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Abstract: TH-PO616

ATP-Citrate Lyase Is an Epigenetic Regulator to Promote Renal Injury in Metabolic Syndrome

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1301 Health Maintenance, Nutrition, and Metabolism: Basic

Authors

  • Chen, Yinyin, Dept. of Medicine, University of Chicago, Chicago, Illinois, United States
  • Deb, Dilip K, Dept. of Medicine, University of Chicago, Chicago, Illinois, United States
  • Li, Yanchun, Dept. of Medicine, University of Chicago, Chicago, Illinois, United States
Background

Metabolic syndrome, characterized by obesity and type 2 diabetes, is a leading cause of chronic kidney disease. Obesity-related renal injury, characterized by ectopic lipid accumulation in the kidney, has increased dramatically in recent years. Hyperglycemia and hyperlipidemia, key features of metabolic syndrome, drive excess nutrient flows into kidney cells; as a result, enhanced cell metabolism increases intracellular acetyl-CoA concentration, which provides the substrate for de novo lipid synthesis as well as for histone acetylation. Here we tested the hypothesis that ATP-citrate lyase (Acly), an enzyme that converts citrate to acetyl-CoA, functions as an epigenetic regulator of renal injury by promoting ectopic lipid synthesis and histone acetylation.

Methods

Acly, lipogenic and fibrogenic genes in the kidney of ob/ob BTBR mice and mesangial cells were quantified by qRT-PCR and Western blotting. Kidney sections were analyzed by H&E, PAS and oil red O staining. Histone acetylation in gene promoters was assessed by ChIP assays.

Results

Ob/ob BTBR mice developed glomerulomegaly, glomerulosclerosis and ectopic lipid accumulation in the kidney compared with ob/+ controls, accompanied by increases in total lipids, triglyceride and cholesterol contents in the renal cortex. Acly, lipogenic (ACC, FAS, HMGCR) and fibrogenic (TGF-β1, FN) genes were markedly up-regulated in the kidney of ob/ob BTBR mice, so was histone acetylation at the H3K9/14 and H3K27 sites. Inhibition of Acly activity by SB-204990 not only blocked histone acetylation but also suppressed the expression of the lipogenic and fibrogenic genes in the ob/ob BTBR kidneys. ChIP assays confirmed that these gene promoters were hyperacetylated at the H3K9/14 and H3K27 sites. Exposing mesangial cells to a combination of high glucose, sodium palmitate and TNF-α synergistically stimulated Acly expression and enzymatic activity, increased H3K4/19 and H3K27 acetylation, up-regulated the lipogenic and fibrogenic genes and promoted histone acetylation in these gene promoters. Blockage of Acly by SB-204990 or siRNA attenuated these regulatory processes, whereas Acly overexpression enhanced these regulations.

Conclusion

These observations strongly suggest that Acly is a critical epigenetic regulator to promote renal injury via epigenetic mechanisms in obesity