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 endoth...

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Bibliographic Details
Published in:Science advances 2024-09, Vol.10 (39), p.eadq3075
Main Authors: Lichtenstein, Laeticia, Cheng, Chew W, Bajarwan, Muath, Evans, Elizabeth L, Gaunt, Hannah J, Bartoli, Fiona, Chuntharpursat-Bon, Eulashini, Patel, Shaili, Konstantinou, Charalampos, Futers, T Simon, Reay, Melanie, Parsonage, Gregory, Moore, J Bernadette, Bertrand-Michel, Justine, Sukumar, Piruthivi, Roberts, Lee D, Beech, David J
Format: Article
Language:English
Subjects:
Animals
Bile - metabolism
Bile Acids and Salts - metabolism
Cholesterol - blood
Cholesterol - metabolism
Cholesterol 7-alpha-Hydroxylase - genetics
Cholesterol 7-alpha-Hydroxylase - metabolism
Endothelial Cells - metabolism
Endothelium - metabolism
Hepatocytes - metabolism
Humans
Ion Channels - genetics
Ion Channels - metabolism
Life Sciences
Lipid Metabolism
Lipids - blood
Liver - metabolism
Mice
Nitric Oxide - metabolism
Nitric Oxide Synthase Type III - genetics
Nitric Oxide Synthase Type III - metabolism
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Summary: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 , 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 . Activation of hepatic endothelial PIEZO1 channels promoted phosphorylation of nitric oxide synthase 3, and portal flow-mediated suppression of depended on nitric oxide synthesis, suggesting endothelium-to-hepatocyte coupling via nitric oxide. 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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adq3075