Bibliographic Details
| Title: |
Sirt1 Mediates Vitamin D Deficiency-Driven Gluconeogenesis in the Liver via mTorc2/Akt Signaling |
| Authors: |
Qi Yuan, Ridong Zhang, Mengyue Sun, Xiao Guo, Jinglei Yang, Wen Bian, Chunfeng Xie, Dengshun Miao, Li Mao |
| Source: |
Journal of Diabetes Research, Vol 2022 (2022) |
| Publisher Information: |
Hindawi Limited, 2022. |
| Publication Year: |
2022 |
| Collection: |
LCC:Diseases of the endocrine glands. Clinical endocrinology |
| Subject Terms: |
Diseases of the endocrine glands. Clinical endocrinology, RC648-665 |
| More Details: |
As an active form of vitamin D (VD), 1,25-dihydroxyvitamin D (1,25(OH)2D3) is involved in the development of many metabolic diseases, such as diabetes, autoimmune diseases, and tumours. While prospective epidemiological studies have consistently implicated VD deficiency in the regulation of glucose metabolism and insulin sensitivity, the specific mechanism remains unclear. Here, we generated 1α(OH)ase-null mice (targeted ablation of the 25-hydroxyvitamin D 1α hydroxylase enzyme) and found that these mice developed hepatic glucose overproduction, glucose intolerance, and hepatic insulin resistance accompanied by reduced Sirtuin 1 (Sirt1) expression. The chromatin immunoprecipitation (ChIP) and a luciferase reporter assay revealed that 1,25(OH)2D3-activated VD receptor (VDR) directly interacted with one VD response element (VDRE) in the Sirt1 promoter to upregulate Sirt1 transcription, triggering a cascade of serine/threonine kinase (AKT) phosphorylation at S473 and FOXO1 phosphorylation at S256. This phosphorylation cascade reduced the expression of gluconeogenic genes, eventually attenuating glucose overproduction in the liver. In addition, a signaling pathway was found to modulate gluconeogenesis involving VDR, Sirt1, Rictor (a component of mTOR complex 2 [mTorc2]), AKT, and FOXO1, and Sirt1 and FOXO1 were identified as key modulators of dysregulated gluconeogenesis due to VD deficiency. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2314-6753 |
| Relation: |
https://doaj.org/toc/2314-6753 |
| DOI: |
10.1155/2022/1755563 |
| Access URL: |
https://doaj.org/article/918dea00374b40e59dc9f220e34ed6ba |
| Accession Number: |
edsdoj.918dea00374b40e59dc9f220e34ed6ba |
| Database: |
Directory of Open Access Journals |
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