Delayed clearance of chylomicron remnants following vitamin-A-containing oral fat loads in broad-beta disease (type III hyperlipoproteinemia).

Abstract Chylomicron “remnants” are formed by the selective removal of triglyceride catalyzed by lipoprotein lipase. To investigate a possible defect in the clearance of these remnants in the pathophysiology of broad-β disease (type III hyperlipoproteinemia), subjects with this disorder and comparison subjects with endogenous hypertriglyceridemia (and type IV lipoprotein patterns) ingested an oral fat load (corn oil:cocoa butter, 1:1, 50 g/sq M) containing retinyl ester, 100 mg, with or without 15 μCi 15-14C-retinol (43.7 mCi/mg). The content of triglyceride and vitamin A was sequentially determined in chylomicrons (Sf > 400) and very low density lipoproteins (VLDL, Sf20–400) over the ensuing 24–72 hr. Vitamin A was chosen as a marker for exogenous sterol assimilation since, like cholesterol, it is absorbed in the small intestine and cosecreted in esterified form with triglyceride in the chylomicron core; however, unlike cholesterol, once having been removed by the liver, it cannot be recycled into VLDL, but subsequently circulates only as a complex with the high density retinol binding protein. Thus measurements of the vitamin A/triglyceride ratio in Sf > 20 lipoproteins reflected the relative efficiency of vitamin A versus triglyceride removal within these lipoproteins. These studies confirmed the initial concentration of exogenous vitamin A in chylomicrons but invariably disclosed an increasing proportion of the remaining Sf > 20 vitamin A in VLDL 24 hr after its ingestion. The vitamin A/triglyceride ratio also invariably increased between 6 and 24 hr in the Sf20–30 subfraction, reflecting the formation of vitamin A-rich “remnants” as intermediate species in the catabolism of chylomicrons and VLDL. Among those with mild to moderate endogenous hypertriglyceridemia the Sf > 400 vitamin A/triglyceride ratio declined between 6 and 24 hr, reflecting the efficient passage of the vitamin A through this fraction and/or continued secretion of Sf > 400 particles rich in triglyceride. Among those with severe endogenous hypertriglyceridemia, both the peak and decline in the Sf > 400 vitamin A/triglyceride ratio were delayed. However, among those with broad-β disease, an increasing vitamin A/triglyceride ratio between 6 and 24 hr was frequent within all VLDL subfractions and invariable among lipoproteins of Sf > 400 regardless of the degree of antecedent hypertriglyceridemia. Although additional experiments disclosed a similar delay in both vitamin A and triglyceride assimilation when basal triglyceride levels were high in these subjects, marked reduction of triglyceride levels did not correct the rise in the Sf > 400 vitamin A/triglyceride ratio between 6 and 24 hr. Experiments employing preparative electrophoresis confirmed the identity of VLDL containing a high vitamin A/triglyceride ratio with the β-VLDL which accumulate in broad-β disease. Thus these studies demonstrate: (1) the transport of exogenous lipid in VLDL (usually presumed to be entirely of endogenous origin); (2) the formation of vitamin A-rich remnants as intermediates in chylomicron catabolism in hypertriglyceridemic subjects; and suggest that (3) chylomicron (and exogenously-derived VLDL) remnants may accumulate in the plasma of subjects with broad-β disease by virtue of a defect in their removal and/or further catabolism which may be specific to this disorder.