Familial Deficiency of Apolipoproteins A-I and C-III and Precocious Coronary-Artery Disease

Norum, Robert A.; Lakier, Jeffrey B.; Ángel, A.; Goldberg, Ronald; Block, Walter D.; Noffze, Donna K.; Dolphin, Peter J.; Edelglass, John; Bogorad, David; Alaupovic, Petar

doi:10.1056/nejm198206243062503

Cited by 291 publications

(81 citation statements)

References 31 publications

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“…Lipoprotein disorders are frequently associated with alterations in the morphology and lipid composition of the cornea. Corneal opacities are found in several syndromes associated with HDL deficiency including Tangier disease (58), apoA-I deficiency (59,60) as well as FED and FLD (12,61). 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.…”

Section: Discussionmentioning

confidence: 95%

Analysis of Glomerulosclerosis and Atherosclerosis in Lecithin Cholesterol Acyltransferase-deficient Mice

Lambert

Sakai

Vaisman

et al. 2001

Journal of Biological Chemistry

118

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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.As the key enzyme responsible for the esterification of free cholesterol present in circulating lipoproteins, LCAT 1 plays a major role in HDL metabolism (1). Several lines of evidence that include epidemiological data, transgenic animal studies, and, more recently, prospective human clinical trials (2-6) 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 (7,8). 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 (1). 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 (9, 10). Alternatively HDL-CE may be transferred to apoB-containing lipoproteins as a result of the activity of cholesterol ester transfer protein (CETP) (8).The important role that LCAT plays in HDL metabolism has been established by the ide...

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Section: Discussionmentioning

confidence: 95%

Analysis of Glomerulosclerosis and Atherosclerosis in Lecithin Cholesterol Acyltransferase-deficient Mice

Lambert

Sakai

Vaisman

et al. 2001

Journal of Biological Chemistry

118

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“…The first proband was a 33-year-old white woman who had yellow-orange, indurated plaques on her trunk, neck, eyelids, chest, arms, and back since adolescence, significant three-vessel coronary artery disease, a decreased left ventricular ejection fraction, and mild diffuse corneal opacification (first noted in the periphery of the cornea at 31 years of age). 86 A biopsy of one skin xanthoma revealed perivascular histiocytic lipid deposition. Her tonsils were normal, and she had symptoms of dyspnea, orthopnea, and palpitations.…”

Section: Familial Deficiency Of Apollpoprotelns A-l and C-lllmentioning

confidence: 99%

Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency.

Schaefer¹

1984

Arteriosclerosis

162

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P lasma high density lipoproteins (HDL, density = 1.063 -1.21 g/ml) mostly have alpha mobility on lipoprotein electrophoresis, and are composed (weight %) of approximately 50% protein, 25% phospholipid, 20% cholesterol (mainly esterified), and triglyceride. 1 " 1 Fluctuations in HDL levels have been associated largely with alterations in HDL (d = 1.063-1.125 g/ml). 5 Cholesterol is the HDL constituent commonly measured (following precipitation of other lipoproteins), and decreased plasma HDL cholesterol concentrations have been associated with premature coronary artery disease (CAD).*" 11 The normal values for this parameter are given in Table 1.

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“…In contrast, a congenital deficiency of apo A-I and C-I11 is associated with severe premature arterial disease (43).…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein A-I (Glu 198→Lys): A Mutant of the Major Apolipoprotein of High-Density Lipoproteins Occurring in a Family with Dyslipoproteinemia

et al. 1988

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Familial Deficiency of Apolipoproteins A-I and C-III and Precocious Coronary-Artery Disease

Cited by 291 publications

References 31 publications

Analysis of Glomerulosclerosis and Atherosclerosis in Lecithin Cholesterol Acyltransferase-deficient Mice

Analysis of Glomerulosclerosis and Atherosclerosis in Lecithin Cholesterol Acyltransferase-deficient Mice

Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency.

Apolipoprotein A-I (Glu 198→Lys): A Mutant of the Major Apolipoprotein of High-Density Lipoproteins Occurring in a Family with Dyslipoproteinemia

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