A Sexually Dimorphic Hepatic Cycle of Very Low Density Lipoprotein Uptake and Assembly

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. Using human samples, we were able to recapitulate both VLDLR's pericentral expression as well as higher mRNA and protein levels in premenopausal women compared to similarly aged men. In humans, we found that VLDLR expression depends not just on age but also body mass index. Conversely, several genes involved in VLDL assembly are periportally biased, and we corroborated periportal VLDL generation with electron microscopy, optimized for detecting low density lipid particles. Together, this suggests a hepatic cycle of periportal formation and pericentral uptake of VLDL. Crucially, these processes provide a new window into the sexual dimorphism characterizing differences in VLDL kinetics and atherosclerotic cardiovascular disease. The work was supported by a Swiss National Science Foundation grant. The authors declare no conflicting interests. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.