The Korean Journal of Physiology and Pharmacology

  • 제22권1호
  • /
  • Pages.23-33
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  • 2018
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  • 1226-4512(pISSN)
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  • 2093-3827(eISSN)
대한약리학회 (The Korean Society of Pharmacology)
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Histone deacetylase inhibition attenuates hepatic steatosis in rats with experimental Cushing's syndrome

  • Kim, Mina (Department of Pharmacology, Kyungpook National University School of Medicine) ;
  • Lee, Hae-Ahm (Department of Pharmacology, Kyungpook National University School of Medicine) ;
  • Cho, Hyun-Min (Department of Pharmacology, Kyungpook National University School of Medicine) ;
  • Kang, Seol-Hee (Department of Pharmacology, Kyungpook National University School of Medicine) ;
  • Lee, Eunjo (Department of Pharmacology, Kyungpook National University School of Medicine) ;
  • Kim, In Kyeom (Department of Pharmacology, Kyungpook National University School of Medicine)
  • 투고 : 2017.03.29
  • 심사 : 2017.07.30
  • 발행 : 2018.01.01
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초록

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 through GR acetylation in experimental CS.

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참고문헌

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