Bae Kwi-Hyun, Min Ae-Kyung, Kim Jung-Guk, Lee In-Kyu, Park Keun-Gyu
Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, South Korea.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, South Korea.
Biochem Biophys Res Commun. 2014 Dec 12;455(3-4):212-7. doi: 10.1016/j.bbrc.2014.10.147. Epub 2014 Nov 5.
Hepatic expression of fibroblast growth factor 21 (FGF21), one of the most promising therapeutic candidates for metabolic syndrome, is induced by multiple factors associated with fasting, including cyclic AMP response element-binding protein H (CREBH). Alpha lipoic acid (ALA), a naturally occurring thiol antioxidant, has been shown to induce metabolic changes that are similar to those induced by FGF21, including weight loss and increased energy expenditure. Here, we investigated the effect of ALA on hepatic FGF21 expression. ALA treatment enhanced CREBH and FGF21 mRNA expression and protein abundance in cultured hepatocytes. ALA increased FGF21 promoter activity by up-regulating CREBH expression and increasing CREBH binding to the FGF21 promoter, indicating that ALA up-regulates FGF21 at the transcriptional level. Moreover, inhibition of endogenous CREBH expression by siRNA attenuated ALA-induced FGF21 expression. Finally, treatment of mice with ALA enhanced fasting-induced up-regulation of CREBH and FGF21 in the liver and inhibited feeding-induced suppression of their expression. Consistently, ALA increased serum FGF21 levels in both fasted and fed mice. Collectively, these results indicate that ALA increases hepatic FGF21 expression via up-regulation of CREBH, identifying ALA as a novel positive regulator of FGF21.
成纤维细胞生长因子21（FGF21）是代谢综合征最具前景的治疗候选药物之一，其肝脏表达由多种与禁食相关的因素诱导，包括环磷酸腺苷反应元件结合蛋白H（CREBH）。α硫辛酸（ALA）是一种天然存在的硫醇抗氧化剂，已被证明可诱导与FGF21诱导的代谢变化相似的变化，包括体重减轻和能量消耗增加。在此，我们研究了ALA对肝脏FGF21表达的影响。ALA处理增强了培养肝细胞中CREBH和FGF21 mRNA表达以及蛋白质丰度。ALA通过上调CREBH表达并增加CREBH与FGF21启动子的结合来增加FGF21启动子活性，表明ALA在转录水平上调FGF21。此外，通过siRNA抑制内源性CREBH表达减弱了ALA诱导的FGF21表达。最后，用ALA处理小鼠增强了禁食诱导的肝脏中CREBH和FGF21的上调，并抑制了进食诱导的它们表达的抑制。一致地，ALA在禁食和进食小鼠中均增加血清FGF21水平。总体而言，这些结果表明ALA通过上调CREBH增加肝脏FGF21表达，确定ALA为FGF21的新型正调节因子。
