The 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
hist... More
The 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, TGF-β3,
CTGF and extracellular matrix (ECM) proteins fibronectin and collagen type IV, whereas ACL
overexpression further enhanced HG induction of histone acetylation as well as these pro-fibrotic factors
and ECM proteins. Collectively, these observations demonstrate that HG promotes ACL expression and
translocation into the nucleus, where ACL converts citrate to acetyl-CoA to provide the substrate for
histone acetylation, leading to up-regulation of fibrogenic genes. Therefore, ACL plays a critical role in
epigenetic regulation of diabetic renal fibrosis.
