, Volume 62, Issue 12, pp 1372-1378
Date: 07 Apr 2005

Familial hypobetalipoproteinemia: genetics and metabolism

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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 ∼5% 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.)

Received 27 October 2004; received after revision 1 February 2005; accepted 22 February 2005