Circulating microRNAs (miRNA) are relatively stable in plasma and are a new class of disease biomarkers. Here we present evidence that high-density lipoprotein (HDL) transports endogenous miRNAs and delivers them to recipient cells with functional targeting capabilities. Cellular export of miRNAs to HDL was demonstrated to be regulated by neutral sphingomyelinase. Reconstituted HDL injected into mice retrieved distinct miRNA profiles from normal and atherogenic models. HDL delivery of both exogenous and endogenous miRNAs resulted in the direct targeting of mRNA reporters. Furthermore, HDL-mediated delivery of miRNAs to recipient cells was demonstrated to be scavenger receptor BI-dependent. The human HDL-miRNA profile from normal subjects is significantly different than familial hypercholesterolemia subjects. Notably, HDL-miRNA from atherosclerotic subjects induced differential gene expression, with significant loss of conserved mRNA targets in cultured hepatocytes. Collectively, these observations suggest that HDL participates in a mechanism of intercellular communication involving the transport and delivery of miRNAs.

BackgroundEndogenous sex hormones are important for metabolic health in men and women. Before menopause, women are protected from atherosclerotic cardiovascular disease (ASCVD) relative to men. Women have fewer cardiovascular complications of obesity compared to men with obesity. Endogenous estrogens have been proposed as a mechanism that lessens ASCVD risk, as risk of glucose and lipid abnormalities increases when endogenous estrogens decline with menopause. While baseline risk is higher in males than females, endogenously produced androgens are also protective against fatty liver, diabetes and ASCVD, as risk goes up with androgen deprivation and with the decline in androgens with age.Scope of ReviewIn this review, we discuss evidence of how endogenous sex hormones and hormone treatment approaches impact fatty acid, triglyceride, and cholesterol metabolism to influence metabolic and cardiovascular risk. We also discuss potential reasons for why treatment strategies with estrogens and androgens in older individuals fail to fully recapitulate the effects of endogenous sex hormones.Major ConclusionsThe pathways that confer ASCVD protection for women are of potential therapeutic relevance. Despite protection relative to men, ASCVD is still the major cause of mortality in women. Additionally, diabetic women have similar ASCVD risk as diabetic men, suggesting that the presence of diabetes may offset the protective cardiovascular effects of being female through unknown mechanisms.

Before menopause, women are protected from atherosclerotic heart disease associated with obesity relative to men. Sex hormones have been proposed as a mechanism that differentiates this risk. In this review, we discuss the literature around how the endogenous sex hormones and hormone treatment approaches after menopause regulate fatty acid, triglyceride and cholesterol metabolism to influence cardiovascular risk. The important regulatory functions of estrogen signaling pathways with regard to lipid metabolism have been in part obscured by clinical trials with hormone treatment of women after menopause, due to different formulations, routes of delivery, and pairings with progestins. Oral hormone treatment with several estrogen preparations increase VLDL triglyceride production. Progestins oppose this effect by stimulating VLDL clearance in both humans and animals. Transdermal estradiol preparations do not increase VLDL production or serum triglycerides. Many aspects of sex-differences in atherosclerotic heart disease risk are influenced by the distributed actions of estrogens in muscle, adipose and liver. In humans, 17β estradiol (E2) is the predominant circulating estrogen, and signals through Estrogen Receptor alpha (ERα), Estrogen Receptor beta (ER β) and G-protein coupled Estrogen Receptor (GPER). Over 1000 human liver genes display a sex-bias in their expression, and the top biological pathways are in lipid metabolism and genes related to cardiovascular disease. Many of these genes display variation depending on estrus cycling in the mouse. Future directions will likely rely on targeting estrogens to specific tissues, or specific aspects of the signaling pathways in order to recapitulate the protective physiology of pre-menopause therapeutically after menopause.