Erythrocyte Membrane Alterations in Lecithin: Cholesterol Acyltransferase Deficiency

Godin, David V.; Gray, G. R.; Frohlich, J.

doi:10.3109/00365517809104920

Cited by 22 publications

(14 citation statements)

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“…The non HDL cholesterol and apoB levels were similar in both study groups. On the HF/HC diet, the plasma levels of a total cholesterol, phospholipids, CE, HDL cholesterol, non-HDL cholesterol, apoA-I, apoA-II, and apoB of LCAT-KO mice were decreased to 45,48,44,6,52,17,50, and 45% of controls, respectively (p Ͻ 0.01; all), whereas the plasma triglycerides levels remained unchanged. The plasma CE levels dramatically increased as a result of the HF/HC diet in both controls and LCAT-KO mice.…”

Section: Resultsmentioning

confidence: 96%

“…Despite the absence of hyperbilirubinemia, the proportion of target cells (11.2 Ϯ 2.6 versus 2.3 Ϯ 0.5%, p Ͻ 0.01) as well as reticulocytes (13.5 Ϯ 4.1 versus 3.2 Ϯ 1.4%, p Ͻ 0.04) was increased in LCAT-KO mice compared with controls, indicating increased red blood cell hemolysis. As described in FLD patients (17,18,48), the osmotic fragility tests showed that red blood cells from LCAT-KO mice were more resistant to hemolysis than those of controls (5.3 Ϯ 1.5 versus 43.7 Ϯ 3.1% hemoglobin leakage in 0.5% NaCl and 86.3 Ϯ 3.5 versus 97.7 Ϯ 2.1% in 0.4% NaCl; p Ͻ 0.01, all).…”

Section: Blood-blood Samples From Lcat-ko and Control Micementioning

confidence: 99%

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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: Resultsmentioning

confidence: 96%

Section: Blood-blood Samples From Lcat-ko and Control Micementioning

confidence: 99%

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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“…Thus, it would appear that the variation in 2T',, with temperature in the patients who are likely homozygotes for the abnormal genetic trait [5,9] and in their parents (who are presumed heterozygous carriers for the disorder [5.9] ) serves to clearly distinguish these individuals from the normal population. The fact that the clinically unaffected sibling also exhibits the abnormal profile suggests that he too is a carrier.…”

Section: Resultsmentioning

confidence: 99%

“…Gjone et a1 [4,6] and Godin et a1 [5] have shown that LCAT deficiency is accompanied by an increase in erythrocyte membrane phosphatidylcholine (PC) and a decrease Abbreviations used in this paper: LCAT, Lecithin: cholesterol acyltransferase; ESR, electron spin resonance; 5-doxy1 stearic acid, 2-( 3-carboxypropyl)-4,4-dimethyl-2-tridecyl-3-oxazolindinyl-l-oxyl; PC, phosphatidylcholine; PE, phosphatidyle thanolamine.…”

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confidence: 99%

“…The electron spin resonance technique is well established as a valuable tool for exploring structural aspects of biological membranes [8]. In the present study we have employed a spin labeled fatty acid probe [2-(3-carboxypropyl)-4,4-dimethyl-2-tridecyl-3-oxazolindinyl-1 -oxyl or trivially known as 5-doxy1 stearic acid] incorporated into hemoglobin-free erythrocyte membranes from two recently identified patients with LCAT deficiency and their relatives [5]. The temperature dependent spectral characteristics of 5-doxy1 stearic acid show that the physiochemical state of membrane components in clinically affected individuals is abnormal and that similar but distinguishable alterations are present in the membranes of clinically unaffected relatives who are presumed carriers of this genetic disorder.…”

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Detection of erythrocyte membrane structural abnormalities in lecithin: Cholesterol acyltransferase deficiency using a spin label approach

1979

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The membrane fluidity of erythrocytes from patients with Lecithin: cholesterol acyltransferase (LCAT) deficiency was studied by means of electron spin resonance. The temperature dependence of the separation of the outer extrema of the spectra of 2-(3-carboxy-propyl)-4,4-dimethyl, 2-tridecyl-3-oxazolidinyloxyl spin probe was monitored for normal, presumed carrier and clinically affected subjects. The temperature profile of controls was significantly different from that of the presumed carriers and the clinically affected individuals. The results show that the compositional abnormalities previously noted in erythrocyte membranes from patients with LCAT deficiency are associated with alterations in the physiocochemical state of the membrane. An investigation of the spectral lineshapes below 10 degrees C allowed a distinction to be made at the membrane level between clinically affected subjects and clinically normal heterozygous carriers. Alterations in the temperature dependence of elec-ron spin resonance parameters may provide a sensitive index of red cell membrane alterations in pathological states of generalized membrane involvement.

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Decreased sodium influx and abnormal red cell membrane lipids in a patient with familial plasma lecithin:Cholesterol acyltransferase deficiency

et al. 1984

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Red cell membrane metabolism in familial lecithin:cholesterol acyltransferase (LCAT) deficiency was investigated. The family presented here is the third case discovered in Japan. An increase of free cholesterol was observed in the red cell membranes, concomitant with increased phosphatidyl choline. Osmotic fragility of the patient's red cells was diminished rather than increased. Red cell survival (51Cr T1/2) was shortened (15 days). Sodium influx was markedly decreased, although sodium efflux, both ouabain-sensitive and ouabain-insensitive, was normal. The activity of acetyl-cholinesterase as a marker of the outer leaflet of the red cell membranes was decreased, while the activity of glyceraldehyde-3-phosphate dehydrogenase as a marker of the inner leaflet was normal. No abnormalities of adenosine triphosphatases in red cell membranes were observed. These results suggest that the alteration of cholesterol metabolism in the plasma of LCAT deficiency increases the red cell membrane cholesterol and affects the functions of the red cell membranes, especially of the outer leaflet, which may result in decreased sodium influx.

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Erythrocyte Membrane Alterations in Lecithin: Cholesterol Acyltransferase Deficiency

Cited by 22 publications

References 0 publications

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

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

Detection of erythrocyte membrane structural abnormalities in lecithin: Cholesterol acyltransferase deficiency using a spin label approach

Decreased sodium influx and abnormal red cell membrane lipids in a patient with familial plasma lecithin:Cholesterol acyltransferase deficiency

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