Enhanced fractional catabolic rate of apo A-I and apo A-II in heterozygous subjects for apo A-I(Zaragoza) (L144R).
We have recently reported a new apolipoprotein (apo) A-I variant (apo A-I(Zaragoza) L144R) in a Spanish family with HDL-C levels below the 5th percentile for age and sex and low apo A-I concentrations. All the apo A-I(Zaragoza) subjects were heterozygous and none of them showed evidence of coronary artery disease (CAD). Mean plasma HDL-C, apo A-I, and apo A-II levels were lower in apo A-I(Zaragoza) carriers as compared to control subjects (40, 60, and 50%, respectively). Lipid composition analysis revealed that apo A-I(Zaragoza) carriers had HDL particles with a higher percentage of HDL triglyceride and a lower percentage of HDL esterified cholesterol as compared to those of control subjects. Lecithin:cholesterol acyltransferase (LCAT) activity and cholesterol esterification rate of apo A-I(Zaragoza) carriers were normal. Apo A-I and apo A-II metabolic studies were performed on two heterozygous apo A-I(Zaragoza) carriers and on six control subjects. We used a primed constant infusion of [5,5,5-2H3]leucine and HDL apo A-I and apo A-II tracer/tracee ratios were determined by gas chromatography mass spectrometry and fitted to a monoexponential equation using SAAM II software. Both subjects carrying apo A-I(Zaragoza) variant showed mean apo A-I fractional catabolic rate (FCR) values more than two-fold higher than mean FCR values of their controls (0.470+/-0.0792 vs. 0.207+/-0.0635 x day(-1), respectively). Apo A-I secretion rate (SR) of apo A-I(Zaragoza) subjects was slightly increased compared with controls (17.32+/-0.226 vs. 12.76+/-3.918 mg x kg(-l) x day(-1), respectively). Apo A-II FCR was also markedly elevated in both subjects with apo A-I(Zaragoza) when compared with controls (0.366+/-0.1450 vs. 0.171+/-0.0333 x day(-1), respectively) and apo A-II SR was normal (2.31+/-0.517 vs. 2.1+/-0.684 mg x kg(-l) x day(-1), respectively). Our results show that the apo A-I(Zaragoza) variant results in heterozygosis in abnormal HDL particle composition and in enhanced catabolism of apo A-I and apo A-II without affecting significantly the secretion rates of these apolipoproteins and the LCAT activation.
Departamento de Bioquimica y Biologia Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009, Zaragoza, Spain. drecalde@posta.unizar.es
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Recalde
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Velez-Carrasco
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Civeira
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Cenarro
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Gomez-Coronado
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Ordovas
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D000328:Adult; D016632:Apolipoprotein A-I / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D016633:Apolipoprotein A-II / Q000097:blood*; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000097:blood; D006579:Heterozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D012016:Reference Values
D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D008076:Cholesterol, HDL; C426725:apolipoprotein A-I Zaragoza