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345 EFFECT OF NEPHROTIC SYNDROME ON HEPATIC HIGH-DENSITY LIPOPROTEIN ENDOCYTIC RECEPTOR (β CHAIN OF ADENOSINE TRIPHOSPHATE SYNTHASE) AND ABCA-1 EXPRESSIONS.
  1. V. H. Ha,
  2. H. Moradi,
  3. N. D. Vaziri
  1. Division of Nephrology and Hypertension, University of California, Irvine, CA

Abstract

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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