Postprandial Lipoprotein Metabolism in Familial Hypobetalipoproteinemia

Abstract

Familial hypobetalipoproteinemia (FHBL) is an autosomal codominantly inherited disorder of lipoprotein metabolism characterized by decreased plasma concentrations of low-density lipoprotein-cholesterol and apolipoprotein (apo) B. We examined the effect of truncated apoB variants (<apoB-48) causing FHBL on postprandial triglyceride-rich lipoprotein (TRL) metabolism. A standardized oral fat load was given after a 12-h fast to six heterozygous [apoB-6.9 (n=3), apoB-25.8 (n=1), apoB-40.3 (n=2)] FHBL subjects and 10 normolipidemic controls. Plasma was obtained every 2 h for 10 h. Large TRLs [containing chylomicrons (CM)] and small TRLs (containing CM remnants) were isolated by ultracentrifugation. Compared with controls, FHBL subjects had significantly decreased fasting plasma cholesterol (2.3+/-0.5 vs. 4.8+/-0.5 mmol/liter), triglyceride (0.4+/-0.3 vs. 1.5+/-0.5 mmol/liter), low-density lipoprotein-cholesterol (0.6+/-0.4 vs. 3.0+/-0.5 mmol/liter), and apoB (0.22+/-0.05 vs. 0.95+/-0.14 g/liter) concentrations (all P<0.001). The postprandial incremental area under the curve in FHBL subjects was decreased for large TRL-triglyceride (-61%; P<0.005), small TRL-cholesterol (-86%; P<0.001), and small TRL-triglyceride (-86%; P<0.001) relative to controls. Multicompartmental modeling analysis showed that the delay time of apoB-48 was shorter and that apoB-48 production was decreased in FHBL subjects compared with controls. We have demonstrated that heterozygous FHBL subjects with apoB truncations shorter than apoB-48, and therefore only a single fully-functional apoB-48 allele, have decreased TRL production but normal postprandial TRL particle clearance.