Open AccessHepatic Gadd45β promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1α
Author(s) -
Ling Wu,
Yang Jiao,
Yao Li,
Jingjing Jiang,
Lin Zhao,
Menghui Li,
Bin Li,
Yue Zheng,
Xuejin Chen,
Xiaoying Li,
Yan Lu
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20201475
Subject(s) - dna demethylation , gadd45 , epigenomics , gluconeogenesis , biology , endocrinology , glucose homeostasis , dna damage , medicine , carbohydrate metabolism , knockout mouse , dna methylation , diabetes mellitus , metabolism , gene expression , biochemistry , dna , insulin resistance , gene , cell cycle , cell cycle checkpoint
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.