The impact of sex hormones and sex chromosomes on the HDL anti-inflammatory capacity in transgender individuals

Background Interest in the cardiovascular disease (CVD) field is shifting from high-density lipoprotein cholesterol (HDL-C) levels to exploring function of HDL particles. Among these, anti-inflammatory properties of HDL emerged as key metric associated with protection against incident CVD events, notably in a highly sexually dimorphic manner. Therefore, the present study investigated the impact of sex hormones and sex chromosomes on the HDL anti-inflammatory activity. Methods The HDL anti-inflammatory capacity (HDL-mediated suppression of TNFα-induced VCAM-1 mRNA expression in endothelial cells) was determined in 14 transgender men and 17 transgender women during gender-affirming hormone therapy at T0 (baseline), T1 (hormonal castration) and T12 (following 11 months of hormone substitution). HDL subspecies were characterized by nuclear magnetic resonance spectroscopy, the HDL lipidome by liquid chromatography/tandem mass spectrometry. Results The HDL anti-inflammatory capacity remained largely unaffected by hormonal changes. HDL-C and total HDL particle numbers did not correlate with the HDL anti-inflammatory activity but, interestingly, specific associations with distinct HDL subpopulations emerged ( p <0.05). Increases in HDL core lipids were related to a worse HDL anti-inflammatory function ( p <0.05), while increases in specific sphingomyelin, phosphatidylcholine, phosphatidylserine and phosphatidylinositol subspecies showed an opposite association (each p <0.05). Conclusion Combined, these data indicate that (i) neither sex chromosomes nor substantial changes in sex hormones have a fundamental impact on the HDL anti-inflammatory function and (ii) specific HDL subspecies and HDL lipids associate with the anti-inflammatory function of HDL, potentially opening an avenue to therapeutically improve HDL functionality.