ABSTRACT
How cardiovascular activity beneficially regulates lipid homeostasis is unclear. Here we hypothesise a mechanism in which mechanical force sensed by PIEZO1 ion channels in endothelium links blood flow to lipid regulation. We engineered mice for conditional deletion of PIEZO1 in endothelium and determined consequences for lipid regulation. Prominent are upregulated expression of hepatic Cyp7a1 and intestinal Ldlr genes, which are pivotal in cholesterol catabolism and excretion. Consistent with such regulation is endothelial PIEZO1-dependence of hepatic, intestinal and whole body cholesterol and bile homeostasis. There is organ perfusion-dependent gene regulation via endothelial PIEZO1 and downstream nitric oxide synthase. Endothelial PIEZO1-deleted mice are protected against hyperlipidaemia and ectopic fat deposition. Human PIEZO1 gene variants and a recapitulated human PIEZO1 gain-of-function variant in mice associate with dyslipidaemia. The data suggest lipid-promoting effects of endothelial force sensing and new opportunity for understanding and addressing problems of hyperlipidaemia.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵† Lead Author: Dr Laeticia Lichtenstein, Leeds Institute of Cardiovascular and Metabolic Medicine, LIGHT Building, Clarendon Way, School of Medicine, University of Leeds, Leeds LS2 9JT, UK. E-mail l.lichtenstein{at}leeds.ac.uk.
↵* Senior Author: Professor David Beech, Leeds Institute of Cardiovascular and Metabolic Medicine, LIGHT Building, Clarendon Way, School of Medicine, University of Leeds, Leeds LS2 9JT, UK. E-mail d.j.beech{at}leeds.ac.uk.
