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Updated: Jun 4, 2026
A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Familial hypobetalipoproteinemia due to a novel early stop mutation
Paul N Durrington1, Valentine Charlton-Menys, Christopher J Packard
1Cardiovascular Research Group, Division of Cardiovascular and Endocrine Science, Core Technology Facility, 3rd Floor, University of Manchester, 46 Garfton Street, Manchester M13 9NT, UK.
Background:
Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder associated with low circulating levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (ApoB). A proband was identified in whom the condition was due to an E110X mutation of APOB, creating a particularly early truncation of ApoB in the region of the molecule necessary for very-low-density lipoprotein (VLDL) assembly. The mutation was also associated with nonalcoholic fatty liver disease.
Objective:
To assess the effect of the mutation on metabolism and the formation of VLDL and LDL subfractions.
Results:
Both the proband and his son, who had the same mutation, had low LDL cholesterol and decreased ApoB, but an increased small-dense LDL level. Lipoprotein profiles were normal in the proband's sister and grandson, in whom the mutation was absent. In the proband. there was a profoundly diminished rate of production of VLDL-2. VLDL-1 production, however, was relatively preserved and, because of its decreased catabolism, its pool size was increased. Direct formation of intermediate-density lipoprotein (IDL) and LDL was undetectable. Intermediate-density lipoprotein catabolism was greatly increased and its conversion to LDL was increased. The LDL produced was entirely small-dense LDL. High-density lipoprotein cholesterol levels were low, perhaps also related to the relative increase in VLDL-1, which is an avid acceptor of cholesteryl ester.
Conclusions:
This novel mutation provides evidence to support the hypothesis that hepatic production of large VLDL-1 leads to the creation of small-dense LDL.
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