Abstract 9: Metabolic Pathways for HDL Subtypes in Low-HDL Overweight Phenotype Compared With Normal

Abstract

Introduction: A prevailing concept of HDL metabolism in plasma is that HDL is secreted into plasma as a small discoidal particle; and then expands and contracts by uptake and removal of cholesterol. This process has not been studied directly in humans. Hypothesis: We hypothesized that the 4 common sizes of HDL will show interconversions suggesting reverse cholesterol transport and that is impaired in those who have low HDL-c levels. Methods: We studied 12 adults, ages 30 to 70; six had low HDL-c (mean 39 mg/dL) and were overweight, and 6 had high HDL-c (mean 79 mg/dL) and normal body weight. They received a intravenous bolus of trideuterated leucine with serial blood sampling for 94 hours. HDL sizes, very small (<7.1 nm), small (7.1-8.2 nm), medium (8.2-9.5 nm) and large (9.5-12.2), were separated, and the isotope enrichments and masses of apoA-I in each HDL size were measured by mass spectrometry. We tested many kinetic models using SAAM-II. Results: In both HDL groups, we found similar peak enrichment heights and times in the four HDL sizes suggesting mostly independent metabolism which was confirmed by the final model that had excellent fits to the data. Most of each plasma HDL size subfraction originated from direct secretion into plasma. Only small amounts of apoA-I flux went from smaller to larger HDL, 19% in the low vs 2% in the high HDL group (p=0.006); and in the opposite direction, 3% in the low vs 9% in the high HDL group (ns). ApoA-I in medium and large HDL had faster fractional catabolic rates (FCRs) in the low than in the high HDL group (0.61 vs 0.31 pools/day [p=0.004] and 0.51 vs 0.24 pools/day [p=0.01]), respectively). In contrast, apoA-I in very small (prebeta) HDL had slower FCR in the low than high HDL group (0.51 vs 0.73/d [p=0.048]). Secretion rates of apoA-I into plasma HDL of each size were not significantly different between the groups. Total apoA-I secretion was 12 vs 14 mg/kg/d in the low vs high HDL group (ns). Conclusions: Our results question the concepts of reverse cholesterol transport dominating plasma HDL metabolism, and of its impairment in those with low plasma HDL-c levels. Differences in apoA-I FCR of HDL subfractions explained the well-known shift in size distribution toward smaller HDL in those who have low HDL-c.