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

Tomaz Martini, Cédric Gobet, Andrea Salati, Jérôme Blanc, Aart Mookhoek, Michael Reinehr, Graham Knott, Jessica Sordet-Dessimoz and Felix Naef ()
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Tomaz Martini: Ecole Polytechnique Fédérale de Lausanne
Cédric Gobet: Ecole Polytechnique Fédérale de Lausanne
Andrea Salati: Ecole Polytechnique Fédérale de Lausanne
Jérôme Blanc: Ecole Polytechnique Fédérale de Lausanne
Aart Mookhoek: University of Bern
Michael Reinehr: University Hospital Zurich
Graham Knott: Ecole Polytechnique Fédérale de Lausanne
Jessica Sordet-Dessimoz: Ecole Polytechnique Fédérale de Lausanne
Felix Naef: Ecole Polytechnique Fédérale de Lausanne

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Recent single-cell transcriptomes revealed spatiotemporal programmes of liver function on the sublobular scale. However, how sexual dimorphism affected this space-time logic remained poorly understood. We addressed this by performing scRNA-seq in the mouse liver, which revealed that sex, space and time together markedly influence xenobiotic detoxification and lipoprotein metabolism. The very low density lipoprotein receptor (VLDLR) exhibits a pericentral expression pattern, with significantly higher mRNA and protein levels in female mice. Conversely, VLDL assembly is periportally biased, suggesting a sexually dimorphic hepatic cycle of periportal formation and pericentral uptake of VLDL. In humans, VLDLR expression is also pericentral, with higher mRNA and protein levels in premenopausal women compared to similarly aged men. Individuals with low hepatic VLDLR expression show a high prevalence of atherosis in the coronary artery already at an early age and an increased incidence of heart attack.

Date: 2024
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DOI: 10.1038/s41467-024-52751-2

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