Inflammatory remodeling of the HDL proteome impairs cholesterol efflux capacity

Area of Science:

• Cardiovascular Science
• Lipid Metabolism
• Immunology

Background:

• High-Density Lipoprotein (HDL) cholesterol efflux capacity is linked to cardioprotection, independent of HDL-cholesterol (HDL-C) levels.
• Mechanisms impairing HDL cholesterol efflux during vascular disease remain unclear.
• Inflammation is a cardiovascular disease risk factor known to reduce HDL's cholesterol efflux capacity.

Purpose of the Study:

• To investigate if changes in HDL's protein cargo mediate impaired cholesterol efflux capacity during inflammation.
• To identify specific HDL proteins associated with reduced cholesterol efflux during acute inflammation.

Main Methods:

• Inducing acute inflammation in humans using low-level endotoxin.
• Measuring HDL cholesterol efflux capacity and proteomic analysis of HDL protein content.
• Utilizing mouse models with and without genetic ablation of serum amyloid A (SAA)1 and SAA2 during induced inflammation.

Main Results:

• Acute inflammation in humans impaired HDL cholesterol efflux capacity without altering HDL-C levels.
• HDL cholesterol efflux capacity inversely correlated with HDL content of serum amyloid A (SAA)1 and SAA2.
• Inflammation-induced impairment of HDL cholesterol efflux in mice was dependent on SAA1 and SAA2.

Conclusions:

• Inflammatory impairment of HDL cholesterol efflux capacity is partly mediated by SAA-induced remodeling of HDL's protein cargo.
• SAA proteins play a critical role in the functional decline of HDL during inflammatory states.
• Targeting SAA may offer a therapeutic strategy to preserve HDL function in inflammatory cardiovascular disease.