硫辛酸透過SIRT1及AMPK蛋白對脂肪代謝的調控

Alpha-Lipoic Acid Regulates Lipid Metabolism through Induction of SIRT1 and Activation of AMP-Activated Protein Kinase

陳韋陸(Weu-Lu Chen)

指導教授 ： 李宏謨

臺北醫學大學/醫學院/醫學科學研究所/博士(2011年)

https://doi.org/10.6831/TMU.2011.00029

摘要

由於飲食過剩所造成的肥胖及因肥胖而造成的脂肪肝、非酒精性脂肪性肝炎及代謝症候群(metabolic syndrome)在全世界已成為重要的健康問題。Sirtuin 1 (SIRT1) 過去被認為是一個調控壽命的相關蛋白，近年來則被認為在對能量代謝的調節上扮演重要的角色，因此SIRT1被視為是改善肥胖及代謝性症候群的治療標的。硫辛酸(α-Lipoic acid, ALA) 為一個硫化有機物的抗氧化化合物，它可以經由調控下視丘AMPK 途徑，進而抑制食慾，預防肥胖的產生。更重要的是ALA可增加細胞內的AMPK活性。在本研究中，我們證實了ALA可以透過活化SIRT1及增加SIRT1表現來達到減少脂肪堆積的效果。在肌小管細胞，我們發現ALA藉由增加NAD+/NADH的比值來加強SIRT1的活性及表現量，活化的SIRT1會將LKB-1去乙醯化而使AMPK (AMP-activated protein kinase) 和ACC (acetyl-CoA carboxylase) 磷酸化並且增加棕櫚酸的β-氧化，在細胞培養液中加入nicotinamide (SIRT1 抑制劑) 或將SIRT1 siRNA送入細胞後，均可以有效抑制ALA所引起的作用，包括AMPK/ACC的磷酸化和棕櫚酸β-氧化的增加；也就是說SIRT1是AMPK上游的調控蛋白。此外，我們也發現ALA能增加ATGL (adipose triglyceride lipase) 的蛋白表現並且抑制FAS (fatty acid synthase) 的蛋白表現來減少細胞內三酸甘油酯的堆積。在高脂飲食誘發第二型糖尿病鼠及db/db 基因轉殖鼠上，以口服方式投以ALA治療，可降低小鼠之體重和內臟脂肪的質量。本研究證實了ALA不論在體內和體外試驗均能透過活化SIRT1和AMPK來達到減少脂肪的效果；總結以上的發現，ALA可能在治療代謝症候群和肥胖上有所助益。

關鍵字

硫辛酸, AMPK, 三酸甘油酯分解酶, SIRT1

並列摘要

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.

並列關鍵字

alpha-lipoic acid, AMPK, adipose triglyceride lipase (ATGL), SIRT1

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