Endothelial force sensing signals to parenchymal cells to regulate bile and plasma lipids
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 <i>Cyp7a1</i>, 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 <i>Cyp7a1</i>. Activation of hepatic endothelial PIEZO1 channels promoted phosphorylation of nitric oxide synthase 3, and portal flow-mediated suppression of <i>Cyp7a1</i> depended on nitric oxide synthesis, suggesting endothelium-to-hepatocyte coupling via nitric oxide. <i>PIEZO1</i> 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.
Authors
- Laeticia Lichtenstein (ORCID: https://orcid.org/0000-0003-3900-786X)
- Elizabeth L. Evans (ORCID: https://orcid.org/0000-0003-1237-7262)
- Piruthivi Sukumar (ORCID: https://orcid.org/0000-0002-3294-989X)
- David J. Beech (ORCID: https://orcid.org/0000-0002-7683-9422)
- Melanie Reay (ORCID: https://orcid.org/0000-0002-7562-0277)
- T. Simon Futers (ORCID: https://orcid.org/0000-0003-3810-190X)
- Chew W. Cheng
- Justine Bertrand‐Michel (ORCID: https://orcid.org/0000-0001-9815-1517)
- Charalampos Konstantinou (ORCID: https://orcid.org/0000-0001-8521-0522)
- Shaili Patel (ORCID: https://orcid.org/0000-0002-0330-2763)
- J. Bernadette Moore (ORCID: https://orcid.org/0000-0003-4750-1550)
- Gregory Parsonage (ORCID: https://orcid.org/0000-0002-3666-5288)
- Fiona Bartoli (ORCID: https://orcid.org/0000-0001-9487-9551)
- Lee D. Roberts (ORCID: https://orcid.org/0000-0002-1455-5248)
- Eulashini Chuntharpursat‐Bon (ORCID: https://orcid.org/0000-0002-0767-6877)
- Muath Bajarwan
- Hannah J. Gaunt
Institutions
- University of Leeds (GB)
- Inserm (FR)
- St James's University Hospital (GB)
- Institut des Maladies Métaboliques et Cardiovasculaires (FR)
Publication Details
- Journal
- Science Advances
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1126/sciadv.adq3075
- Citations
- 11
- Primary Topic
- Erythrocyte Function and Pathophysiology
- Type
- article
- Field-Weighted Citation Impact
- 3.59
Funders
- Institut National de la Santé et de la Recherche Médicale
- Biotechnology and Biological Sciences Research Council