Histone deacetylase 6 (HDAC6) is an essential modifier of glucocorticoid-induced hepatic gluconeogenesis.
In the current study, we investigated the importance of histone deacetylase (HDAC)6 for glucocorticoid receptor-mediated effects on glucose metabolism and its potential as a therapeutic target for the prevention of glucocorticoid-induced diabetes. Dexamethasone-induced hepatic glucose output and glucocorticoid receptor translocation were analyzed in wild-type (wt) and HDAC6-deficient (HDAC6KO) mice. The effect of the specific HDAC6 inhibitor tubacin was analyzed in vitro. wt and HDAC6KO mice were subjected to 3 weeks' dexamethasone treatment before analysis of glucose and insulin tolerance. HDAC6KO mice showed impaired dexamethasone-induced hepatic glucocorticoid receptor translocation. Accordingly, dexamethasone-induced expression of a large number of hepatic genes was significantly attenuated in mice lacking HDAC6 and by tubacin in vitro. Glucose output of primary hepatocytes from HDAC6KO mice was diminished. A significant improvement of dexamethasone-induced whole-body glucose intolerance as well as insulin resistance in HDAC6KO mice compared with wt littermates was observed. This study demonstrates that HDAC6 is an essential regulator of hepatic glucocorticoid-stimulated gluconeogenesis and impairment of whole-body glucose metabolism through modification of glucocorticoid receptor nuclear translocation. Selective pharmacological inhibition of HDAC6 may provide a future therapeutic option against the prodiabetogenic actions of glucocorticoids.
Institute of Pharmacology, Department of Endocrinology, Diabetes and Nutrition, Charité Medical University, the Center for Cardiovascular Research, Berlin, Germany.
Robin
R
Winkler
Verena
V
Benz
Markus
M
Clemenz
Mandy
M
Bloch
Anna
A
Foryst-Ludwig
Sami
S
Wardat
Nicole
N
Witte
Manuela
M
Trappiel
Pawel
P
Namsolleck
Knut
K
Mai
Joachim
J
Spranger
Gabriele
G
Matthias
Tim
T
Roloff
Oliver
O
Truee
Kai
K
Kappert
Michael
M
Schupp
Patrick
P
Matthias
Ulrich
U
Kintscher
D000107:Acetylation; D021581:Active Transport, Cell Nucleus; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000378:metabolism
D006657:Histones; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose; D003345:Corticosterone