Familial hypobetalipoproteinemia: genetics and metabolism.

Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8046, St. Louis, Missouri 63110, USA. gschonfe@im.wustl.edu

Familial hypobetalipoproteinemia (FHBL), an autosomal dominant disorder, is defined as <5th percentile LDL-cholesterol or apolipoprotein (apo) B in the plasma. FHBL subjects are generally heterozygous and asymptomatic. Three genetic forms exist: (i) premature stop codon specifying mutations of APOB; (ii) FHBL linked to a susceptibility locus on the chromosome 3p21; and (iii) FHBL linked neither to APOB nor to the chromosome 3p21. In heterozygous apoB-defective FHBL, the hepatic VLDL export system is defective because apoB 100, the product of the normal allele, is produced at approximately 25% of normal rate, and truncated apoB is cleared too rapidly. The reduced capacity for hepatic triglyceride export increases hepatic fat three-fold. Indexes of adiposity and insulin action are similar to controls. 'Knock-in' mouse models of apoB truncations resemble human FHBL phenotypes. Liver fat in the chromosome 3p21-linked FHBL is normal. Elucidation of the genetic basis of the non-apoB FHBL could uncover attractive targets for lipid-lowering therapy. (See note added in proof.).

PMID: 15818469 [PubMed - indexed for MEDLINE]