TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis

Abstract

Edited by Jeffrey E. PessinMaintenance 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-␤1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-␤1/Smad3 signals suppressed endogenous glucose production. TGF-␤1 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-␤1 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-␤1/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.Glucose homeostasis is achieved via the integration of physiological processes occurring in multiple organs. Glycolysis and gluconeogenesis represent two competing processes that regulate blood glucose levels (1). Hepatic gluconeogenesis is a critical mechanism for endogenous glucose production during periods of prolonged fasting. However, deregulated hepatic gluconeogenesis is a common feature in patients with type 2 diabetes (T2D) 2 (2). Expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatases (G6Pase) (3), key rate-limiting enzymes for hepatic gluconeogenesis, increases abnormally in T2D (4). Likewise, the transgenic overexpression of these enzymes in mice results in hyperglycemia, hyperinsulinemia, and insulin resistance (5, 6). In contrast, deletion of PEPCK reverses hyperglycemia and insulin resistance in diabetes-prone db/db mice (7).The AMP-activated protein kinase (AMPK) signaling pathway, among others, regulates the expression of PEPCK and G6Pase (8). AMPK is a heterotrimeric protein, consisting of ␣1/2, ␤1/2, and ␥1/2/3 subunits, that regulates glucose and fatty acid metabolism (9). Phosphorylation of Thr-172 in the ␣1 subunit is important for AMPK activation, which is in turn regulated by two upstream kinases, LKB1 and Ca 2ϩ calmodulin-dependent protein kinases ␣ ...

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