Song Young Mi, Lee Yong-ho, Kim Ji-Won, Ham Dong-Sik, Kang Eun-Seok, Cha Bong Soo, Lee Hyun Chul, Lee Byung-Wan
a Brain Korea 21 PLUS Project for Medical Science ; Yonsei University College of Medicine ; Seoul , Korea.
Autophagy. 2015;11(1):46-59. doi: 10.4161/15548627.2014.984271.
Metformin activates both PRKA and SIRT1. Furthermore, autophagy is induced by either the PRKA-MTOR-ULK1 or SIRT1-FOXO signaling pathways. We aimed to elucidate the mechanism by which metformin alleviates hepatosteatosis by examining the molecular interplay between SIRT1, PRKA, and autophagy. ob/ob mice were divided into 3 groups: one with ad libitum feeding of a standard chow diet, one with 300 mg/kg intraperitoneal metformin injections, and one with 3 g/d caloric restriction (CR) for a period of 4 wk. Primary hepatocytes or HepG2 cells were treated with oleic acid (OA) plus high glucose in the absence or presence of metformin. Both CR and metformin significantly improved body weight and glucose homeostasis, along with hepatic steatosis, in ob/ob mice. Furthermore, CR and metformin both upregulated SIRT1 expression and also stimulated autophagy induction and flux in vivo. Metformin also prevented OA with high glucose-induced suppression of both SIRT1 expression and SIRT1-dependent activation of autophagy machinery, thereby alleviating intracellular lipid accumulation in vitro. Interestingly, metformin treatment upregulated SIRT1 expression and activated PRKA even after siRNA-mediated knockdown of PRKAA1/2 and SIRT1, respectively. Taken together, these results suggest that metformin alleviates hepatic steatosis through PRKA-independent, SIRT1-mediated effects on the autophagy machinery.
二甲双胍可激活蛋白激酶A（PRKA）和沉默信息调节因子1（SIRT1）。此外，自噬可由PRKA-雷帕霉素靶蛋白（mTOR）- unc-51样自噬激活激酶1（ULK1）信号通路或SIRT1-叉头框蛋白O（FOXO）信号通路诱导。我们旨在通过研究SIRT1、PRKA和自噬之间的分子相互作用，阐明二甲双胍减轻肝脂肪变性的机制。将ob/ob小鼠分为3组：一组自由摄食标准饲料，一组腹腔注射300 mg/kg二甲双胍，一组进行为期4周的每日3 g热量限制（CR）。在有无二甲双胍的情况下，用油酸（OA）加高糖处理原代肝细胞或HepG2细胞。CR和二甲双胍均显著改善了ob/ob小鼠的体重和葡萄糖稳态，以及肝脂肪变性。此外，CR和二甲双胍均上调了SIRT1表达，并在体内刺激了自噬诱导和自噬通量。二甲双胍还可防止OA加高糖诱导的SIRT1表达抑制以及SIRT1依赖性自噬机制激活，从而减轻体外细胞内脂质积累。有趣的是，即使分别通过小干扰RNA（siRNA）介导敲低PRKAA1/2和SIRT1后，二甲双胍处理仍上调了SIRT1表达并激活了PRKA。综上所述，这些结果表明二甲双胍通过对自噬机制的PRKA非依赖性、SIRT1介导的作用减轻肝脂肪变性。
