Genes and nutrition in the regulation of human lipoprotein metabolism.

Abstract

To illustrate the unitary and mutually inducive nature of clinical and basic research, five related studies of normal and abnormal lipoprotein metabolism in man are reported. 1. Regional lipoprotein metabolism was studied by 39 sets of arteriovenous difference measurements in the splanchnic and peripheral territories to localise and quantify some aspects of the production, conversion and catabolism of very low and low density lipoproteins. 2. By kinetic analyses in 43 patients with genetically defined hyperlipidaemias and in controls the metabolic bases of these disorders were partly characterized; the distinct kinetic mechanisms so defined and a genetic classification of primary hyperlipidaemia were shown to correspond, lending support to the validity of this classification. 3. In a patient with hypertriglyceridaemia due to failure to activate the enzyme lipoprotein lipase, resulting from the rare disorder of absence of apolipoprotein CII, the enzyme was activated acutely by infusion of a source of apo CII; serial changes in the concentration of each lipoprotein class were observed, confirming the protean effects of this enzyme on lipid transport. 4. The mechanisms by which commonly employed therapeutic diets influence hyperlipidaemia were studied by measuring lipoprotein synthesis and fractional catabolism in patients receiving high- and low-fat diets and different ratios of saturated and polyunsaturated fats; the kinetic basis in both instances was a change in synthetic rate of low density lipoprotein. 5. Lastly, studies are presented of the very wide individual differences in the degree of hypercholesterolaemia induced by cholesterol feeding. The efficiency of homeostasis against this challenge correlated with the degree to which the rate of cholesterol synthesis was down-regulated in isolated cells, and with the activity of high-affinity low density lipoprotein receptors on these cells. In subsequent twin studies this receptor activity was shown to be strongly influenced by genetic factors suggesting that this aspect of lipid homeostasis may largely be a familial characteristic.