HDL Dysfunction Caused by Mutations in apoA-I and Other Genes that are Critical for HDL Biogenesis and Remodeling

Area of Science:

• Cardiovascular Science
• Lipid Metabolism
• Molecular Biology

Background:

• The traditional HDL hypothesis linking high HDL cholesterol (HDL-C) to reduced cardiovascular disease (CVD) risk is being re-evaluated.
• Recent studies suggest HDL functionality, influenced by its components (proteins, lipids, RNA), is more critical than HDL-C levels for CVD risk assessment.

Purpose of the Study:

• To review how HDL composition, size, and functionality are altered in monogenic HDL metabolism disorders.
• To explore the utility of mouse models in validating human patient data and evaluating novel therapeutic strategies for HDL abnormalities.

Main Methods:

• Review of human genetic studies on monogenic HDL metabolism disorders.
• Analysis of data from genetically modified mouse models of HDL biogenesis pathways.
• Discussion of adenovirus-mediated gene transfer for correcting HDL abnormalities.

Main Results:

• Monogenic disorders significantly impact HDL composition, size, and atheroprotective functions.
• Mouse models provide valuable validation for human findings and preclinical testing grounds.
• Novel therapeutic strategies, including gene therapy, show promise for addressing HDL dysfunction.

Conclusions:

• HDL functionality, rather than HDL-C levels, is a more accurate predictor of CVD risk.
• Characterizing HDL changes in genetic disorders is crucial for identifying diagnostic and therapeutic biomarkers.
• Investigating HDL metabolism through human studies and animal models is essential for advancing CVD treatment.