HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 287/5/F1038    most recent 00150.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Vaziri, N. D. Articles by Liang, K. Search for Related Content PubMed PubMed Citation Articles by Vaziri, N. D. Articles by Liang, K.

ACAT inhibition reverses LCAT deficiency and improves plasma HDL in chronic renal failure

Division of Nephrology and Hypertension, University of California, Irvine, California 92697

Submitted 28 April 2004 ; accepted in final form 21 July 2004

Chronic renal failure (CRF) is associated with increased risk of arteriosclerotic cardiovascular disease and profound alteration of plasma lipid profile. Uremic dyslipidemia is marked by increased plasma concentration of ApoB-containing lipoproteins and impaired high-density lipoprotein (HDL)-mediated reverse cholesterol transport. These abnormalities are, in part, due to acquired LCAT deficiency and upregulation of hepatic acyl-CoA:cholesterol acyltransferase (ACAT). ACAT catalyzes intracellular esterification of cholesterol, thereby promoting hepatic production of ApoB-containing lipoproteins and constraining HDL-mediated cholesterol uptake in the peripheral tissues. In view of the above considerations, we tested the hypothesis that pharmacological inhibition of ACAT may ameliorate CRF-induced dyslipidemia. 5/6 Nephrectomized rats were treated with either ACAT inhibitor IC-976 (30 mg·kg^–1·day^–1) or placebo for 6 wk. Sham-operated rats served as controls. Key cholesterol-regulating enzymes, plasma lipids, and creatinine clearance were measured. The untreated CRF rats exhibited increased plasma low-density lipoprotein (LDL) and very LDL (VLDL) cholesterol, unchanged plasma HDL cholesterol, elevated total cholesterol-to-HDL cholesterol ratio, reduced liver microsomal free cholesterol, and diminished creatinine clearance. This was accompanied by reduced plasma LCAT, increased hepatic ACAT-2 mRNA, ACAT-2 protein and ACAT activity, and unchanged hepatic HMG-CoA reductase and cholesterol 7-hydroxylase. ACAT inhibitor raised plasma HDL cholesterol, lowered LDL and VLDL cholesterol, and normalized total cholesterol-to-HDL cholesterol ratio without changing total cholesterol concentration (hence, a shift from ApoB-containing lipoproteins to HDL). This was accompanied by normalizations of hepatic ACAT activity and plasma LCAT. In conclusion, inhibition of ACAT reversed LCAT deficiency and improved plasma HDL level in CRF rats. Future studies are needed to explore the efficacy of ACAT inhibition in humans with CRF.

high-density lipoprotein; hyperlipidemia; lecithin:cholesterol acyltransferase; cholesterol; acyl-CoA:cholesterol acyltransferase; progression of renal disease; atherosclerosis; cardiovascular disease; end-stage renal disease

This article has been cited by other articles:

				M. V. Pahl, Z. Ni, L. Sepassi, H. Moradi, and N. D. Vaziri Plasma phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase in end-stage renal disease (ESRD) Nephrol. Dial. Transplant., August 1, 2009; 24(8): 2541 - 2546. [Abstract] [Full Text] [PDF]

				H. J. Kim, H. Moradi, J. Yuan, K. Norris, and N. D. Vaziri Renal mass reduction results in accumulation of lipids and dysregulation of lipid regulatory proteins in the remnant kidney Am J Physiol Renal Physiol, June 1, 2009; 296(6): F1297 - F1306. [Abstract] [Full Text] [PDF]

				N. D. Vaziri Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences Am J Physiol Renal Physiol, February 1, 2006; 290(2): F262 - F272. [Abstract] [Full Text] [PDF]