Semaphorin-3A regulates liver sinusoidal endothelial cell porosity and promotes hepatic steatosis.

Autor: Eberhard D; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany., Balkenhol S; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany.; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Köster A; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany., Follert P; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany., Upschulte E; Cécile & Oskar Vogt Institute of Brain Research, Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany.; Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.; Helmholtz AI, Research Center Jülich, Jülich, Germany., Ostermann P; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany., Kirschner P; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany., Uhlemeyer C; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Charnay I; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany., Preuss C; German Center for Diabetes Research (DZD), Neuherberg, Germany.; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany., Trenkamp S; German Center for Diabetes Research (DZD), Neuherberg, Germany.; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany., Belgardt BF; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., Dickscheid T; Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.; Helmholtz AI, Research Center Jülich, Jülich, Germany.; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Computer Science, Düsseldorf, Germany., Esposito I; Institute of Pathology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany., Roden M; German Center for Diabetes Research (DZD), Neuherberg, Germany.; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.; Division of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany., Lammert E; Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany. lammert@hhu.de.; Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany. lammert@hhu.de.; German Center for Diabetes Research (DZD), Neuherberg, Germany. lammert@hhu.de.
Jazyk: angličtina
Zdroj: Nature cardiovascular research [Nat Cardiovasc Res] 2024 Jun; Vol. 3 (6), pp. 734-753. Date of Electronic Publication: 2024 Jun 14.
DOI: 10.1038/s44161-024-00487-z
Abstrakt: Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, increases worldwide and associates with type 2 diabetes and other cardiometabolic diseases. Here we demonstrate that Sema3a is elevated in liver sinusoidal endothelial cells of animal models for obesity, type 2 diabetes and MASLD. In primary human liver sinusoidal endothelial cells, saturated fatty acids induce expression of SEMA3A, and loss of a single allele is sufficient to reduce hepatic fat content in diet-induced obese mice. We show that semaphorin-3A regulates the number of fenestrae through a signaling cascade that involves neuropilin-1 and phosphorylation of cofilin-1 by LIM domain kinase 1. Finally, inducible vascular deletion of Sema3a in adult diet-induced obese mice reduces hepatic fat content and elevates very low-density lipoprotein secretion. Thus, we identified a molecular pathway linking hyperlipidemia to microvascular defenestration and early development of MASLD.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: