ATP-citrate lyase is essential for high glucose-induced histone hyperacetylation and fibrogenic gene up-regulation in mesangial cells.

ATP-citrate lyase is essential for high glucose-induced histone hyperacetylation and fibrogenic gene up-regulation in mesangial cells. Am J Physiol Renal Physiol. 2017 May 10;:ajprenal.00029.2017 Authors: Deb DK, Chen Y, Sun J, Wang Y, Li YC Abstract TThe goal of this study was to address the role of ATP-citrate lyase (ACL), an enzyme that converts citrate to acetyl-CoA, in high glucose (HG)-induced histone acetylation and pro-fibrotic gene expression. Our recent ChIP-Seq studies have demonstrated that HG induces genome-wide histone hyperacetylation in mesangial cells (MCs). Here we showed that exposure of MCs to HG markedly increased histone acetylation at the H3K9/14 and H3K18 marks and induced the expression of potent pro-fibrotic factors TGF-β1, TGF-β3 and CTGF. The induction of these pro-fibrotic factors was further enhanced by histone deacetylase inhibitor but suppressed by histone acetyl-transferase inhibitor, confirming the importance of histone acetylation in this regulation. Interestingly, HG not only up-regulated ACL expression but also promoted ACL nuclear translocation, evidenced by increased ACL concentration and activity in the nuclear extracts. Consistent with this observation, transfection of MCs with a plasmid carrying GFP-ACL fusion protein led to GFP nuclear accumulation when cultured in HG condition. Silencing ACL with siRNAs alleviated HG-induced histone hyperacetylation as well as up-regulation of TGF-β1, TG...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research