Histone deacetylase inhibition attenuates hepatic steatosis in rats with experimental Cushing's syndrome

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.

A Quantitative Systems Pharmacology Platform Reveals NAFLD Pathophysiological States and Targeting Strategies

“…In addition, vorinostat ameliorated disease-induced cytotoxicity. Interestingly, in contrast to our results using vorinostat in the LAMPS model, recent reports show that vorinostat also reduced steatosis [64] and lipid metabolism pathways [65] in rat and HCC monoculture studies, respectively. These contrasting findings demonstrate the variability between animal models and simple cell culture models in assessing drug effects, highlighting the need for implementing all-human MPS model systems in drug testing platforms.…”

GR-mediated FTO transactivation induces lipid accumulation in hepatocytes via demethylation of m6A on lipogenic mRNAs

“…The metabolic effects of GC are mediated by intracellular GR, which translocates to the nucleus and binds to the GREs to regulate the transcription of its target genes [38]. Previous studies have reported that DEX stimulates the expression of lipogenic genes via direct GR binding at their promoters in HepG2 cells [39]. Also, long-term GC exposure induces fat accumulation in mouse adipocytes via GR-dependent miR-27b transactivation [40].…”

Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders

“…However, inflammation during NASH development was not assessed in these models and the effect of SCFAs on liver inflammation needs further investigation. and sterol regulatory element binding protein 1c (Srebp1c) 138 . This finding provides important mechanistic insights, reviewed elsewhere 127,128 .…”