ATP‐citrate lyase is an epigenetic regulator to promote obesity‐related kidney injury

ABSTRACT Obesity is a leading cause of chronic kidney disease (CKD), but how obesity promotes renal injury remains poorly understood. Here we showed that ATP‐citrate lyase (ACL), an enzyme converting citrate to acetyl‐CoA, is highly induced in the kidney of overweight or obese patients with CKD and ob/ob BTBR mice. ACL induction is associated with increased ectopic lipid accumulation (ELA), glomerulosclerosis, and albuminuria. Acety1‐CoA is the substrate for de novo lipogenesis as well as for histone acetylation. By raising acetyl‐CoA concentration ACL promotes H3K9/14 and H3K27 hyperacetylation leading to up‐regulation of several rate‐limiting lipogenic enzymes and fibrogenic factors. On the other hand, the excess acetyl‐CoA generated as a result of ACL induction provides the substrate for these lipogenic enzymes to drive de novo lipogenesis leading to ELA, a detrimental event toward renal injury. In mesangial cells, ACL is synergistically induced by high glucose, palmitate, and TNF‐α via NF‐κB and PKA pathways. Under these conditions, H3K9/14 and H3K27 hyperacetylation, as well as the induction of the lipogenic and fibrogenic proteins, are completely blocked in the presence of an ACL inhibitor. Collectively, these data suggest that ACL is an epigenetic regulator that promotes renal ELA and fibrogenesis leading to renal injury in obesity.—Chen, Y., Deb, D. K., Fu, X., Yi, B., Liang, Y., Du, J., He, L., Li, Y. C. ATP‐citrate lyase is an epigenetic regulator to promote obesity‐related kidney injury. FASEB J. 33, 9602–9615 (2019). www.fasebj.org