Post-transcriptional nature of uremia-induced downregulation of hepatic apolipoprotein A-I production》.pdfVIP

ORIGINAL ARTICLES Post-transcriptional nature of uremia-induced downregulation of hepatic apolipoprotein A-I production HAMID MORADI, HAMID M. SAID, and NOSRATOLA D. VAZIRI IRVINE, CALIF Chronic kidney disease is associated with premature death from cardiovascular dis- ease, which is, in part, driven by high density lipoprotein deficiency and dysfunction. One of the main causes of high density lipoprotein deficiency in chronic kidney dis- ease is diminished plasma apolipoprotein (Apo)A-I level. Plasma ApoA-I is reduced in dialysis patients and hepatic ApoA-I messenger RNA (mRNA) is decreased in the uremic rats. This study explored the mechanism of uremia-induced downregulation of ApoA-I. Human hepatoma derived cells were incubated in media containing whole plasma or plasma subfractionation from normal subjects and patients with end stage renal disease pre- and posthemodialysis. Cells and culture media were isolated to measure ApoA-I protein and mRNA. ApoA-I promoter activity was mea- sured using transfection with a luciferase promoter construct containing the –2096 to 1293 segment of ApoA-I gene. Finally, effect of uremic and control plasma was as- sessed on ApoA-I RNA stability. Exposure to uremic plasma significantly reduced ApoA-I mRNA expression and ApoA-I protein production. These effects were re- versed by replacing uremic plasma with normal plasma. Although no difference in ApoA-I promoter activity was found betwe