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J Lipid Res 2021 Jan 01;62:100145. doi: 10.1016/j.jlr.2021.100145.
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Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension.

Lakk M , Hoffmann GF , Gorusupudi A , Enyong E , Lin A , Bernstein PS , Toft-Bertelsen T , MacAulay N , Elliott MH , Križaj D .

Despite the association of cholesterol with debilitating pressure-related diseases such as glaucoma, heart disease, and diabetes, its role in mechanotransduction is not well understood. We investigated the relationship between mechanical strain, free membrane cholesterol, actin cytoskeleton, and the stretch-activated transient receptor potential vanilloid isoform 4 (TRPV4) channel in human trabecular meshwork (TM) cells. Physiological levels of cyclic stretch resulted in time-dependent decreases in membrane cholesterol/phosphatidylcholine ratio and upregulation of stress fibers. Depleting free membrane cholesterol with m-β-cyclodextrin (MβCD) augmented TRPV4 activation by the agonist GSK1016790A, swelling and strain, with the effects reversed by cholesterol supplementation. MβCD increased membrane expression of TRPV4, caveolin-1, and flotillin. TRPV4 did not colocalize or interact with caveolae or lipid rafts, apart from a truncated ∼75 kDa variant partially precipitated by a caveolin-1 antibody. MβCD induced currents in TRPV4-expressing Xenopus laevis oocytes. Thus, membrane cholesterol regulates trabecular transduction of mechanical information, with TRPV4 channels mainly located outside the cholesterol-enriched membrane domains. Moreover, the biomechanical milieu itself shapes the lipid content of TM membranes. Diet, cholesterol metabolism, and mechanical stress might modulate the conventional outflow pathway and intraocular pressure in glaucoma and diabetes in part by modulating TM mechanosensing.

PubMed ID: 34710431
PMC ID: PMC8633027
Article link: J Lipid Res
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: acta2 cav1 trpv4
GO keywords: lipid metabolic process [+]

Disease Ontology terms: heart disease [+]

Article Images: [+] show captions
References [+] :
Anishkin, Stiffened lipid platforms at molecular force foci. 2013, Pubmed