title: 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.
  
  
  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 inhibition of ACAT reverses NS-induced LDL receptor, HDL receptor, and LCAT deficiencies; improves plasma lipid profile; and ameliorates proteinuria in nephrotic animals. Further studies are needed to explore the effect of ACAT inhibition in nephrotic humans.
authors.affiliation: Division of Nephrology and Hypertension, University of California, Irvine, USA. ndvaziri@uci.edu
authors.forename: N D
authors.initials: ND
authors.lastname: Vaziri
authors.forename: K H
authors.initials: KH
authors.lastname: Liang
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D006949:Hyperlipidemias / Q000188:drug therapy / Q000209:etiology; D034141:Hypoalbuminemia / Q000188:drug therapy / Q000209:etiology; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000188:drug therapy / Q000209:etiology; D008099:Liver / Q000737:chemistry; D008297:Male; D009404:Nephrotic Syndrome / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D011507:Proteinuria / Q000188:drug therapy / Q000209:etiology; D012333:RNA, Messenger / Q000096:biosynthesis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000172:deficiency; D011973:Receptors, LDL / Q000172:deficiency; D051116:Receptors, Scavenger; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D014280:Triglycerides / Q000097:blood; D000097587:Sterol O-Acyltransferase 2
chemical_list: D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D051116:Receptors, Scavenger; D002785:Sterol O-Acyltransferase; D014280:Triglycerides; D000097587:Sterol O-Acyltransferase 2