SAMP1 Facilitates Importin-Mediated Nuclear Translocation to Activate the PKA/CREB Pathway and Hepatic Gluconeogenesis
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Background & Aims
Hepatic gluconeogenesis is pathologically elevated in type 2 diabetes (T2DM). Although the PKA/CREB axis is a central regulator, the mechanisms fine-tuning its activity, particularly nuclear events, remain elusive. This study investigates the role of the inner nuclear membrane protein SAMP1/TMEM201 in this process.
Methods
SAMP1 expression was assessed in diabetic (db/db) mice. Gain- and loss-of-function studies were performed in vivo (via AAV8-mediated hepatocyte-specific manipulation in mice) and in vitro (in primary mouse hepatocytes). Mechanisms were probed using co-immunoprecipitation, Western blotting, ELISA, and pharmacological inhibition.
Results
Hepatic SAMP1 was upregulated in db/db mice. Overexpression of SAMP1 exacerbated hyperglycemia and glucose intolerance, enhanced gluconeogenic gene expression (Pck1, G6pc), and increased glucose output. Conversely, SAMP1 knockdown attenuated these effects. Mechanistically, SAMP1 interacted with Importinα, facilitating its nuclear translocation. This led to enhanced CREB phosphorylation and activation of gluconeogenic genes, an effect abolished by the CREB inhibitor KG-501.
Conclusions
SAMP1 is a novel critical enhancer of hepatic gluconeogenesis. It functions by promoting Importinα-mediated nuclear import of PKA, thereby amplifying the PKA/CREB pathway. Targeting SAMP1 represents a promising strategy for curbing excessive hepatic glucose production in T2DM.
