Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, and the function is linked to cellular metabolism including mitochondrial biogenesis. Hepatic l-serine concentration is decreased significantly in fatty liver disease. We reported that the supplementation of the amino acid ameliorated the alcoholic fatty liver by enhancing l-serine-dependent homocysteine metabolism. In this study, we hypothesized that the metabolic production of NAD⁺ from l-serine and thus activation of SIRT1 contribute to the action of l-serine. To this end, we evaluated the effects of l-serine on SIRT1 activity and mitochondria biogenesis in C2C12 myotubes. l-Serine increased intracellular NAD⁺ content and led to the activation of SIRT1 as determined by p53 luciferase assay and western blot analysis of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) acetylation. l-Serine treatment increased the expression of the genes associated with mitochondrial biogenesis and enhanced mitochondrial mass and function. In addition, l-serine reversed cellular insulin resistance determined by insulin-induced phosphorylation of Akt and GLUT4 expression and membrane translocation. l-Serine-induced mitochondrial gene expression, fatty acid oxidation, and insulin sensitization were mediated by enhanced SIRT1 activity, which was verified by selective SIRT1 inhibitor (Ex-527) and siRNA directed to SIRT1. l-Serine effect on cellular NAD⁺ level is dependent on the l-serine metabolism to pyruvate that is subsequently converted to lactate by lactate dehydrogenase. In summary, these data suggest that l-serine increases cellular NAD⁺ level and thus SIRT1 activity in C2C12 myotubes.

中文翻译：

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L-丝氨酸激活SIRT1会增加脂肪酸氧化，并逆转C2C12肌管中的胰岛素抵抗。

沉默信息调节剂1（SIRT1）是烟酰胺腺嘌呤二核苷酸（NAD ⁺）依赖性脱乙酰基酶，其功能与细胞代谢（包括线粒体生物发生）相关。在脂肪肝疾病中，肝脏l-丝氨酸浓度明显降低。我们报道了氨基酸的补充通过增强1-丝氨酸依赖性高半胱氨酸代谢而改善了酒精性脂肪肝。在这项研究中，我们假设代谢产生的NAD ⁺从升丝氨酸，从而激活SIRT1的促进的作用升丝氨酸。为此，我们评估的影响，升-丝氨酸对C2C12肌管中SIRT1活性和线粒体生物发生的影响。1-丝氨酸增加了细胞内NAD ^+的含量，并导致了SIRT1的活化，这是通过p53荧光素酶测定和过氧化物酶体增殖物激活的受体γ共激活物1-α（PGC-1α）乙酰化的蛋白质印迹分析确定的。1-丝氨酸处理增加了与线粒体生物发生有关的基因的表达，并增强了线粒体的质量和功能。另外，1-丝氨酸逆转了细胞胰岛素抵抗，其由胰岛素诱导的Akt和GLUT4表达和膜易位的磷酸化确定。升-丝氨酸诱导的线粒体基因表达，脂肪酸氧化和胰岛素敏感性由增强的SIRT1活性介导，这通过选择性SIRT1抑制剂（Ex-527）和针对SIRT1的siRNA进行了验证。1-丝氨酸对细胞NAD ⁺水平的作用取决于1-丝氨酸代谢为丙酮酸，其随后通过乳酸脱氢酶转化为乳酸。总之，这些数据表明1-丝氨酸增加了细胞NAD ⁺水平，从而增加了C2C12肌管中SIRT1的活性。