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

Kuroda, Masayuki; Holleboom, Adriaan G.; Stroes, Erik S.G.; Asada, Sakiyo; Aoyagi, Yasuyuki; Kamata, Kouju; Yamashita, Shizuya; Ishibashi, Shun; Saitō, Yasushi; Bujo, Hideaki

doi:10.1161/atvbaha.114.303420

Cited by 22 publications

(23 citation statements)

References 29 publications

(36 reference statements)

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“…One of the most striking discoveries of our study, when analyzing the differences between the lipoprotein distribution by different methods, between the two FLD patients with renal disease and the FLD patient without renal disease, was the presence of abnormal lipoprotein profile in FPLC with higher concentrations of small–medium VLDL in NMR. Similar data have been reported by other studies [7,27]. LpX was confirmed by agarose gel electrophoresis and filipin-staining, and estimated by the distribution of FC and CE by NMR.…”

Section: Discussionsupporting

confidence: 89%

“…In FLD, the LCAT enzyme is either absent in plasma, or exhibits no catalytic activity on any lipoprotein [6]. However, FED is characterized by a partial enzyme deficiency, in which LCAT does not esterify cholesterol in HDL, but retains some activity on lipoproteins containing apo B (VLDL and LDL) [7]. Individuals with FED have very low levels of HDL cholesterol and corneal opacities [3,8].…”

Section: Introductionmentioning

confidence: 99%

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Lipid Profile Rather Than the LCAT Mutation Explains Renal Disease in Familial LCAT Deficiency

Lamíquiz-Moneo

Civeira

Gómez-Coronado

et al. 2019

JCM

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Renal complications are the major cause of morbidity and mortality in patients with familial lecithin–cholesterol acyltransferase (LCAT) deficiency (FLD). We report three FLD patients, two of them siblings—only one of whom developed renal disease—and the third case being a young man with early renal disease. The aim of this study was to analyze the clinical characteristics and possible mechanisms associated with renal disease in these patients. Plasma lipid levels, LCAT activity, lipoprotein particle profile by NMR and FPLC, free and esterified cholesterol, presence of lipoprotein X (LpX) and DNA sequencing in the three FLD patients have been determined. The three cases presented clinical characteristics of FLD, although only one of the siblings developed renal disease, at 45 years of age, while the other patient developed the disease in his youth. Genetic analysis revealed new missense homozygous mutations, p.(Ile202Thr) in both siblings and p.(Arg171Glu) in the other patient. Lipoprotein particle analysis showed that the two patients with renal disease presented higher numbers of small very low-density lipoprotein (VLDL) and a higher concentration of triglycerides in VLDL. This study reports three new cases of LCAT deficiency, not previously described. Renal disease is not only dependent on LCAT deficiency, and could be due to the presence of VLDL particles, which are rich in triglycerides, free cholesterol and LpX.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Lipid Profile Rather Than the LCAT Mutation Explains Renal Disease in Familial LCAT Deficiency

Lamíquiz-Moneo

Civeira

Gómez-Coronado

et al. 2019

JCM

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“…The resulting cholesteryl esters (CE) are stored in the hydrophobic core of HDL to be transferred to the liver. In familial LCAT deficiency (FLD) patients, loss of function of LCAT results in lower plasma HDL-C, which may contribute to the pathogenesis of corneal opacity, dyslipidemia and proteinuria with a poor renal prognosis [17]. Overexpression of human LCAT in squirrel monkeys, a non-human primate model, increased HDL-C by 100%, and recombinant human LCAT increased the HDL-C in a phase 1 clinical trial [18–20].…”

Section: Introductionmentioning

confidence: 99%

Deficient Cholesterol Esterification in Plasma of apoc2 Knockout Zebrafish and Familial Chylomicronemia Patients

2017

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Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Apolipoprotein C-II (APOC2) is an obligatory cofactor for lipoprotein lipase (LPL), the major enzyme catalyzing plasma triglyceride hydrolysis. We have created an apoc2 knockout zebrafish model, which mimics the familial chylomicronemia syndrome (FCS) in human patients with a defect in the APOC2 or LPL gene. In this study, we measured plasma levels of free cholesterol (FC) and cholesterol esters (CE) and found that apoc2 mutant zebrafish have a significantly higher FC to CE ratio (FC/CE), when compared to the wild type. Feeding apoc2 mutant zebrafish a low-fat diet reduced triglyceride levels but not the FC/CE ratio. In situ hybridization and qPCR results demonstrated that the hepatic expression of lecithin-cholesterol acyltransferase (lcat), the enzyme responsible for esterifying plasma FC to CE, and of apolipoprotein A-I, a major protein component of HDL, were dramatically decreased in apoc2 mutants. Furthermore, the FC/CE ratio was significantly increased in the whole plasma and in a chylomicron-depleted fraction of human FCS patients. The FCS plasma LCAT activity was significantly lower than that of healthy controls. In summary, this study, using a zebrafish model and human patient samples, reports for the first time the defect in plasma cholesterol esterification associated with LPL deficiency.

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“…There are, however, several other lipoprotein abnormalities in FLD that could also potentially contribute to renal disease. In particular, the enrichment of FC on apoBcontaining lipoproteins, which was also observed in this study, has also been proposed to be nephrotoxic (Kuroda et al, 2014), but this has not been experimentally tested. were kept on normal chow diet.…”

Section: Discussionmentioning

confidence: 67%

LCAT Enzyme Replacement Therapy Reduces LpX and Improves Kidney Function in a Mouse Model of Familial LCAT Deficiency

Vaisman

Neufeld

Freeman

et al. 2018

J Pharmacol Exp Ther

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Familial LCAT deficiency (FLD) is due to mutations in lecithin: cholesterol acyltransferase (LCAT), a plasma enzyme that esterifies cholesterol on lipoproteins. FLD is associated with markedly reduced levels of plasma high-density lipoprotein and cholesteryl ester and the formation of a nephrotoxic lipoprotein called LpX. We used a mouse model in which the LCAT gene is deleted and a truncated version of the SREBP1a gene is expressed in the liver under the control of a protein-rich/carbohydrate-low (PRCL) diet-regulated PEPCK promoter. This mouse was found to form abundant amounts of LpX in the plasma and was used to determine whether treatment with recombinant human LCAT (rhLCAT) could prevent LpX formation and renal injury. After 9 days on the PRCL diet, plasma total and free cholesterol, as well as phospholipids, increased 6.1 6 0.6-, 9.6 6 0.9-, and 6.7 6 0.7-fold, respectively, and liver cholesterol and triglyceride concentrations increased 1.7 6 0.4-and 2.8 6 0.9-fold, respectively, compared with chow-fed animals. Transmission electron microscopy revealed robust accumulation of lipid droplets in hepatocytes and the appearance of multilamellar LpX particles in liver sinusoids and bile canaliculi. In the kidney, LpX was found in glomerular endothelial cells, podocytes, the glomerular basement membrane, and the mesangium. The urine albumin/creatinine ratio increased 30-fold on the PRCL diet compared with chow-fed controls. Treatment of these mice with intravenous rhLCAT restored the normal lipoprotein profile, eliminated LpX in plasma and kidneys, and markedly decreased proteinuria. The combined results suggest that rhLCAT infusion could be an effective therapy for the prevention of renal disease in patients with FLD. grant (grant no. HL002058 to A.T.R.).

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

Cited by 22 publications

References 29 publications

Lipid Profile Rather Than the LCAT Mutation Explains Renal Disease in Familial LCAT Deficiency

Lipid Profile Rather Than the LCAT Mutation Explains Renal Disease in Familial LCAT Deficiency

Deficient Cholesterol Esterification in Plasma of apoc2 Knockout Zebrafish and Familial Chylomicronemia Patients

LCAT Enzyme Replacement Therapy Reduces LpX and Improves Kidney Function in a Mouse Model of Familial LCAT Deficiency

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