Menopause-associated proteomic and lipidomic alterations in high-density lipoprotein: Perimenopause is characterized by smaller triacylglycerols-enriched particles.
High-density lipoprotein particles (HDL) possess anti-inflammatory, anti-thrombotic, cytoprotective, and anti-oxidative properties, thus protecting against cardiovascular diseases. Menopause is associated with changes in serum metabolome and HDL size distribution. We analyzed the protein and lipid composition of the HDL particles from pre-, peri-, and postmenopausal women (N=216) with nuclear magnetic resonance and mass spectrometry to get a deeper insight into the composition of HDL in different stages of menopause. Both particle size and composition differed; in perimenopause, the proportion of small HDL particles (8.7 nm on average) was higher, and the proportion of large HDL particles (12.1 nm on average) was lower than in pre- or postmenopause. In perimenopause, each particle size class was enriched with triacylglycerols, and the calculated lipid class ratio of triacylglycerol/cholesteryl ester was the highest within perimenopausal HDL particles. This potentially affects the HDL interaction with lipid-modifying enzymes. We also observed directionally opposite associations for HDL cholesteryl ester and unesterified cholesterol with systemic estradiol and follicle-stimulating hormone levels, especially regarding S-sized HDL particles, but not the hormone associations with HDL triacylglycerols. Perimenopausal HDL also exhibited a lower proportion of apolipoproteins (apoA-I, apoA-II, apoC-I, apoC-III, apoD and apoE) per particle than premenopausal or postmenopausal HDL. In summary, we found that premenopausal and postmenopausal HDL particles were compositionally similar and differed from perimenopausal ones. We suggest that menopause, and especially the unbalanced hormonal state in perimenopause, are reflected in the lipid and protein compositions of the HDL, which, in turn, may affect the functions of the HDL particle.