Structure-function relationships of HDL in diabetes and coronary heart disease

Area of Science:

• Cardiovascular Biology
• Metabolic Diseases
• Lipidomics

Background:

• High-density lipoproteins (HDL) possess diverse cell-protective functions.
• Understanding HDL structure-function-disease relationships is crucial for metabolic and cardiovascular health.

Purpose of the Study:

• To comprehensively characterize HDL composition and function in healthy individuals and patients with type 2 diabetes (T2DM) and/or coronary heart disease (CHD).
• To identify determinants of HDL functionality and their association with disease states.

Main Methods:

• Characterization of HDL from 51 healthy subjects and 98 patients (T2DM, CHD, or both) for protein and lipid composition and cellular functionality.
• Integration of clinical data, NMR features, protein/lipid profiles, and functional read-outs using high-dimensional statistical modeling.
• Validation of identified HDL determinants using artificially reconstituted HDL.

Main Results:

• Coronary heart disease (CHD) and type 2 diabetes (T2DM) exhibit distinct alterations in HDL size, composition, and function.
• HDL's various cellular functions are weakly correlated and influenced by different structural components; cholesterol efflux capacity (CEC) is not a universal proxy.
• Sphingomyelin SM 42:3, glycosylphosphatidylinositol-phospholipase D1, and apolipoprotein F were identified as novel determinants of specific HDL functions.

Conclusions:

• HDL structure and function are significantly altered in T2DM and CHD, with distinct profiles for each disease.
• HDL functionality is complex and multifactorial, not reducible to single measures like CEC.
• Novel HDL components impacting cellular apoptosis inhibition and adipocyte respiration offer new insights into HDL's role in health and disease.