Hepatic Gadd45β promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1α.

ABSTRACT: 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. O

SUBMITTER: Wu L 

PROVIDER: S-EPMC7953268 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature