Article Text

  1. V. H. Ha,
  2. H. Moradi,
  3. N. D. Vaziri
  1. Division of Nephrology and Hypertension, University of California, Irvine, CA


Heavy proteinuria, otherwise known as nephrotic syndrome (NS), results in profound dysregulation of lipid/lipoprotein metabolism and high-density lipoprotein (HDL)-mediated reverse cholesterol transport. For instance, maturation of cholesterol-poor HDL-3 to cholesterol-rich HDL-2 is impaired, HDL-2/HDL-3 ratio is reduced, and transport of surplus cholesterol by HDL from extrahepatic tissues for disposal in the liver is impaired. Optimal cholesterol uptake by HDL-3 or nascent HDL requires reversible binding to ABCA-1, which leads to the efflux of free cholesterol and phospholipids from the cell to the surface of HDL as well as esterification of free cholesterol by LCAT. Disposal of HDL-born cholesterol occurs by docking receptor SRB-1 or the endocytic receptor, recently identified as being identical to the β chain of adenosine triphosphate (ATP) synthase. Previously, we have found marked reductions of hepatic SRB-1 abundance and plasma LCAT (due to loss of LCAT in urine) in rats with nephrotic syndrome, events that can, in part, account for the impairment of HDL maturation and HDL-mediated reverse cholesterol transport. The present study was designed to determine the possible effects of NS on hepatic expressions of the β chain of ATP synthase and ABCA-1. Accordingly, mRNA (real-time PCR) and protein abundance (Western blot analysis) of the above molecules were determined in the liver of rats with puromycin-induced NS and control animals. Also examined was the effect of avasemibe (ACAT) inhibitor) administration, which was previously shown by us to reverse LCAT and SRB-1 deficiencies in this model. Compared to the controls, the untreated NS group exhibited marked elevation of serum cholesterol, triglycerides, LDL, VLDL and LDL/HDL cholesterol ratio. These abnormalities were significantly ameliorated by ACAT inhibition. The NS group showed upregulation of hepatic β chain of ATP synthase but no significant change in ABCA-1 expression. ACAT inhibition significantly increased expression of β chain of ATP synthase in both NS and control groups but had no significant effect on ABCA-1. Thus, SRB-1 deficiency in NS is accompanied by upregulation of β chain of ATP synthase. These findings point to increase catabolism (endocytosis) and reduced recycling and, hence, inefficient use of HDL in NS.

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