title: Vanin-1 is a key activator for hepatic gluconeogenesis.
abstract: 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 γ coactivator 1α (PGC-1α) and hepatocyte nuclear factor-4α (HNF-4α). A chromatin immunoprecipitation analysis indicated that PGC-1α was present near the HNF-4α 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.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, China.
authors.forename: Siyu
authors.initials: S
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, China.
authors.forename: Wenxiang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, China.
authors.forename: Chunqi
authors.initials: C
authors.lastname: Tang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, China changliu@njnu.edu.cn.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology*; D051557:Hepatocyte Nuclear Factor 4 / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000187:drug effects; D015398:Signal Transduction; D014157:Transcription Factors
chemical_list: D058851:GPI-Linked Proteins; D051557:Hepatocyte Nuclear Factor 4; D047495:PPAR gamma; D014157:Transcription Factors; D000581:Amidohydrolases; C022314:pantetheinase