Histone deacetylase inhibition attenuates hepatic steatosis in rats with experimental Cushing's syndrome.
10.4196/kjpp.2018.22.1.23
- Author:
Mina KIM
1
;
Hae Ahm LEE
;
Hyun Min CHO
;
Seol Hee KANG
;
Eunjo LEE
;
In Kyeom KIM
Author Information
1. Department of Pharmacology, Kyungpook National University School of Medicine, Daegu 41944, Korea. inkim@knu.ac.kr
- Publication Type:Original Article
- Keywords:
Cushing's syndrome;
Glucocorticoid receptor;
HDAC inhibitor;
Hepatic steatosis;
Sodium valproate
- MeSH:
Acetyl-CoA Carboxylase;
Acetylation;
Adrenocorticotropic Hormone;
Animals;
Cushing Syndrome*;
Dexamethasone;
Drinking Water;
Hep G2 Cells;
Histone Deacetylase Inhibitors;
Histone Deacetylases*;
Histones*;
Hydrocortisone;
Infusions, Subcutaneous;
Lipogenesis;
Liver;
Rats*;
Rats, Sprague-Dawley;
Receptors, Glucocorticoid;
Response Elements;
Sterol Regulatory Element Binding Protein 1;
Valproic Acid
- From:The Korean Journal of Physiology and Pharmacology
2018;22(1):23-33
- CountryRepublic of Korea
- Language:English
-
Abstract:
Cushing's syndrome (CS) is a collection of symptoms caused by prolonged exposure to excess cortisol. Chronically elevated glucocorticoid (GC) levels contribute to hepatic steatosis. We hypothesized that histone deacetylase inhibitors (HDACi) could attenuate hepatic steatosis through glucocorticoid receptor (GR) acetylation in experimental CS. To induce CS, we administered adrenocorticotropic hormone (ACTH; 40 ng/kg/day) to Sprague-Dawley rats by subcutaneous infusion with osmotic mini-pumps. We administered the HDACi, sodium valproate (VPA; 0.71% w/v), in the drinking water. Treatment with the HDACi decreased steatosis and the expression of lipogenic genes in the livers of CS rats. The enrichment of GR at the promoters of the lipogenic genes, such as acetyl-CoA carboxylase (Acc), fatty acid synthase (Fasn), and sterol regulatory element binding protein 1c (Srebp1c), was markedly decreased by VPA. Pan-HDACi and an HDAC class I-specific inhibitor, but not an HDAC class II a-specific inhibitor, attenuated dexamethasone (DEX)-induced lipogenesis in HepG2 cells. The transcriptional activity of Fasn was decreased by pretreatment with VPA. In addition, pretreatment with VPA decreased DEX-induced binding of GR to the glucocorticoid response element (GRE). Treatment with VPA increased the acetylation of GR in ACTH-infused rats and DEX-induced HepG2 cells. Taken together, these results indicate that HDAC inhibition attenuates hepatic steatosis hrough GR acetylation in experimental CS.
