Enhanced fractional catabolic rate of apo A-I and apo A-II in heterozygous subjects for apo A-IZaragoza (L144R)

We have recently reported a new apolipoprotein (apo) A-I variant (apo A-IZaragoza 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-IZaragoza 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-IZaragoza carriers as compared to control subjects (40, 60, and 50%, respectively). Lipid composition analysis revealed that apo A-IZaragoza 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-IZaragoza carriers were normal. Apo A-I and apo A-II metabolic studies were performed on two heterozygous apo A-IZaragoza 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-IZaragoza 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 day−1, respectively). Apo A-I secretion rate (SR) of apo A-IZaragoza subjects was slightly increased compared with controls (17.32±0.226 vs. 12.76±3.918 mg kg−l day−1, respectively). Apo A-II FCR was also markedly elevated in both subjects with apo A-IZaragoza when compared with controls (0.366±0.1450 vs. 0.171±0.0333 day−1, respectively) and apo A-II SR was normal (2.31±0.517 vs. 2.1±0.684 mg kg−l day−1, respectively). Our results show that the apo A-IZaragoza 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.