Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Next-Generation Sequencing in Medicine (Upcoming)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia
Christopher Jones, … , Joachim Herz, Helen H. Hobbs
Christopher Jones, … , Joachim Herz, Helen H. Hobbs
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):165-174. https://doi.org/10.1172/JCI29415.
View: Text | PDF
Research Article

Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia

  • Text
  • PDF
Abstract

Genetic defects in LDL clearance result in severe hypercholesterolemia and premature atherosclerosis. Mutations in the LDL receptor (LDLR) cause familial hypercholesterolemia (FH), the most severe form of genetic hypercholesterolemia. A phenocopy of FH, autosomal recessive hypercholesterolemia (ARH), is due to mutations in an adaptor protein involved in LDLR internalization. Despite comparable reductions in LDL clearance rates, plasma LDL levels are substantially lower in ARH than in FH. To determine the metabolic basis for this difference, we examined the synthesis and catabolism of VLDL in murine models of FH (Ldlr–/–) and ARH (Arh–/–). The hyperlipidemic response to a high-sucrose diet was greatly attenuated in Arh–/– mice compared with Ldlr–/– mice despite similar rates of VLDL secretion. The rate of VLDL clearance was significantly higher in Arh–/– mice than in Ldlr–/– mice, suggesting that LDLR-dependent uptake of VLDL is maintained in the absence of ARH. Consistent with these findings, hepatocytes from Arh–/– mice (but not Ldlr–/– mice) internalized β-migrating VLDL (β-VLDL). These results demonstrate that ARH is not required for LDLR-dependent uptake of VLDL by the liver. The preservation of VLDL remnant clearance attenuates the phenotype of ARH and likely contributes to greater responsiveness to statins in ARH compared with FH.

Authors

Christopher Jones, Rita Garuti, Peter Michaely, Wei-Ping Li, Nobuyo Maeda, Jonathan C. Cohen, Joachim Herz, Helen H. Hobbs

×

Figure 1

Plasma cholesterol and triglyceride levels (A) and lipoprotein cholesterol levels (B) in sucrose-fed wild-type, Ldlr–/–, Arh+/–, and Arh–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Plasma cholesterol and triglyceride levels (A) and lipoprotein cholester...
Male Arh–/–, Arh+/–, and wild-type littermates, ages 16–18 weeks, and age-matched Ldlr–/– mice (n = 6 per genotype) were fed a high-sucrose diet for 6 weeks. Mice were sacrificed and blood was drawn from the inferior vena cava. Individual plasma cholesterol and triglyceride levels (A) were measured as described in Methods, and the means ± SEM are given. (B) Aliquots of plasma from the animals in each group were pooled and size fractionated by FPLC. The cholesterol content of each fraction was measured as described (39).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts