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Postprandial Lipoprotein Metabolism in Familial Hypobetalipoproteinemia

Department of Core Clinical Pathology and Biochemistry (A.J.H., K.R., F.M.v.B., J.R.B.), PathWest Laboratory Medicine WA, Royal Perth Hospital, Perth 6000, Australia; School of Medicine and Pharmacology (A.J.H., P.H.R.B., J.R.B.) and School of Surgery and Pathology (F.M.v.B.), University of Western Australia, Crawley 6009, Australia; and Department of Internal Medicine II (K.G.P.), Klinikum Grosshadern, Ludwig-Maximilians University, 81377 Munich, Germany

Address all correspondence and requests for reprints to: Dr. John R. Burnett, Department of Core Clinical Pathology and Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital, Wellington Street, GPO Box X2213, Perth, Western Australia 6847, Australia. E-mail: john.burnett{at}health.wa.gov.au.

Objective: 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.

Methods and Results: 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.

Conclusions: 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.