Abstract 17553: Intrinsic Biological Atheroprotective Activities Of HDL Particles Are Impaired In Familial Apolipoprotein A-I Deficiency

Abstract

Genetic factors may regulate both circulating levels and functionality of HDL. As mutations in proteins involved in HDL metabolism can affect HDL levels, composition, structure and function, we evaluated functional and compositional properties of HDL particles in a kindred with familial apolipoprotein A-I deficiency. Two homozygotes and six heterozygotes, with a nonsense mutation at APOA1 codon -2 that results in a termination codon, were recruited together with ten age- and sex-matched healthy controls. The homozygotes displayed markedly decreased HDL-C (3±1 mg/dl), undetectable apoA-I and normal triglyceride (94±10 mg/dl) levels in plasma. The heterozygotes revealed low HDL-C (27±9 mg/dl), low apoA-I (65±13 mg/dl) and normal TG (130±45 mg/dl) concentrations. All five HDL subpopulations fractionated from plasma of both homo- and heterozygous subjects with apoA-I-deficiency revealed reduced intrinsic cholesterol efflux capacity from THP-1 cells (up to -40%, on a phospholipid basis) relative to controls. Moreover, small, dense HDL3 particles from the heterozygotes exhibited diminished intrinsic capacity to protect LDL from oxidative stress (up to -94%, on a total particle mass basis) relative to their counterparts from controls. Unexpectedly, the homozygotes possessed HDL with normal antioxidative activity. HDL subpopulations from the both homo- and heterozygotes displayed markedly altered chemical composition, with enrichment in triglyceride and depletion in cholesteryl ester (up to +70% and -60%), consistent with enhanced CETP activity (up to +89%). Polar lipids of the HDL surface monolayer were also affected by apoA-I deficiency, with decreased phospholipid (up to -40%) and increased free cholesterol (up to +100%) content. In addition, HDL subpopulations from the heterozygotes were depleted in apoA-I (up to -41%) and enriched in apoA-II (up to +47%). Defective atheroprotective activities of HDL3 particles were correlated with diminished HDL content of phospholipid and apoA-I, two major components determining HDL functionality. Clearly then, the impaired atheroprotective activities of HDL particles in familial apoA-I deficiency are closely related to marked alterations in their lipidome and proteome.