Yadav Hariom, Devalaraja Samir, Chung Stephanie T, Rane Sushil G
Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20854.
Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20854.
J Biol Chem. 2017 Feb 24;292(8):3420-3432. doi: 10.1074/jbc.M116.764910. Epub 2017 Jan 9.
Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-β1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-β1/Smad3 signals suppressed endogenous glucose production. TGF-β1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-β1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-β1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance.
维持葡萄糖稳态对正常生理功能至关重要。血糖水平偏离正常范围,无论升高还是降低,都会增加患低血糖和糖尿病等严重医学并发症的易感性。葡萄糖稳态的维持是通过肝脏、骨骼肌、脂肪组织、大脑和内分泌胰腺等各种器官之间的功能相互作用来实现的。肝脏是内源性葡萄糖生成的主要部位,尤其是在长期禁食状态下。然而,糖异生增强也是2型糖尿病(T2D)的一个标志性特征。因此,阐明调节肝脏糖异生的信号通路将有助于更好地了解正常内源性葡萄糖生成过程以及该过程在T2D中是如何受损的。在此,我们证明TGF-β1/Smad3信号通路在长期禁食和T2D期间均促进肝脏糖异生。相反,对TGF-β1/Smad3信号的基因和药理学抑制会抑制内源性葡萄糖生成。TGF-β1和Smad3信号通过靶向肝脏糖异生的关键调节因子蛋白磷酸酶2A(PP2A)、AMP激活的蛋白激酶(AMPK)和FoxO1蛋白来实现这一效应。具体而言,TGF-β1信号抑制LKB1-AMPK轴,从而促进FoxO1的核转位并激活关键的糖异生基因葡萄糖-6-磷酸酶和磷酸烯醇式丙酮酸羧激酶。这些发现强调了TGF-β1/Smad3信号在肝脏糖异生中的重要作用,无论是在正常生理状态还是在糖尿病等代谢疾病的病理生理学中,因此具有重要的医学意义。