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A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
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Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia

Christopher Jones1, Rita Garuti, Peter Michaely

  • 1Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

The Journal of Clinical Investigation
|January 4, 2007
PubMed

Insights

Autosomal recessive hypercholesterolemia (ARH) preserves LDL receptor-dependent VLDL clearance, unlike familial hypercholesterolemia (FH). This maintains lower LDL levels and better statin response in ARH patients.

Area of Science:

  • Lipid metabolism
  • Cardiovascular genetics
  • Molecular endocrinology

Background:

  • Genetic defects in low-density lipoprotein (LDL) clearance cause severe hypercholesterolemia and atherosclerosis.
  • Familial hypercholesterolemia (FH) results from LDL receptor (LDLR) mutations.
  • Autosomal recessive hypercholesterolemia (ARH) is caused by mutations in an adaptor protein crucial for LDLR internalization.

Purpose of the Study:

  • To investigate the metabolic basis for lower plasma LDL levels in ARH compared to FH.
  • To examine very-low-density lipoprotein (VLDL) synthesis and catabolism in murine models of FH and ARH.

Main Methods:

  • Utilized Ldlr(-/-) and Arh(-/-) mouse models.
  • Assessed hyperlipidemic response to a high-sucrose diet.
  • Measured VLDL secretion and clearance rates.
  • Examined VLDL uptake by isolated hepatocytes.

Main Results:

  • The hyperlipidemic response to a high-sucrose diet was attenuated in Arh(-/-) mice compared to Ldlr(-/-) mice.
  • VLDL clearance rates were significantly higher in Arh(-/-) mice.
  • Hepatocytes from Arh(-/-) mice, but not Ldlr(-/-) mice, internalized beta-migrating VLDL (beta-VLDL).

Conclusions:

  • Autosomal recessive hypercholesterolemia (ARH) is not required for LDLR-dependent VLDL uptake by the liver.
  • Preserved VLDL remnant clearance in ARH attenuates its clinical phenotype.
  • This preservation may contribute to the greater responsiveness to statins observed in ARH compared to FH.

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