Human Lecithin:Cholesterol Acyltransferase Deficiency

Nishiwaki, Masato; Ikewaki, Katsunori; Bader, Giovanni; Nazih, Hassan; Hannuksela, Minna L.; Remaley, Alan T.; Shamburek, Robert D.; Brewer, H. Bryan

doi:10.1161/01.atv.0000217910.90210.99

Cited by 26 publications

(10 citation statements)

References 23 publications

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“…In a study of 2 LCAT-deficient patients and 17 normal subjects, Nishiwaki et al report on the metabolic basis for the complex changes in LDL properties in LCAT-deficiency in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology. 10 As expected, the LCAT-deficient subjects had very low HDL cholesterol levels and also lower apoA-I, apoB, and LDL cholesterol levels than the normal controls. It has been well established in previous studies based on treatment with hypolipidemic agents that net LDL clearance is affected by both LDL receptor activity and LDL particle properties.…”

Section: See Page 1370supporting

confidence: 68%

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Lipoprotein Metabolism

Berglund

2006

ATVB

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Metabolic studies of lipoproteins have yielded important insights into regulation of energy distribution as well as providing fundamental understanding of cardiovascular risk properties of different lipoproteins. Although many factors on the molecular level have the potential to impact metabolic regulation of lipids, metabolic studies provide valuable information from a comprehensive regulatory viewpoint. With increasing emphasis on lipoprotein subfractions and their roles in promoting or protecting from cardiovascular risk, the focus of metabolic studies is largely moving toward more detailed understanding of lipoprotein subclass and individual apolipoprotein properties. See page 1370The atherogenic and antiatherogenic roles of LDL and HDL cholesterol, respectively, are well established and, by now, part of the general public knowledge. However, hereditary diseases of lipoprotein metabolism with dramatically different LDL and/or HDL cholesterol levels offer great promise to further investigate this complex system, and we have already gained considerable insight from such studies. Thus, it is well known that some hereditary conditions result in phenotypes with unusual LDL and HDL compositions. Thus, carriers of apoA-I Milano appear protected from cardiovascular disease in spite of low HDL cholesterol levels. 1,2 In another hereditary condition, lecithin:cholesterol acyltransferase (LCAT) deficiency, HDL metabolism is severely affected, and carriers of this deficiency have low levels of both HDL and LDL cholesterol with the accumulation of an aberrant lipoprotein, Lp-X. 3,4 However, in spite of low HDL cholesterol levels, cardiovascular disease is not common among LCAT-deficient subjects. 5,6 LCAT is critical for esterification of cholesterol, and in the absence of this enzyme HDL maturation is affected, resulting in small discoidal HDL particles which are thought to be deficient in promoting reverse cholesterol transport. 7 On the other hand, LDL particles are also affected by the deficiency in cholesterol esterification and have higher relative amounts of phospholipids, triglyceride, and cholesterol. 8,9 The physicochemical changes in lipoprotein properties observed in LCAT deficiency are likely to be associated with significant metabolic aberrations. Thus, the relative lack of cholesteryl esters in LDL could result in an LDL fraction with reduced atherogenicity, which might contribute to the apparent lack of CAD in these patients. The relative triglyceride enrichment of LDL under these conditions might further make LDL a better substrate for lipase activity, which could contribute to a reduction in LDL plasma circulation time. In a study of 2 LCAT-deficient patients and 17 normal subjects, Nishiwaki et al report on the metabolic basis for the complex changes in LDL properties in LCAT-deficiency in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology. 10 As expected, the LCAT-deficient subjects had very low HDL cholesterol levels and also lower apoA-I, apoB, and LDL cholesterol levels than the norma...

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Section: See Page 1370supporting

confidence: 68%

“…10 They report an unchanged VLDL or IDL apoB clearance but an increased VLDL apoB-production rate in parallel with a decrease in IDL apoB production in the patients. In the LCAT-deficient subjects, more of the VLDL was cleared directly and less converted to IDL and LDL compared with normals.…”

Section: See Page 1370mentioning

confidence: 94%

Lipoprotein Metabolism

Berglund

2006

ATVB

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“…15 LpX is FCand PL-rich but TG-poor lipid particles (30%, 60%, and 2%, respectively) 22 without apolipoproteins, which range from very low density lipoprotein to large LDL fractions in fast performance liquid chromatography analysis. 31 The abnormal particles have been shown to be decreased by lipid-lowering therapy in a patient with FLD. 21 Lipoproteins in Lp8 were different from LpX in the lipid contents; the fractions were rich in FC and PL and also rich in TG (13.2±1.3%, 41.4±3.3%, and 45.8±3.8%, respectively).…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein Subfractions Highly Associated With Renal Damage in Familial Lecithin:Cholesterol Acyltransferase Deficiency

Kuroda

Holleboom

Stroes

et al. 2014

ATVB

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Objective-In familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD), deposition of abnormal lipoproteins in the renal stroma ultimately leads to renal failure. However, fish-eye disease (FED) does not lead to renal damage although the causative mutations for both FLD and FED lie within the same LCAT gene. This study was performed to identify the lipoproteins important for the development of renal failure in genetically diagnosed FLD in comparison with FED, using high-performance liquid chromatography with a gel filtration column. Approach and Results-Lipoprotein profiles of 9 patients with LCAT deficiency were examined. Four lipoprotein fractions specific to both FLD and FED were identified: (1) large lipoproteins (>80 nm), (2) lipoproteins corresponding to large lowdensity lipoprotein (LDL), (3) lipoproteins corresponding to small LDL to large high-density lipoprotein, and (4) to small high-density lipoprotein. Contents of cholesteryl ester and triglyceride of the large LDL in FLD (below detection limit and 45.8±3.8%) and FED (20.7±6.4% and 28.0±6.5%) were significantly different, respectively. On in vitro incubation with recombinant LCAT, content of cholesteryl ester in the large LDL in FLD, but not in FED, was significantly increased (to 4.2±1.4%), whereas dysfunctional high-density lipoprotein was diminished in both FLD and FED. Conclusions-Our novel analytic approach using high-performance liquid chromatography with a gel filtration column identified large LDL and high-density lipoprotein with a composition specific to FLD, but not to FED.

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“…In addition, lipoprotein X (Lp-X)–like particles accumulate, which are large multilamellar phospholipid vesicles that contain various apolipoproteins but do not contain a neutral lipid core. Kinetic studies in humans with genetic LCAT deficiency have revealed that they have hypercatabolism of not only HDL but also LDL [7], which along with the decrease transfer of cholesterol from HDL to LDL probably accounts for the fact that familial LCAT deficiency (FLD) patients usually have low LDL cholesterol (LDL-C).…”

Section: Lcat Biochemistry and Role In Hdl Metabolismmentioning

confidence: 99%

Lecithin Cholesterol Acyltransferase: An Anti- or Pro-atherogenic Factor?

Rousset

Shamburek

Vaisman

et al. 2011

Curr Atheroscler Rep

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Lecithin cholesterol acyl transferase (LCAT) is a plasma enzyme that esterifies cholesterol and raises high-density lipoprotein cholesterol, but its role in atherosclerosis is not clearly established. Studies of various animal models have yielded conflicting results, but studies done in rabbits and non-human primates, which more closely simulate human lipoprotein metabolism, indicate that LCAT is likely atheroprotective. Although suggestive, there are also no biomarker studies that mechanistically link LCAT with cardiovascular disease. Imaging studies of patients with LCAT deficiency have also not yielded a clear answer to the role of LCAT in atherosclerosis. Recombinant LCAT, however, is currently being developed as a therapeutic product for enzyme replacement therapy of patients with genetic disorders of LCAT for the prevention and/or treatment of renal disease, but it may also have value for the treatment of acute coronary syndrome.

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Human Lecithin:Cholesterol Acyltransferase Deficiency

Cited by 26 publications

References 23 publications

Lipoprotein Metabolism

Lipoprotein Metabolism

Lipoprotein Subfractions Highly Associated With Renal Damage in Familial Lecithin:Cholesterol Acyltransferase Deficiency

Lecithin Cholesterol Acyltransferase: An Anti- or Pro-atherogenic Factor?

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