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Originally published In Press as doi:10.1074/jbc.M008466200 on February 7, 2001

J. Biol. Chem., Vol. 276, Issue 18, 15090-15098, May 4, 2001
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Analysis of Glomerulosclerosis and Atherosclerosis in Lecithin Cholesterol Acyltransferase-deficient Mice*

Gilles LambertDagger §, Naohiko SakaiDagger §, Boris L. VaismanDagger , Edward B. NeufeldDagger , Benoit MarteynDagger , Chi-Chao Chan||, Beverly Paigen**, Enrico LupiaDagger Dagger , Alton ThomasDagger Dagger , Liliane J. StrikerDagger Dagger , Joan Blanchette-Mackie§§, Gyorgy Csako¶¶, John N. Brady||||, Rene Costello¶¶, Gary E. StrikerDagger Dagger , Alan T. RemaleyDagger , H. Bryan Brewer Jr.Dagger , and Silvia Santamarina-FojoDagger

From the Dagger  Molecular Disease Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, the || Laboratory of Immunology, NEI, National Institutes of Health, Bethesda, Maryland 20892, the ** Jackson Laboratory, Bar Harbor, Maine 04609, the Dagger Dagger  Renal Cell Biology Laboratory, University of Miami School of Medicine, Miami, Florida 33101, the §§ Lipid Cell Biology Laboratory, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, the ¶¶ Clinical Pathology Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, and the |||| Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892

To evaluate the biochemical and molecular mechanisms leading to glomerulosclerosis and the variable development of atherosclerosis in patients with familial lecithin cholesterol acyl transferase (LCAT) deficiency, we generated LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E KO, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transfer protein transgenic mice. LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased red blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipoprotein X and developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduced the plasma high density lipoprotein (HDL) cholesterol (-70 to -94%) and non-HDL cholesterol (-48 to -85%) levels in control, apoE-KO, LDLr-KO, and cholesteryl ester transfer protein-Tg mice. Transcriptome and Western blot analysis demonstrated up-regulation of hepatic LDLr and apoE expression in LCAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantly reduced (-35% to -99%) in all mouse models with LCAT deficiency. Our studies indicate (i) that the plasma levels of apoB containing lipoproteins rather than HDL may determine the atherogenic risk of patients with hypoalphalipoproteinemia due to LCAT deficiency and (ii) a potential etiological role for lipoproteins X in the development of glomerulosclerosis in LCAT deficiency. The availability of LCAT-KO mice characterized by lipid, hematologic, and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

To whom correspondence should be addressed: Molecular Disease Branch, NHLBI, NIH, Bldg. 10, Rm. 7N115, 10 Center Dr., Bethesda, MD 20892-1666. Tel.: 301-496-6750; Fax: 301-402-0190; E-mail: gl68i@nih.gov.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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