A sexually dimorphic hepatic cycle of periportal VLDL generation and subsequent pericentral VLDLR-mediated lipoprotein re-uptake

Abstract

The liver shows striking sexual dimorphism, which is reflected in differences between women and men in pathologies inherently 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 lipid processing, including 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, which is conserved in the human liver. In addition, several genes involved in VLDL assembly are periportally biased, and we corroborated periportal VLDL generation with electron microscopy. Together, this suggests a hepatic cycle of periportal formation and pericentral uptake of VLDL. In addition, we demonstrated that in humans VLDLR expression depends also on age and body mass index. Crucially, these processes provide a new window into the sexual dimorphism characterizing atherosclerotic cardiovascular disease.