Fatty liver mediated by peroxisome proliferator-activated receptor-α DNA methylation can be reversed by a methylation inhibitor and curcumin.

Abstract

Our studies in vitro and in vivo aimed to investigate the influence of DNA methylation of peroxisome proliferator activated receptor-α (PPAR-α) gene in non-alcoholic fatty liver disease (NAFLD) pathogenesis and to observe whether the DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR) and the herbal medicine curcumin might reverse the effect both in vivo and in vitro. Steatotic hepatocyte model of cell lines and NAFLD rat models were established following protocols documented in previous studies. Subsequently, the models received 5-Aza-CdR and curcumin treatment. Morphological, histological and laboratory variables in each group were determined by routine methods, including PPAR-α mRNA expression by polymerase chain reaction (PCR), PPAR-α protein expression by Western blot and DNA methylation by pyrosequencing. The steatotic hepatocyte model and NAFLD rat model were completely established. The expressions of PPAR-α mRNA and protein were significantly lower in the steatotic hepatocyte and NAFLD rat model groups than in the controls (P < 0.05). The mean DNA methylation levels of the PPAR-α gene were significantly higher in the two steatotic model groups than in the controls, especially at several CpG sites (P < 0.05). 5-Aza-CdR and curcumin treatment significantly reversed the DNA methylation levels, increased PPAR-α mRNA and protein expression, and improved lipid accumulation in the two steatotic models (P < 0.05). DNA methylation at the PPAR-α gene is involved in the pathogenesis of NAFLD and is possibly reversible by 5-Aza-CdR and curcumin. Curcumin may be a promising candidate for NAFLD therapy.