Lipoprotein metabolism in APOB L343V familial hypobetalipoproteinemia Abbreviated title: Lipoprotein metabolism in APOB L343V FHBL

Context: Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder of lipoprotein metabolism characterized by decreased plasma concentrations of low density lipoprotein (LDL)cholesterol and apolipoprotein (apo) B. Objective: To examine the effect of heterozygous APOB L343V FHBL on postprandial triglyceriderich lipoprotein (TRL) and fasting lipoprotein metabolism. Methods: Plasma incremental area under the curve (iAUC) apoB-48 and apoB-48 kinetics were determined after ingestion of a standardized oral fat load using compartmental modeling. Very low density lipoprotein (VLDL)-, intermediate density lipoprotein (IDL)-, and LDL-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. Results: The postprandial iAUC (0-10 h) in FHBL subjects (n=3) was lower for large TRLtriglyceride (-77%; P<0.0001), small TRL-cholesterol (-83%; P<0.001), small TRLtriglyceride (88%; P<0.001), and plasma triglyceride (-70%; P<0.01) and apoB (-63%, P<0.0001) compared with controls. Compartmental analysis showed that apoB-48 production was lower (-91%; P<0.05) compared with controls. VLDL-apoB concentrations in FHBL subjects (n=2) were lower by more than 75% compared with healthy, normolipidemic control subjects (P<0.01). VLDL-apoB fractional catabolic rate (FCR) was more than 5-fold higher in the FHBL subjects (P=0.07). ApoB production rates and IDLand LDL-apoB FCRs were not different between FHBL subjects and controls. Conclusions: We conclude that when compared to controls, APOB L343V FHBL heterozygotes show lower TRL production with normal postprandial TRL particle clearance. In contrast, VLDL-apoB production was normal, while the FCR was higher in heterozygotes compared with lean control subjects. These mechanisms account for the marked hypolipidemic state observed in these FHBL subjects.