A sexually dimorphic hepatic cycle of very low density lipoprotein uptake and assembly

Abstract

ABSTRACTThe liver shows striking sexual dimorphism, which is reflected in differences between women and men in pathologies associated with hepatic function. Recent single-cell transcriptomes revealed spatiotemporal programmes of liver function on the sublobular scale. However, how sexual dimorphism affects this space-time logic remains poorly understood. To address this, we performed single-cell RNA-seq in the mouse liver, which allowed us to model how lobular position, circadian time and sex shape the transcriptome. We found that sex, space and time markedly influence xenobiotic detoxification and lipoprotein metabolism. Crucially, the very low density lipoprotein receptor (VLDLR) is restricted to the pericentral zone, with significantly higher mRNA and protein levels in female mice. In humans, VLDLR expression is pericentral, with higher mRNA and protein levels in premenopausal women compared to similarly aged men. HepaticVLDLRexpression changes with age and body mass index, and is lower in individuals with atherosclerosis or myocardial infarction. In mice, several genes involved in VLDL assembly are periportally biased. Electron microscopy confirmed a periportal bias in VLDL production, revealing a previously unknown sexually dimorphic hepatic cycle of periportal formation and pericentral uptake of VLDL. Together, our work provides new insights into the sexual dimorphism characterizing differences in VLDL kinetics and atherosclerotic cardiovascular disease.