PPP1R3C mediates metformin-inhibited hepatic gluconeogenesis
Autor: | Qianqian Liu, Yun Liu, Feiye Zhou, Yuqing Zhang, Qin Zhu, Kecheng Zhu, Xiao Wang, Shushu Wang, Linlin Zhang, Hongju Tang, Libin Zhou, Xueying Ji |
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Rok vydání: | 2019 |
Předmět: |
Blood Glucose
Male 0301 basic medicine medicine.medical_specialty Endocrinology Diabetes and Metabolism Primary Cell Culture 8-Bromo Cyclic Adenosine Monophosphate Gene Expression 030209 endocrinology & metabolism Mechanistic Target of Rapamycin Complex 1 CREB Dephosphorylation Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology Internal medicine medicine Animals Hypoglycemic Agents Gene knockdown Glycogen biology Chemistry Gluconeogenesis Intracellular Signaling Peptides and Proteins AMPK Metformin Liver Glycogen Mice Inbred C57BL 030104 developmental biology Liver Gene Knockdown Techniques Hepatocytes biology.protein Phosphorylation medicine.drug |
Zdroj: | Metabolism. 98:62-75 |
ISSN: | 0026-0495 |
Popis: | Background Metformin has been widely used to alleviate hyperglycemia in patients with type 2 diabetes mainly via suppressing hepatic gluconeogenesis. However, the underlying mechanism remains incompletely clear. Here, we aimed to explore the role of PPP1R3C in metformin-mediated inhibition of hepatic gluconeogenesis. Methods The differentially expressed genes in primary mouse hepatocytes incubated with 8-Br-cAMP and metformin were analyzed by microarrays. Hepatic glucose production and gluconeogenic gene expressions were detected after adenovirus-mediated overexpression or silence of PPP1R3C in vitro and in vivo. The phosphorylation level and location of transducer of regulated CREB activity 2 (TORC2) were determined by Western blot and immunofluorescence. Results Metformin and adenovirus-mediated activation of AMPK suppressed 8-Br-cAMP–stimulated Ppp1r3c mRNA expression in primary mouse hepatocytes. Overexpression of PPP1R3C in primary mouse hepatocytes or the livers of wild-type mice promoted hepatic glucose production and gluconeogenic gene expressions. On the contrary, adenovirus-mediated knockdown of PPP1R3C in primary mouse hepatocytes decreased hepatic gluconeogenesis, with the suppression of cAMP-stimulated gluconeogenic gene expressions and TORC2 dephosphorylation. Notably, Ppp1r3c expression was increased in the liver of db/db mice. After PPP1R3C silence in the livers of wild-type and db/db mice, blood glucose levels and hepatic glucose production were markedly lowered, with decreased expressions of key gluconeogenic enzymes and transcript factors as well as liver glycogen content. Conclusion Metformin-activated AMPK decreases hepatic PPP1R3C expression, leading to the suppression of hepatic gluconeogenesis through blocking cAMP-stimulated TORC2 dephosphorylation. Hepatic specific silence of PPP1R3C provides a promising therapeutic strategy for type 2 diabetes. |
Databáze: | OpenAIRE |
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