![]()
|
|
||||||||
J. Biol. Chem., Vol. 276, Issue 18, 15090-15098, May 4, 2001
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the 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 (
Analysis of Glomerulosclerosis and Atherosclerosis in
Lecithin Cholesterol Acyltransferase-deficient Mice*
§¶,
§,
,
,
,
,
,
,
,
,
,
,
, and
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

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
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.
This article has been cited by other articles:
![]() |
R. S. Kiss, N. Kavaslar, K.-i. Okuhira, M. W. Freeman, S. Walter, R. W. Milne, R. McPherson, and Y. L. Marcel Genetic Etiology of Isolated Low HDL Syndrome: Incidence and Heterogeneity of Efflux Defects Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1139 - 1145. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. Sarov-Blat, R. S. Kiss, B. Haidar, N. Kavaslar, M. Jaye, M. Bertiaux, K. Steplewski, M. R. Hurle, D. Sprecher, R. McPherson, et al. Predominance of a Proinflammatory Phenotype in Monocyte-Derived Macrophages From Subjects With Low Plasma HDL-Cholesterol Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1115 - 1122. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. Haidar, R. S. Kiss, L. Sarov-Blat, R. Brunet, C. Harder, R. McPherson, and Y. L. Marcel Cathepsin D, a Lysosomal Protease, Regulates ABCA1-mediated Lipid Efflux J. Biol. Chem., December 29, 2006; 281(52): 39971 - 39981. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. T. Flowers, A. K. Groen, A. T. Oler, M. P. Keller, Y. Choi, K. L. Schueler, O. C. Richards, H. Lan, M. Miyazaki, F. Kuipers, et al. Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet J. Lipid Res., December 1, 2006; 47(12): 2668 - 2680. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Cuchel and D. J. Rader Macrophage Reverse Cholesterol Transport: Key to the Regression of Atherosclerosis? Circulation, May 30, 2006; 113(21): 2548 - 2555. [Full Text] [PDF] |
||||
![]() |
H. Song, L. Zhu, C. M. Picardo, G. Maguire, V. Leung, P. W. Connelly, and D. S. Ng Coordinated alteration of hepatic gene expression in fatty acid and triglyceride synthesis in LCAT-null mice is associated with altered PUFA metabolism Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E17 - E25. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. G. Lee, K. L. Kelley, J. K. Sawyer, R. V. Farese Jr, J. S. Parks, and L. L. Rudel Plasma Cholesteryl Esters Provided by Lecithin:Cholesterol Acyltransferase and Acyl-Coenzyme A:Cholesterol Acyltransferase 2 Have Opposite Atherosclerotic Potential Circ. Res., November 12, 2004; 95(10): 998 - 1004. [Abstract] [Full Text] [PDF] |
||||
![]() |
X. Zhu, A. M. Herzenberg, M. Eskandarian, G. F. Maguire, J. W. Scholey, P. W. Connelly, and D. S. Ng A Novel in Vivo Lecithin-Cholesterol Acyltransferase (LCAT)-Deficient Mouse Expressing Predominantly LpX Is Associated with Spontaneous Glomerulopathy Am. J. Pathol., October 1, 2004; 165(4): 1269 - 1278. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. Afzali, A. A. Haydar, K. Vinen, and D. J.A. Goldsmith From Finland to Fatland: Beneficial Effects of Statins for Patients with Chronic Kidney Disease J. Am. Soc. Nephrol., August 1, 2004; 15(8): 2161 - 2168. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. E. Wu, F. Basso, R. D. Shamburek, M. J. A. Amar, B. Vaisman, G. Szakacs, C. Joyce, T. Tansey, L. Freeman, B. J. Paigen, et al. Hepatic ABCG5 and ABCG8 Overexpression Increases Hepatobiliary Sterol Transport but Does Not Alter Aortic Atherosclerosis in Transgenic Mice J. Biol. Chem., May 28, 2004; 279(22): 22913 - 22925. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. E. Akiyama, G. Lambert, C. J. Nicol, K. Matsusue, J. M. Peters, H. B. Brewer Jr., and F. J. Gonzalez Peroxisome Proliferator-activated Receptor {beta}/{delta} Regulates Very Low Density Lipoprotein Production and Catabolism in Mice on a Western Diet J. Biol. Chem., May 14, 2004; 279(20): 20874 - 20881. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Buzello, C. S. Haas, F. Hauptmann, M. L. Gross, J. Faulhaber, S. Schultze-Mosgau, H. Ehmke, E. Ritz, and K. Amann No aggravation of renal injury in apolipoprotein E knockout mice (ApoE-/-) after subtotal nephrectomy Nephrol. Dial. Transplant., March 1, 2004; 19(3): 566 - 573. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Lambert, M. J. A. Amar, G. Guo, H. B. Brewer Jr., F. J. Gonzalez, and C. J. Sinal The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis J. Biol. Chem., January 17, 2003; 278(4): 2563 - 2570. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. S. Ng, G. F. Maguire, J. Wylie, A. Ravandi, W. Xuan, Z. Ahmed, M. Eskandarian, A. Kuksis, and P. W. Connelly Oxidative Stress Is Markedly Elevated in Lecithin:Cholesterol Acyltransferase-deficient Mice and Is Paradoxically Reversed in the Apolipoprotein E Knockout Background in Association with a Reduction in Atherosclerosis J. Biol. Chem., March 29, 2002; 277(14): 11715 - 11720. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. W. Furbee Jr., J. K. Sawyer, and J. S. Parks Lecithin:Cholesterol Acyltransferase Deficiency Increases Atherosclerosis in the Low Density Lipoprotein Receptor and Apolipoprotein E Knockout Mice J. Biol. Chem., January 25, 2002; 277(5): 3511 - 3519. [Abstract] [Full Text] [PDF] |
||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |