Adenosine triphosphate citrate lyase mediates hypocitraturia in rats

Joel Z. Melnick, Paul A. Srere, Nabil A. Elshourbagy, Orson W. Moe, Patricia A. Preisig, Robert J. Alpern

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


Chronic metabolic acidosis increases proximal tubular citrate uptake and metabolism. The present study addressed the effect of chronic metabolic acidosis on a cytosolic enzyme of citrate metabolism, ATP citrate lyase. Chronic metabolic acidosis caused hypocitraturia in rats and increased renal cortical ATP citrate lyase activity by 67% after 7 d. Renal cortical ATP citrate lyase protein abundance increased by 29% after 3 d and by 141% after 7 d of acid diet. No significant change in mRNA abundance could be detected. Hypokalemia, which causes only intracellular acidosis, caused hypocitraturia and increased renal cortical ATP citrate lyase activity by 28%. Conversely, the hypercitraturia of chronic alkali feeding was associated with no change in ATP citrate lyase activity. Inhibition of ATP citrate lyase with the competitive inhibitor, 4S-hydroxycitrate, significantly abated hypocitraturia and increased urinary citrate excretion fourfold in chronic metabolic acidosis and threefold in K+-depletion. In summary, the hypocitraturia of chronic metabolic acidosis is associated with an increase in ATP citrate lyase activity and protein abundance, and is partly reversed by inhibition of this enzyme. These results suggest an important role for ATP citrate lyase in proximal tubular citrate metabolism.

Original languageEnglish (US)
Pages (from-to)2381-2387
Number of pages7
JournalJournal of Clinical Investigation
Issue number10
StatePublished - Nov 15 1996


  • acidosis
  • citrate
  • hydroxycitrate
  • hypokalemia
  • urolithiasis

ASJC Scopus subject areas

  • Medicine(all)


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