| First Author | Wu L | Year | 2021 |
| Journal | J Exp Med | Volume | 218 |
| Issue | 5 | PubMed ID | 33688917 |
| Mgi Jnum | J:322177 | Mgi Id | MGI:6724817 |
| Doi | 10.1084/jem.20201475 | Citation | Wu L, et al. (2021) Hepatic Gadd45beta promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1alpha. J Exp Med 218(5) |
| abstractText | Although widely used for their potent anti-inflammatory and immunosuppressive properties, the prescription of glucocorticoid analogues (e.g., dexamethasone) has been associated with deleterious glucose metabolism, compromising their long-term therapeutic use. However, the molecular mechanism remains poorly understood. In the present study, through transcriptomic and epigenomic analysis of two mouse models, we identified a growth arrest and DNA damage-inducible beta (Gadd45beta)-dependent pathway that stimulates hepatic glucose production (HGP). Functional studies showed that overexpression of Gadd45beta in vivo or in cultured hepatocytes activates gluconeogenesis and increases HGP. In contrast, liver-specific Gadd45beta-knockout mice were resistant to high-fat diet- or steroid-induced hyperglycemia. Of pathophysiological significance, hepatic Gadd45beta expression is up-regulated in several mouse models of obesity and diabetic patients. Mechanistically, Gadd45beta promotes DNA demethylation of PGC-1alpha promoter in conjunction with TET1, thereby stimulating PGC-1alpha expression to promote gluconeogenesis and hyperglycemia. Collectively, these findings unveil an epigenomic signature involving Gadd45beta/TET1/DNA demethylation in hepatic glucose metabolism, enabling the identification of pathogenic factors in diabetes. |
