Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes.
Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes.
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DOI：
10.1016/j.cell.2017.03.001
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发表时间：
2017-03-23
期刊：
影响因子：
64.5
通讯作者：
Puigserver P
中科院分区：
文献类型：
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作者：
Sharabi K;Lin H;Tavares CDJ;Dominy JE;Camporez JP;Perry RJ;Schilling R;Rines AK;Lee J;Hickey M;Bennion M;Palmer M;Nag PP;Bittker JA;Perez J;Jedrychowski MP;Ozcan U;Gygi SP;Kamenecka TM;Shulman GI;Schreiber SL;Griffin PR;Puigserver P
2型糖尿病（T2 D）是一种全球流行病，医疗上需要额外的靶向治疗。抑制肝葡萄糖生成（HGP）可有效改善糖尿病，并可用于其治疗。我们假设，靶向肝脏中的PGC-1α乙酰化（一种已知可抑制肝细胞生成的化学修饰）可能用于治疗T2 D。因此，我们设计了一个高通量的化学筛选平台来定量细胞中的PGC-1α乙酰化，并鉴定了增加PGC-1α乙酰化、抑制肝细胞中促凋亡基因表达和减少葡萄糖产生的小分子。基于效力和生物利用度，我们选择了一种小分子SR-18292，其在T2 D的饮食和遗传小鼠模型中降低血糖，强烈增加肝脏胰岛素敏感性并改善葡萄糖稳态。这些研究对于理解葡萄糖代谢的调节机制和T2 D的治疗具有重要意义。简而言之，靶向血管生成的小分子改善了2型糖尿病动物的葡萄糖稳态，这表明了这种代谢疾病的新治疗方法。
Type 2 diabetes (T2D) is a world-wide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression and reduce glucose production in hepatocytes. Based on the potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D. In brief - A small molecule targeting gluconeogenesis improves glucose homeostasis in animals with type 2 diabetes, suggesting a new therapeutic approach for this metabolic disease.