Journal
DIABETES
Volume 63, Issue 6, Pages 2073-2085Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db13-0788
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Funding
- National Basic Research Program of China (973 Program) [2012CB947600, 2013CB911600]
- National Natural Science Foundation of China [31171137, 31271261]
- Program for New Century Excellent Talents in University by the Chinese Ministry of Education [NCET-11-0990]
- Program for the Top Young Talents by the Organization Department of the CPC Central Committee
- Collaborative Innovation Center for Cardiovascular Disease Translational Medicine (Nanjing Medical University)
- Priority Academic Program Development of Jiangsu Higher Education Institutions
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Vanin-1 (VNN1) is a liver-enriched oxidative stress sensor that has been implicated in the regulation of multiple metabolic pathways. Clinical investigations indicated that the levels of VNN1 were increased in the urine and blood of diabetic patients, but the physiological significance of this phenomenon remains unknown. In this study, we demonstrated that the hepatic expression of VNN1 was induced in fasted mice or mice with insulin resistance. Gain- and loss-of-function studies indicated that VNN1 increased the expression of gluconeogenic genes and hepatic glucose output, which led to hyperglycemia. These effects of VNN1 on gluconeogenesis were mediated by the regulation of the Akt signaling pathway. Mechanistically, vnn1 transcription was activated by the synergistic interaction of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) and hepatocyte nuclear factor-4 alpha (HNF-4 alpha). A chromatin immunoprecipitation analysis indicated that PGC-1 alpha was present near the HNF-4 alpha binding site on the proximal vnn1 promoter and activated the chromatin structure. Taken together, our results suggest an important role for VNN1 in regulating hepatic gluconeogenesis. Therefore, VNN1 may serve as a potential therapeutic target for the treatment of metabolic diseases caused by overactivated gluconeogenesis.
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