TGF-{beta}1/Smad3 pathway targets PP2A-AMPK-FoxO1 to regulate hepatic gluconeogenesis [Molecular Bases of Disease]

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 or diabetes. Maintenance of glucose homeostasis is achieved via functional interactions amongst various organs, liver, skeletal muscle, adipose tissue, brain and the endocrine pancreas. The liver is the primary site for 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 achieve this effect via targeting key regulators of hepatic gluconeogenesis, the protein phosphatase 2A (PP2A), 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 phosphoenol-pyruvate carboxy kinase. 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.

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