Lichtenstein, L. orcid.org/0000-0003-3900-786X, Cheng, C.W., Bajarwan, M. et al. (14 more authors) (2024) Endothelial force sensing signals to parenchymal cells to regulate bile and plasma lipids. Science Advances, 10 (39). eadq3075. ISSN 2375-2548
Abstract
How cardiovascular activity interacts with lipid homeostasis is incompletely understood. We postulated a role for blood flow acting at endothelium in lipid regulatory organs. Transcriptome analysis was performed on livers from mice engineered for deletion of the flow-sensing PIEZO1 channel in endothelium. This revealed unique up-regulation of Cyp7a1, which encodes the rate-limiting enzyme for bile synthesis from cholesterol in hepatocytes. Consistent with this effect were increased gallbladder and plasma bile acids and lowered hepatic and plasma cholesterol. Elevated portal fluid flow acting via endothelial PIEZO1 and genetically enhanced PIEZO1 conversely suppressed Cyp7a1. Activation of hepatic endothelial PIEZO1 channels promoted phosphorylation of nitric oxide synthase 3, and portal flow-mediated suppression of Cyp7a1 depended on nitric oxide synthesis, suggesting endothelium-to-hepatocyte coupling via nitric oxide. PIEZO1 variants in people were associated with hepatobiliary disease and dyslipidemia. The data suggest an endothelial force sensing mechanism that controls lipid regulation in parenchymal cells to modulate whole-body lipid homeostasis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Environment (Leeds) > School of Food Science and Nutrition (Leeds) > FSN Chemistry and Biochemistry (Leeds) |
Funding Information: | Funder Grant number Wellcome Trust 110044/Z/15/Z British Heart Foundation RG/17/11/33042 BBSRC (Biotechnology & Biological Sciences Research Council) BB/R013500/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 12 Aug 2024 13:12 |
Last Modified: | 11 Oct 2024 07:51 |
Published Version: | https://www.science.org/doi/10.1126/sciadv.adq3075 |
Status: | Published |
Publisher: | American Association for the Advancement of Science |
Identification Number: | 10.1126/sciadv.adq3075 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:215943 |