2006 George L. Duff Memorial Lecture—Familial Hypobetalipoproteinemia, a Unique Form of Fatty Liver
Several genetic forms of familial hypobetalipoproteinemia (FHBL) exist: (a) those due to premature stop-codon–specifying mutations or missense mutations of APOB; (b) those due to nonsense or missense mutations of PCSK9; (c) those due to certain mutations of MTP; and (d) those linked to none of the above-mentioned genes. “Knock-in” mouse models of apoB truncations (apoB38.9 and apoB27.6) resemble human FHBL phenotypes. In heterozygous crosses of apoB38.9 or apoB27.6 mice, homozygotes are born at <10% of expected frequencies, suggesting that homozygosity is lethal. In heterozygous apoB-defective FHBL, even the product of the normal allele, apoB100, is produced at only ~25% of the normal rate as a result of increased intracellular degradation. Furthermore, the lipid-ferrying capacities of the abnormal truncated apoBs are reduced. The net result is an impaired hepatic lipid export system via VLDL particles, resulting in increases of hepatic fat despite adaptive decreased synthesis of hepatic fatty acids and cholesterol. To assess the role of genetic factors in the fatty livers of mice, a 10-strain survey was performed. Six-fold differences in hepatic triglyceride levels were found, demonstrating the importance of genetic factors. Breeding of the apoB38.9 defect into low, medium, and high hepatic triglyceride strains yielded 3 congenic strains: the SWR/J-apoB+/38.9, C57BL/J-apoB+38.9, and BALBcByJ-apoB+/38.9, respectively. Significant effects on hepatic triglyceride levels were found by mouse strain, by the apoB38.9 gene, and there were strain–gene interactions. Thus, modifying genes affect the expression of the apoB38.9 defect.