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Effects of HMG-CoA reductase inhibition on hepatic expression of key cholesterol-regulatory enzymes and receptors in nephrotic syndrome.

Abstract：

BACKGROUND:Hypercholesterolemia is one of the major manifestations of nephrotic syndrome. We have previously shown that nephrotic hypercholesterolemia is associated with and, in part, due to dysregulation of hepatic HMG-CoA reductase, acyl-CoA:cholesterol acyltransferase (ACAT) and cholesterol 7alpha-hydroxylase, as well as lecithin:cholesterol acyltransferase (LCAT), low-density lipoprotein (LDL) receptor and high-density lipoprotein (HDL) receptor deficiencies. This study was carried out to discern the effect of inhibition of HMG-CoA reductase on expression of the key enzymes and receptors involved in cholesterol metabolism in the liver. METHODS:Rats with puromycin-induced nephrotic syndrome were treated with either a statin (rosuvastatin 20 mg/kg/day) or placebo for 2 weeks. Placebo-treated normal rats served as controls. Gene expression, protein abundance and/or activities of relevant receptors and enzymes were quantified. RESULTS:The untreated nephrotic rats showed heavy proteinuria, hypoalbuminemia, hypercholesterolemia, elevated total cholesterol:HDL cholesterol ratio and normal creatinine clearance. This was associated with severe reductions in hepatic LDL receptor, hepatic HDL receptor and plasma LCAT concentration, marked upregulation of hepatic ACAT, and unchanged cholesterol 7alpha-hydroxylase (rate-limiting step in cholesterol catabolism). Statin administration for 2 weeks ameliorated hepatic LDL receptor and HDL receptor deficiencies and significantly lowered plasma cholesterol, LDL cholesterol, total cholesterol:HDL cholesterol ratio and proteinuria. CONCLUSIONS:HMG-CoA reductase inhibition improved hepatic LDL and HDL receptor deficiencies, and ameliorated the associated hyperlipidemia in the nephrotic rats.

journal_name

Am J Nephrol

journal_title

American journal of nephrology

authors

Vaziri ND,Liang K

doi

10.1159/000082510

subject

Has Abstract

pub_date

2004-11-01 00:00:00

pages

606-13

issue

6

eissn

0250-8095

issn

1421-9670

pii

82510

journal_volume

24

pub_type

杂志文章

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