In vivo metabolism of ApoB, ApoA-I, and VLDL triglycerides in a form of hypobetalipoproteinemia not linked to the ApoB gene

Familial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder that may result from different mutations in the apolipoprotein B (apoB) ge ne or chromosome 2, However, linkage of FHBL to the apoB gene was ruled out in 2 kindreds reported to date, and the genetic and metabolic bases for FH BL remain unknown. One of the reported kindreds is our 40-member F kindred, in which we found linkage of FHBL to a novel susceptibility region on chro mosome 3p21.1-2, In addition to having low apoB levels, some, but not all, of the affected subjects in the F kindred also had low levels of high densi ty lipoprotein (HDL) cholesterol and apoA-I. Our aim was to define the meta bolic bases of the disorder in the F kindred. Therefore, we studied the in vivo kinetics of apoB and apoA-I and very low density lipoprotein (VLDL) tr iglycerides in 4 affected subjects and 5 normolipidemic relatives. Deuterat ed leucine and deuterated glycerol were used to label the apolipoproteins a nd triglycerides, respectively. Compartmental modeling was used to obtain t he kinetic parameters. Affected subjects had (1) normal fractional cataboli c rates (FCRs) for VLDL apoB, (2) increased FCRs for low density lipoprotei n (LDL) apoB (0.050+/-0.009 versus 0.030+/-0.006 pools per hour for normal subjects, P=0.005), and (3) decreased production rates of VLDL apoB (11.4+/ -1.7 versus 25.6+/-4.9.mg kg(-1) . d(-1), P=0.003), LDL apoB (7.8+/-1.3 ver sus 12.7+/-3.7 mg kg(-1) . d(-1), P=0.04), and VLDL triglycerides (8.2+/-4. 5 versus 19.6+/-10.8 58 mu mol . kg(-1) . h(-1), P=0.09). These data differ from those obtained in previously studied FHBL heterozygotes bearing apoB- 2 and apoB-9, 2 very short truncations of apoB. Low HDL cholesterol and apo A-I levels were caused by higher apoA-I FCRs (0.035+/-0.005 versus 0.018+/- 0.005 pools per hour in controls, P<0.01) without significant decrease in a poA-I production rates (18.7+/-2.7 versus 22.8+/-5.6 mg . kg(-1) . d(-1)). In conclusion, decreased secretion of apoB-containing lipoproteins and hype rcatabolism of LDL account for low apoB and cholesterol levels in this nove l form of FHBL.