Semaphorin-3A regulates liver sinusoidal endothelial cell porosity and promotes hepatic steatosis.
Animals
Humans
Endothelial Cells
/ metabolism
Liver
/ metabolism
Non-alcoholic Fatty Liver Disease
/ metabolism
Semaphorin-3A
/ metabolism
Signal Transduction
Mice, Inbred C57BL
Neuropilin-1
/ metabolism
Obesity
/ metabolism
Cofilin 1
/ metabolism
Disease Models, Animal
Male
Phosphorylation
Cells, Cultured
Mice
Mice, Knockout
Diabetes Mellitus, Type 2
/ metabolism
Diet, High-Fat
/ adverse effects
Journal
Nature cardiovascular research
ISSN: 2731-0590
Titre abrégé: Nat Cardiovasc Res
Pays: England
ID NLM: 9918284280206676
Informations de publication
Date de publication:
Jun 2024
Jun 2024
Historique:
received:
22
02
2023
accepted:
07
05
2024
medline:
28
8
2024
pubmed:
28
8
2024
entrez:
28
8
2024
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 39196233
doi: 10.1038/s44161-024-00487-z
pii: 10.1038/s44161-024-00487-z
doi:
Substances chimiques
Semaphorin-3A
0
Neuropilin-1
144713-63-3
Cofilin 1
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
734-753Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : La1216/6-1
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : RTG 2576 vivid
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : GRK2576
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : La1216/6-1
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : IRTG 1902
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : Priority Program 2041 (SPP 2041)
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : GRK2576
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : GRK2576
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : GRK2576
Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
ID : 101147319 (EBRAINS 2.0 Project)
Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
ID : "CESYDE", Grant agreement No. 759099
Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
ID : HORIZON-HLTH-2022-STAYHLTH-02-01: Panel A
Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
ID : INTERCEPT-T2D consortium
Informations de copyright
© 2024. The Author(s).
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