Semaphorin-3A regulates liver sinusoidal endothelial cell porosity and promotes hepatic steatosis
Daniel Eberhard, Sydney M. Balkenhol, Andrea Köster, Paula Follert, Eric Upschulte, Philipp Niklas Ostermann, Philip Kirschner, Celina Uhlemeyer, Iannis Charnay, Christina Preuss, Sandra Trenkamp, Bengt‐Frederik Belgardt, Timo Dickscheid, Iréne Esposito, Michael Roden, Eckhard Lammert
Abstract
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.