Acyl-Coenzyme A:Cholesterol Acyltransferase Inhibition Ameliorates Proteinuria, Hyperlipidemia, Lecithin-Cholesterol Acyltransferase, SRB-1, and Low-Denisty Lipoprotein Receptor Deficiencies in Nephrotic Syndrome

Abstract

Background-Nephrotic syndrome (NS) is associated with hyperlipidemia, altered lipid regulatory enzymes and receptors, and increased risk of progressive renal and cardiovascular diseases. Acyl-coenzyme A:cholesterol acyltransferase (ACAT) catalyzes intracellular esterification of cholesterol and plays an important role in production of apolipoprotein B-containing lipoproteins, regulation of cholesterol-responsive proteins, and formation of foam cells. Because hepatic ACAT-2 is markedly upregulated in NS, we tested the hypothesis that inhibition of ACAT may improve cholesterol metabolism in NS. Methods and Results-Rats with puromycin-induced NS were treated with either the ACAT inhibitor CI-976 or placebo for 2 weeks. Normal rats served as controls. Plasma lipids, renal function, and key lipid regulatory factors were measured. Untreated NS rats showed heavy proteinuria; hypoalbuminemia; elevated plasma cholesterol, triglyceride, LDL, VLDL, and total cholesterol-to-HDL cholesterol ratio; increased hepatic ACAT activity, ACAT-2 mRNA, and ACAT-2 protein; and reduced LDL receptor, HDL receptor, otherwise known as scavenger receptor B-1 (SRB-1) and plasma lecithin-cholesterol acyltransferase (LCAT). ACAT inhibitor reduced plasma cholesterol and triglycerides, normalized total cholesterol-to-HDL cholesterol ratio, and lowered hepatic ACAT activity without changing ACAT-2 mRNA or protein. This was accompanied by near normalizations of plasma LCAT, hepatic SRB-1, and LDL receptor and a significant amelioration of proteinuria and hypoalbuminemia. Conclusions-Pharmacological

Plasma PCSK9 in Nephrotic Syndrome and in Peritoneal Dialysis: A Cross-sectional Study

“…Previously, we had shown in animal models of spontaneous and puromycin aminonucleoside-induced nephrotic syndrome that hepatic LDLR gene expression level is normal; these new findings help explain why the receptor nevertheless is depleted in nephrotic syndrome. [5][6][7][8] By mediating degradation and limiting recycling of LDLR, upregulation of PCSK9 must play a major role in the pathogenesis of hypercholesterolemia and the associated risk of cardiovascular disease, as we have shown in both humans and animals with nephrotic syndrome. Several studies have demonstrated significant direct correlations between plasma PCSK9 and LDL cholesterol levels in the general population.…”

“…7,24 The potential role of upregulation of ACAT-2 is evidenced by the dramatic amelioration of hypercholesterolemia and marked reduction in plasma LDL cholesterol level with administration of ACAT inhibitor in animals with nephrotic syndrome. 7 In addition, by lowering the uptake of LDL and its cholesterol cargo from the circulation, depletion of hepatic LDLR in nephrotic liver contributes to the reduction in hepatocyte cholesterol, which can increase PCSK9 expression by activation of SREBP-2. Thus, upregulation of PCSK9 and depletion of LDLR participate in a vicious circuit in which each begets and intensifies the other.…”

“…These studies showed a marked reduction in LDLR protein in hepatic tissue. [5][6][7] Interestingly, the severe deficiency in LDLR protein is accompanied by normal LDLR messenger RNA expression, 5,8 suggesting a posttranscriptional or post-translational cause. It should be noted that in addition to causing LDLR deficiency, alteration in the composition of LDL in nephrotic syndrome may contribute to its impaired clearance by interference with the receptor binding process.…”

“…The LDLR then is returned to the cell membrane to repeat the cycle. Given the critical role of LDLR in the clearance of LDL and its cholesterol cargo, the acquired LDLR deficiency shown in the aforementioned rat studies [5][6][7][8] elucidates the principal cause of impaired LDL clearance and elevated serum LDL level in nephrotic syndrome. However, the underlying mechanism(s) by which nephrotic syndrome decreases hepatic LDLR protein expression is not known.…”

Dual Role of Circulating Angiopoietin-Like 4 (ANGPTL4) in Promoting Hypertriglyceridemia and Lowering Proteinuria in Nephrotic Syndrome

“…[1][2][3] Recently in Nature Medicine, Clement et al 4 published a series of experiments that showed that elevation of circulating angiopoietin-like 4 (Angptl4 in rats; ANGPTL4 in humans) appears to be the missing link that ties hypertriglyceridemia to albuminuria in nephrotic syndrome. Nephrotic hyperlipidemia is due largely to the acquired deficiencies of lipoprotein lipase (LPL), [5][6][7] hepatic lipase, 8 the VLDL receptor, 5,9 the LDL receptor, [10][11][12] lecithin-cholesterol acyltransferase (LCAT), 13 and the HDL docking receptor (SRB1; encoded by SCARB1) 14,15 ; upregulation of cholesterylester transfer protein (CETP), 16,17 hepatic acyl coenzyme A cholesterol acyltransferase (ACAT, encoded by ACAT1), 18,19 diglycerol acyltransferase, 20 and lipoprotein(a) 21 ; and altered composition of plasma lipoproteins interfering with their receptor binding and clearance. 22 Triglyceride-rich lipoproteins (VLDL and chylomicrons) deliver fatty acid to various tissues, including myocytes for energy production and adipocytes for energy storage.…”