期刊
DIABETES
卷 67, 期 11, 页码 2167-2182出版社
AMER DIABETES ASSOC
DOI: 10.2337/db18-0674
关键词
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资金
- National Institutes of Health [R01-DK-095118]
- American Diabetes Association Career Development Award [1-15-CD-09]
- Minority Undergraduate Internship Award [1-17-MUI-008]
- American Heart Association [BGIA-7880040]
- Faculty Startup from the Texas A&M University Health Science Center and AgriLife Research
- U.S. Department of Agriculture National Institute of Food and Agriculture [1010958]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK095118, R01DK107641] Funding Source: NIH RePORTER
Dysregulation of hepatic glucose production (HGP) serves as a major underlying mechanism for the pathogenesis of type 2 diabetes. The pancreatic hormone glucagon increases and insulin suppresses HGP, controlling blood glucose homeostasis. The forkhead transcription factor Foxo1 promotes HGP through increasing expression of genes encoding the rate-limiting enzymes responsible for gluconeogenesis. We previously established that insulin suppresses Foxo1 by Akt-mediated phosphorylation of Foxo1 at Ser(256) in human hepatocytes. In this study, we found a novel Foxo1 regulatory mechanism by glucagon, which promotes Foxo1 nuclear translocation and stability via cAMP- and protein kinase A-dependent phosphorylation of Foxo1 at Ser(276). Replacing Foxo1-S276 with alanine (A) or aspartate (D) to block or mimic phosphorylation, respectively, markedly regulates Foxo1 stability and nuclear localization in human hepatocytes. To establish in vivo function of Foxo1-Ser(276) phosphorylation in glucose metabolism, we generated Foxo1-S273A and Foxo1-S273D knock-in (KI) mice. The KI mice displayed impaired blood glucose homeostasis, as well as the basal and glucagon-mediated HGP in hepatocytes. Thus, Foxo1-Ser(276) is a new target site identified in the control of Foxo1 bioactivity and associated metabolic diseases.
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