The hypochylomicronemic effect of beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) is mediated by a decrease in apolipoprotein C-III.

ABSTRACT

Treatment of rats fed a balanced Purina Chow diet with beta,beta'-tetramethyl-substituted hexadecanedioic acid (MEDICA 16) (Bar-Tana, J., Rose-Kahn, G., and Srebnik, M. (1985) J. Biol. Chem. 260, 8404-8410) resulted in an acute 70-80% decrease in plasma chylomicrons-triacylglycerols which was sustained as long as the drug was administered. The hypochylomicronemic effect resulted from an enhanced plasma clearance of chylomicrons whereas their intestinal production and absorption remained unaffected. Chylomicrons-triacylglycerols clearance in MEDICA 16-treated rats was characterized by a fast initial phase lasting for 1-2 min and consisting of elimination of 50-60% of the injected chylomicrons' tracer at a fractional clearance rate of 0.77 +/- 0.27 min-1 as compared to 0.08 +/- 0.01 min-1 in nontreated rats. The fractional clearance rate of chylomicrons-cholesterol ester was similarly affected by MEDICA 16 treatment and amounted to 0.48 +/- 0.05 and 0.05 +/- 0.01 min-1 in MEDICA 16-treated and nontreated rats, respectively. The increased fractional clearance rate of plasma chylomicrons in MEDICA 16-treated rats presumably reflects the primary action of the drug rather than being secondary to the hypochylomicronemic state, since it was similarly observed in MEDICA 16-treated animals made transiently normolipemic by loading them with intestinal lipid. The increase in the fractional clearance rate of plasma chylomicrons resulted from their enhanced uptake by the liver complemented with their activated extrahepatic catabolism. The activation of both catabolic modes in MEDICA 16-treated rats could be accounted for by a 10-fold decrease in the apoC-III content of plasma chylomicrons. No increase was observed in hepatic apoB,E or apoE receptors, nor in the maximal capacity of lipoprotein lipase. The pharmacological reduction of plasma apoC-III may thus offer a treatment mode of choice for selected hyperlipidemic states.