The level of a subfraction of plasma high density lipoproteins (HDL), termed prebeta-migrating HDL (HDLprebeta), is elevated in several forms of dyslipoproteinemia. In man, HDLprebeta mass is correlated with hypercholesterolemia and with triglyceridemia. Elevated levels of HDLprebeta are also induced by the feeding of atherogenic diets in experimental animals. HDLprebeta has been operationally characterized as a small, spherical, very high density lipoprotein containing apolipoprotein Al (apo Al), cholesterol and phospholipid. Hyperlipemic subjects generally display a trend toward decreased total HDL cholesterol (HDL-C) when HDLprebeta is elevated suggesting a disequilibrium in the metabolic processing of the major HDL subfractions, HDL2 and HDL3. Elevated levels of HDLprebeta are also induced by the feeding of atherogenic diets in experimental animals. In the mouse model of diet- induced atherosclerosis a single gene known at Ath-1 controls the level of HDL. In a particular inbred strain, C57BL/6, the diminished HDL results in atherosclerosis 'mimicking' the human findings. Hence mice of this strain and other strains resistant to diet-induced atherosclerosis (due to high levels of HDL-C) will be compared to identify the role HDLprebeta in HDL cholesterol metabolism. Studies will include C57BL/6 mice transgenic for the human form of apo Al which have been """"""""cured"""""""" of their inherent genetic predisposition to develop atherosclerosis. The preliminary observations in man and in animals suggest the following as a working hypothesis: HDLprebeta particles (and related molecular forms) are lipoprotein intermediates which accumulate in pathological lipid states. These lipoproteins are transformed into """"""""mature"""""""" HDL2 and HDL3 particles in plasma by enzymatic processing events. The transformation process is reversible allowing for the generation of HDLprebeta particles. The plasma residence time may differ for HDLprebeta, and for HDL2 and HDL3. Thus elevated levels of HDLprebeta represent a disequilibrium in the synthetic and degradation pathways of HDL. Control of the transformation process can be the basis of future therapeutic goals to re-establish a normal apo Al distribution in dyslipoproteinemias.
| Marzal-Casacuberta, A; Blanco-Vaca, F; Ishida, B Y et al. (1996) Functional lecithin:cholesterol acyltransferase deficiency and high density lipoprotein deficiency in transgenic mice overexpressing human apolipoprotein A-II. J Biol Chem 271:6720-8 |
