Modifying apolipoprotein A-I by malondialdehyde, but not by an array of other reactive carbonyls, blocks cholesterol...

Area of Science:

• Biochemistry
• Cardiovascular Research
• Lipid Metabolism

Background:

• Dysfunctional high-density lipoprotein (HDL) contributes to cardiovascular disease pathogenesis.
• The mechanisms behind HDL dysfunction are not fully understood.
• Apolipoprotein A-I (apoA-I), the primary HDL protein, may be modified by reactive carbonyls.

Purpose of the Study:

• To investigate if specific carbonyl compounds modify lipid-free apoA-I.
• To determine if apoA-I modification inhibits its ability to promote cholesterol efflux via the ABCA1 pathway.
• To identify the sites and nature of apoA-I modification by carbonyls.

Main Methods:

• Incubation of lipid-free apoA-I with various carbonyl compounds (malondialdehyde, hydroxynonenal, glycolaldehyde, glyoxal, methylglyoxal).
• Assessment of apoA-I's ability to promote cholesterol efflux using the ABCA1 pathway.
• Liquid chromatography-electrospray ionization-tandem mass spectrometry to identify apoA-I modification sites and adducts.

Main Results:

• Malondialdehyde (MDA) significantly impaired apoA-I's ABCA1-mediated cholesterol efflux activity.
• Other tested carbonyls did not effectively modify apoA-I or inhibit its function.
• Mass spectrometry identified MDA-lysine adducts and lysine-MDA-lysine cross-links, primarily at C-terminal Lys residues.
• MDA-protein adducts were elevated in HDL from human atherosclerotic lesions.

Conclusions:

• MDA covalently modifies apoA-I, forming specific lysine adducts and cross-links.
• This modification hinders apoA-I's interaction with lipids and ABCA1, impairing reverse cholesterol transport.
• MDA-induced apoA-I dysfunction may contribute to cardiovascular disease by promoting macrophage foam cell formation.