Analysis of Glomerulosclerosis and Atherosclerosis in Lecithin Cholesterol Acyltransferase-deficient Mice
2001; Elsevier BV; Volume: 276; Issue: 18 Linguagem: Inglês
10.1074/jbc.m008466200
ISSN1083-351X
AutoresGilles Lambert, Naohiko Sakai, Boris Vaisman, Edward B. Neufeld, Benoît Marteyn, Chi‐Chao Chan, Beverly Paigen, Enrico Lupia, Alton Thomas, Liliane J. Striker, Joan Blanchette‐Mackie, György Csákó, John Brady, Rene Costello, Gary E. Striker, Alan T. Remaley, H Bryan Brewer, Silvia Santamarina-Fojo,
Tópico(s)Lipid metabolism and disorders
ResumoTo 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. 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. lecithin cholesterol acyl transferase high density lipoprotein low density lipoprotein low density lipoprotein receptor cholesteryl ester(s) cholesteryl ester transfer protein familial LCAT deficiency fish eye disease apolipoprotein high fat/high cholesterol knockout lipoprotein X 4-morpholineethanesulfonic acid very low density lipoprotein intermediate density lipoprotein As the key enzyme responsible for the esterification of free cholesterol present in circulating lipoproteins, LCAT1 plays a major role in HDL metabolism (1Glomset J.A. J. Lipid Res. 1968; 9: 155-167Abstract Full Text PDF PubMed Google Scholar). Several lines of evidence that include epidemiological data, transgenic animal studies, and, more recently, prospective human clinical trials (2Gordon D.J. Rifkind B.M. N. Engl. J. Med. 1989; 321: 1311-1316Crossref PubMed Scopus (1402) Google Scholar, 3Buring J.E. O'Connor G.T. Goldhaber S.Z. Rosner B. Herbert P.N. Blum C.B. Breslow J.L. Hennekens C.H. Circulation. 1992; 85: 22-29Crossref PubMed Scopus (204) Google Scholar, 4Rubin E.M. Krauss R.M. Spangler E.A. Verstuyft J.G. Clift S.M. Nature. 1991; 353: 265-267Crossref PubMed Scopus (858) Google Scholar, 5Duverger N. Kruth H. Emmanuel F. Caillaud J.M. Viglietta C. Castro G. Tailleux A. Fievet C. Fruchart J.C. Houdebine L.M. Denefle P. Circulation. 1996; 94: 713-717Crossref PubMed Scopus (213) Google Scholar, 6Rubins H.B. Robins S.J. Collins D. Fye C.L. Anderson J.W. Elam M.B. Faas F.H. Linares E. Schaefer E.J. Schectman G. Wilt T.J. Wittes J. N. Engl. J. Med. 1999; 341: 410-418Crossref PubMed Scopus (3167) Google Scholar) indicate that increased plasma HDL levels protect against the development of atherosclerosis. One of several proposed functions of HDL as an anti-atherogenic lipoprotein is to facilitate reverse cholesterol transport, a process by which cholesterol is transported from peripheral cells to the liver for removal from the body (7Fielding C.J. Fielding P.E. J. Lipid Res. 1995; 36: 211-228Abstract Full Text PDF PubMed Google Scholar, 8Tall A.R. Eur. Heart J. 1998; 19: A31-A35PubMed Google Scholar). LCAT may play a major role in this process by maintaining a free cholesterol gradient between peripheral cells and the HDL particle surface, thus promoting free cholesterol efflux (1Glomset J.A. J. Lipid Res. 1968; 9: 155-167Abstract Full Text PDF PubMed Google Scholar). The newly generated cholesteryl esters (CE) accumulating in the HDL core may be transferred directly to the liver via whole particle and/or selective uptake (9Eisenberg S. Oschry Y. Zimmerman J. J. Lipid Res. 1984; 25: 121-128Abstract Full Text PDF PubMed Google Scholar, 10Glass C. Pittman R.C. Weinstein D.B. Steinberg D. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 5435-5439Crossref PubMed Scopus (420) Google Scholar). Alternatively HDL-CE may be transferred to apoB-containing lipoproteins as a result of the activity of cholesterol ester transfer protein (CETP) (8Tall A.R. Eur. Heart J. 1998; 19: A31-A35PubMed Google Scholar).The important role that LCAT plays in HDL metabolism has been established by the identification and characterization of patients with LCAT deficiency. Mutations in the human LCAT gene result either in familial LCAT deficiency (FLD) or in fish eye disease (FED). FED patients have a partial deficiency of LCAT function leading to hypoalphalipoproteinemia and the development of corneal opacities (11Carlson L.A. Philipson B. Lancet. 1979; 2: 921-923Abstract Scopus (113) Google Scholar,12Santamarina-Fojo S. Hoeg J.M. Assmann G. Brewer Jr., H.B. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw Hill, New York1999Google Scholar). FLD patients have a total deficiency of LCAT function (12Santamarina-Fojo S. Hoeg J.M. Assmann G. Brewer Jr., H.B. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw Hill, New York1999Google Scholar, 13Norum K.R. Gjone E. Scand. J. Clin. Lab. Invest. 1967; 20: 231-243Crossref Scopus (199) Google Scholar). In addition to hypoalphalipoproteinemia and corneal opacities, many FLD patients also develop a mild normochromic, normocytic anemia, proteinuria, and/or renal dysfunction (14Gjone E. Norum K.R. Acta Med. 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Nephron. 1977; 18: 239-248Crossref PubMed Scopus (16) Google Scholar, 20Borysiewicz L.K. Soutar A.K. Evans D.J. Thompson G.R. Rees A.J. Q. J. Med. 1982; 51: 411-426PubMed Google Scholar), but its pathogenesis is poorly understood. Likewise, the role of LCAT in modulating the development of atherosclerosis in these patients remains unclear. Despite reduced plasma HDL, many patients with FLD or FED do not appear to have an increased risk for developing cardiovascular disease (21Kuivenhoven J.A. Pritchard H. Hill J. Frohlich J. Assmann G. Kastelein J. J. Lipid Res. 1997; 38: 191-205Abstract Full Text PDF PubMed Google Scholar). Nevertheless, premature coronary heart disease has been documented angiographically and clinically in a subset of these patients (22Solajic-Bozicevic N. Stavljenic-Rukavina A. Sesto M. Clin. Invest. 1994; 72: 951-956Crossref PubMed Scopus (25) Google Scholar, 23Kuivenhoven J.A. Stalenhoef A.F.H. Hill J.S. Demacker P.N.M. Errami A. Kastelein J.J.P. Pritchard P.H. 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Chem. 1997; 272: 7506-7510Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar) and others (32Ng D.S. Francone O.L. Forte T.M. Zhang J. Haghpassand M. Rubin E.M. J. Biol. Chem. 1997; 272: 15777-15781Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar) have previously described the generation of LCAT-KO mice. On a regular chow diet these animals have markedly reduced total cholesterol, HDL cholesterol, and apoA-I levels (31Sakai N. Vaisman B.L. Koch C.A. Hoyt Jr., R.F. Meyn S.M. Talley G.D. Paiz J.A. Brewer Jr., H.B. Santamarina-Fojo S. J. Biol. Chem. 1997; 272: 7506-7510Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 32Ng D.S. Francone O.L. Forte T.M. Zhang J. Haghpassand M. Rubin E.M. J. Biol. Chem. 1997; 272: 15777-15781Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). In the present study we characterize the lipid, ophthalmologic, hematological, renal, and cardiovascular organ systems of LCAT-KO mice on both regular and high fat/high cholesterol (HF/HC) diets. LCAT-KO mice develop a clinical phenotype similar to human patients with FLD. In addition to severe hypoalphalipoproteinemia, LCAT-KO mice present with normochromic normocytic anemia and glomerulosclerosis. Our findings indicate that the induction of LpX by the HF/HC diet is associated with the development of glomerulosclerosis in these mice. We also report that, in addition to decreased HDL, LCAT deficiency reduces the plasma levels of apoB-containing lipoproteins by up-regulating LDL receptor gene expression. Despite the low plasma HDL levels, these changes in the plasma lipid profile lead to markedly reduced aortic atherosclerosis in mice with LCAT deficiency. These combined findings provide important new insights into the role that LCAT plays in the development of glomerulosclerosis and atherosclerosis in LCAT-deficient states.DISCUSSIONIn the present study we have investigated potential mechanisms leading to renal disease and altered atherogenic risk in LCAT-KO and LCAT-KO mice crossed with atherosclerosis-susceptible mouse models. LCAT-KO mice present with a clinical phenotype similar to patients with FLD, including normochromic normocytic anemia, glomerulosclerosis, hypoalphalipoproteinemia, and hypertriglyceridemia. In addition, LCAT deficiency alters the plasma levels of the pro-atherogenic apoB containing lipoproteins by modulating the hepatic expression of the LDLr and apoE, which, despite decreased HDL levels, leads to reduced atherogenic risk.LCAT deficiency in mice markedly reduces total cholesterol, HDL cholesterol, and apoA-I levels as well as increases pre-β HDL and triglyceride levels (31Sakai N. Vaisman B.L. Koch C.A. Hoyt Jr., R.F. Meyn S.M. Talley G.D. Paiz J.A. Brewer Jr., H.B. Santamarina-Fojo S. J. Biol. Chem. 1997; 272: 7506-7510Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 32Ng D.S. Francone O.L. Forte T.M. Zhang J. Haghpassand M. Rubin E.M. J. Biol. Chem. 1997; 272: 15777-15781Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). Surprisingly, on the HF/HC diet LCAT-KO mice had significantly lower plasma levels of the proatherogenic apoB-containing lipoproteins. Decreased plasma LDL levels have been reported in some (12Santamarina-Fojo S. Hoeg J.M. Assmann G. Brewer Jr., H.B. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw Hill, New York1999Google Scholar, 13Norum K.R. Gjone E. Scand. J. Clin. Lab. Invest. 1967; 20: 231-243Crossref Scopus (199) Google Scholar, 49Klein H.-G. Santamarina-Fojo S. Duverger N. Clerc M. Dumon M.-F. Albers J.J. Marcovina S. Brewer Jr., H.B. J. Clin. 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A. 1991; 88: 4855-4859Crossref PubMed Scopus (105) Google Scholar) patients with LCAT deficiency reflecting genetic variability absent in LCAT-KO mice. Despite the absence of LCAT activity, LCAT-KO mice had a dramatic increase in their plasma CE levels on the atherogenic diet, suggesting enhanced contribution by the enzyme acylCoA:cholesterol acyltransferase responsible for the intracellular esterification of cholesterol. Further analysis of the plasma lipoproteins in LCAT-KO mice revealed that the VLDL density fractions were triglyceride-enriched. LDL were polydisperse consisting of normal spherical lipoproteins as well as large structures of 66.7 nm in diameter previously designated as large molecular weight LDL (54Gjone E. Blomhoff J.P. Skarbovik A.J. Clin. Chim. Acta. 1974; 54: 11-18Crossref PubMed Scopus (47) Google Scholar). The two major HDL particles described in FLD (i.e. discoidal particles forming rouleaux and spherical particles) (12Santamarina-Fojo S. Hoeg J.M. Assmann G. Brewer Jr., H.B. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw Hill, New York1999Google Scholar) were also present in LCAT knock-out mice with a decreased proportion of discoidal particles and an increase in the mean diameter of the spherical particles after the HF/HC diet. LpX was detected by electrophoresis and immunofixation electrophoresis on agarose and agar gels in a subset of LCAT-KO mice fed a HF/HC diet for 16 weeks. LpX, first described in patients with primary biliary obstruction (55Torsvik H. Berg K. Magnani H.N. McConathy W.J. Alaupovic P. Gjone E. FEBS Lett. 1972; 24: 165-167Crossref PubMed Scopus (57) Google Scholar), appear to be bilayer vesicles with diameters of 30–70 nm (47Lynn E.G. Choy P.C. Magil A. O K. Mol. Cell Biochem. 1997; 175: 187-194Crossref PubMed Scopus (20) Google Scholar, 56Patsch J.R. Aune K.C. Gotto Jr., A.M. Morrisett J.D. J. Biol. 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Assmann G. Reckwerth A. Welp S. J. Clin. Invest. 1991; 87: 371-376Crossref PubMed Scopus (97) Google Scholar, 60Norum R.A. Lakier J.B. Goldstein S. Angel A. Goldberg R.B. Block W.D. Noffze D.K. Dolphin P.J. Edelglass J. Bogorad D.D. Alaupovic P. N. Engl. J. Med. 1982; 306: 1513-1519Crossref PubMed Scopus (201) Google Scholar) as well as FED and FLD (12Santamarina-Fojo S. Hoeg J.M. Assmann G. Brewer Jr., H.B. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw Hill, New York1999Google Scholar, 61McIntyre N. J. Inherited Metab. Dis. 1988; 11: 45-56Crossref PubMed Scopus (42) Google Scholar). However, analysis of the cornea of LCAT-KO mice with hematoxylin and eosin, periodic acid-Schiff, or oil red-O failed to reveal similar changes.LCAT-KO mice developed anemia characterized by normochromic normocytic indices, increased target cells, and reticulocyte count findings consulted with hemolysis. The mild hemolytic anemia appears to be secondary to altered red blood cell membrane lipids resulting from changes in plasma cholesterol metabolism. The red blood cell membrane fragility was decreased in LCAT-KO compared with controls, consistent with altered red blood cell membrane lipids as well as an increased proportion of target cells that are more resistant to hemolysis (62Gjone E. Scand. J. Clin. Lab. Invest. Suppl. 1974; 137: 73-82PubMed Google Scholar).We further examined the consequences of LCAT deficiency on the morphology and function of the kidneys from mice maintained either on regular or HF/HC diets. Glomerulosclerosis was not detected in LCAT-KO mice on a regular chow diet. In contrast, on the HF/HC diet, a subset of LCAT-KO mice developed renal lesions similar to those previously described in patients with FLD (19Myhre E. Gjone E. Flatmark A. Hovig T. Nephron. 1977; 18: 239-248Crossref PubMed Scopus (16) Google Scholar, 20Borysiewicz L.K. Soutar A.K. Evans D.J. Thompson G.R. Rees A.J. Q. J. Med. 1982; 51: 411-426PubMed Google Scholar, 63Imbasciati E. Paties C. Scarpioni L. Mihatsch M.J. Am. J. Nephrol. 1986; 6: 66-70Crossref PubMed Scopus (32) Google Scholar, 64Ohta Y. Yamamoto S. Tsuchida H. Murano S. Saitoh Y. Tohjo S. Okada M. Am. J. Kidney Dis. 1986; VII: 41-46Abstract Full Text PDF Scopus (32) Google Scholar, 65Lager D.J. Rosenberg B.F. Shapiro H. Bernstein J. Mod. Pathol. 1991; 4: 331-335PubMed Google Scholar). Histologically, these lesions were characterized by significant reductions in the vascular space, expanded mesangial region with increased number of mesangial cells and mesangial sclerosis, and increased extracellular matrix with accumulation of lipid droplets and macrophages. Filipin and oil red-O staining demonstrated the accumulation of free cholesterol and polar lipids in the glomeruli. Ultrastructurally, the endothelial cytoplasm and the vascular spaces were smaller in LCAT-KO than in controls, and the mesangial regions contained an increased amount of extracellular matrix. Although significant, the glomerular lesions in LCAT-KO mice fall within the milder spectrum of lesions described in FLD patients. However, most of the tissue analysis has been performed in patients with end stage renal disease. The absence of lesions on a regular chow diet, and the mildness of the lesions after the HF/HC diet, in the LCAT-KO mice, are both consistent with previous observations that the C57Bl/6 mouse strain is resistant to the induction of glomerulosclerosis (66Zheng F. Striker G.E. Esposito C. Lupia E. Striker L.J. Kidney Int. 1998; 54: 1999-2007Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). The plasma albumin, total protein, blood urea nitrogen, and creatinine levels were normal in all study animals, even in LCAT-KO mice found to have renal lesions. In patients with FLD these plasma indicators of renal function remain normal until the development of severe renal disease. Proteinuria, one of the earliest findings in patients with FLD (12Santamarina-Fojo S. Hoeg J.M. Assmann G. Brewer Jr., H.B. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw Hill, New York1999Google Scholar, 13Norum K.R. Gjone E. Scand. J. Clin. Lab. Invest. 1967; 20: 231-243Crossref Scopus (199) Google Scholar, 62Gjone E. Scand. J. Clin. Lab. Invest. Suppl. 1974; 137: 73-82PubMed Google Scholar) was also detected in 10 of 11 LCAT-KO mice on the HF/HC diet. Thus, the renal lesions in LCAT-KO mice lead to abnormal renal function.The pathogenesis of renal injury in FLD is poorly understood. Some investigators have suggested that the renal damages observed in FLD may be immune complex- and complement-mediated (20Borysiewicz L.K. Soutar A.K. Evans D.J. Thompson G.R. Rees A.J. Q. J. Med. 1982; 51: 411-426PubMed Google Scholar, 65Lager D.J. Rosenberg B.F. Shapiro H. Bernstein J. Mod. Pathol. 1991; 4: 331-335PubMed Google Scholar) and may be further exacerbated by the accumulation of oxidized phospholipids in the glomeruli (67Jimi S. Uesugi N. Saku K. Itabe H. Zhang B. Arakawa K. Takebayashi S. Arterioscler. Thromb. Vasc. Biol. 1999; 19: 794-801Crossref PubMed Scopus (50) Google Scholar). It has also been suggested that large LDL particles as well as LpX trapped in capillary loops induce endothelial damage and vascular injury in the kidneys of FLD patients (51Norum K.R. Glomset J.A. Nichols A.V. Forte T. J. Clin. Invest. 1971; 50: 1131-1140Crossref PubMed Scopus (77) Google Scholar, 54Gjone E. Blomhoff J.P. Skarbovik A.J. Clin. Chim. Acta. 1974; 54: 11-18Crossref PubMed Scopus (47) Google Scholar, 63Imbasciati E. Paties C. Scarpioni L. Mihatsch M.J. Am. J. Nephrol. 1986; 6: 66-70Crossref PubMed Scopus (32) Google Scholar). However, these abnormal lipoproteins are not always detected in FLD (20Borysiewicz L.K. Soutar A.K. Evans D.J. Thompson G.R. Rees A.J. Q. J. Med. 1982; 51: 411-426PubMed Google Scholar). It is of interest that LCAT-KO mice developed glomerulosclerosis only while on the HF/HC diet, when the plasma levels of apoB-containing lipoproteins were increased. Both large LDL and LpX were present in the plasma of LCAT-KO mice only on the HF/HC diet. Furthermore, renal lesions were only detected in the group of mice that accumulated LpX. These findings provide strong support for the importance of large LDL and LpX in the development of renal disease in FLD (68O K. Ly M. Fang D.Z. Frohlich J. Choy P.C. Mol. Cell Biochem. 1997; 173: 17-24Crossref PubMed Scopus (12) Google Scholar).In patients with LCAT deficiency the atherogenic risk is variable. The mechanisms leading to altered atherosclerosis are poorly understood. 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