important causes of morbidity and mortality in the general population worldwide. Sirtuin 1 (SIRT1) is a longevity-associated protein, which regulates energy metabolism and lifespan in response to nutrient deprivation. SIRT1 was proposed to be a therapeutic target for obesity and metabolic syndrome. Alpha-lipoic acid (ALA) is a powerful antioxidant, which has been shown to decrease hypothalamic AMPK and thus appetite, and exerts anti-obesity effects. More importantly, ALA activates AMPK signaling pathway in a variety of cells. In the present study, we investigated whether ALA exerts a lipid-lowering effect through regulation of SIRT1 activation and expression in C2C12 myotubes. ALA increased the NAD+-to-NADH ratio to enhance SIRT1 activity and expression in C2C12 myotubes. After deacetylation of LKB-1 by activated SIRT1, ALA increased AMPK and ACC phosphorylation, which increased palmitate β-oxidation in C2C12 myotubes. Treatment of cells with nicotinamide, or transfection with SIRT1 siRNA reduced ALA-mediated AMPK/ACC phosphorylation and palmitate β-oxidation suggesting that SIRT1 is an upstream regulator of AMPK. ALA increased ATGL and suppressed FAS protein expressions, leading to a decrease of intracellular triacylglycerol accumulation in C2C12 myotubes. Oral administration of ALA in type 2 diabetic mice fed a high-fat diet and db/db mice dramatically reduced the body weight and visceral fat content. ALA activates both SIRT1 and AMPK and leads to lipid lowering effects in vitro and in vivo. These findings suggest that ALA may exert beneficial effects in the treatment of dyslipidemia and obesity.
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