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 β (Gadd45β)–dependent pathway that stimulates hepatic glucose production (HGP). Functional studies showed that overexpression of Gadd45β in vivo or in cultured hepatocytes activates gluconeogenesis and increases HGP. In contrast, liver-specific Gadd45β-knockout mice were resistant to high-fat diet– or steroid-induced hyperglycemia. Of pathophysiological significance, hepatic Gadd45β expression is up-regulated in several mouse models of obesity and diabetic patients. Mechanistically, Gadd45β promotes DNA demethylation of PGC-1α promoter in conjunction with TET1, thereby stimulating PGC-1α expression to promote gluconeogenesis and hyperglycemia. Collectively, these findings unveil an epigenomic signature involving Gadd45β/TET1/DNA demethylation in hepatic glucose metabolism, enabling the identification of pathogenic factors in diabetes.
Hepatic Gadd45β promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1α
Disclosures: The authors declare no competing interests exist.
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Ling Wu, Yang Jiao, Yao Li, Jingjing Jiang, Lin Zhao, Menghui Li, Bin Li, Zheng Yan, Xuejin Chen, Xiaoying Li, Yan Lu; Hepatic Gadd45β promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1α. J Exp Med 3 May 2021; 218 (5): e20201475. doi: https://doi.org/10.1084/jem.20201475
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