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Abstract
Several lines of evidence suggest that the metabolism of trigylceride-rich lipoproteins influences that of high density lipoproteins (HDL) and, therefore, controls--to a large extent--the plasma levels of HDL. The objective of this thesis was to explore some of the mechanisms and consequences of this metabolic relationship. In Part I, the molecular basis of lipoprotein lipase (LPL) deficiency--a condition associated with vastly elevated triglyceride levels and very low HDL--was determined by direct genomic sequencing of the promoter, all exons, and all splice sites of the LPL gene of two index cases. A substitution of adenine for guanine at cDNA position 818 was detected, altering the amino acid sequence at residue 188 from glycine to glutamic acid. In Part II, the role of triglyceride catabolism in the formation of the HDL subfraction HDL$\sb2$ was delineated. Very low density lipoproteins (VLDL) were subjected to LPL action in vitro, in a system containing also discoidal HDL, HDL$\sb3$, and lecithin: cholesterol acyltransferase (LCAT) activity. With lipolysis superimposed on the LCAT-mediated transformation of discoidal into spherical HDL, the newly formed lipoproteins displayed the compositional and physicochemical characteristics of native HDL$\sb2$. With no lipolysis taking place, no HDL$\sb2$ were formed; rather, discoidal HDL were converted to small and lipid-depleted particles. These data indicate that LCAT can convert discoidal HDL to HDL$\sb2$ only if additional lipids for HDL$\sb2$ formation are made available by the degradation of VLDL. Part III presents a cross-sectional study designed to test whether--due to the impact of triglyceride metabolism on HDL levels--the accepted epidemiologic association 'low HDL-cholesterol-high coronary artery disease (CAD) risk' is basically one of 'impaired triglyceride metabolism-high CAD risk'.
