Scavenger Receptor Class B Type I Is a Plasma Membrane Cholesterol Sensor

Abstract

Rationale Signal initiation by the HDL receptor scavenger receptor class B, type I (SR-BI), which is important to actions of HDL on endothelium and other processes, requires cholesterol efflux and the C-terminal transmembrane domain (CTTM). The CTTM uniquely interacts with plasma membrane (PM) cholesterol. Objective The molecular basis and functional significance of SR-BI interaction with plasma membrane cholesterol are unknown. We tested the hypotheses that the interaction is required for SR-BI signaling, and that it enables SR-BI to serve as a plasma membrane cholesterol sensor. Methods and Results In studies performed in COS-M6 cells, mutation of a highly-conserved CTTM glutamine to alanine (SR-BI-Q445A) decreased PM cholesterol interaction with the receptor by 71% without altering HDL binding or cholesterol uptake or efflux, and it yielded a receptor incapable of HDL-induced signaling. Signaling prompted by cholesterol efflux to methyl-β-cyclodextrin (CD) was also prevented, indicating that PM cholesterol interaction with the receptor enables it to serve as a PM cholesterol sensor. Using SR-BI-Q445A, we further demonstrated that PM cholesterol sensing by SR-BI does not influence SR-BI-mediated reverse cholesterol transport to the liver in mice. However, the PM cholesterol sensing does underlie apolipoprotein B intracellular trafficking in response to postprandial micelles or CD in cultured enterocytes, and it is required for HDL activation of eNOS and migration in cultured endothelial cells and HDL-induced angiogenesis in vivo. Conclusion Through interaction with plasma membrane cholesterol, SR-BI serves a PM cholesterol sensor, and the resulting intracellular signaling governs processes in both enterocytes and endothelial cells.

Micellar lipid composition affects micelle interaction with class B scavenger receptor extracellular loops

“…recently been hypothesized that the main role of SR-BI was either to facilitate the uptake of other lipid molecules ( 1 ) or to mediate lipid sensing ( 13,14 ), even if a signifi cant involvement in lipid transport cannot be ruled out.…”

“…Sodium taurocholate, free cholesterol, 2-oleoyl-1-palmitoyl-snglycero-3-phosphocholine (phospholipid), 1-palmitoyl-sn -glycero-3-phosphocholine (lysophospholipid), monoolein, OA, palmitic acid (PA), linoleic acid (LA), ␣ -linolenic acid (ALA), arachidonic by guest, on May 10, 2018 www.jlr.org Downloaded from 30 s after the end of the injection (i.e., 150 s after the beginning of injection). The period of time of 120 s was specifi cally chosen during preliminary tests because most of the sensorgrams reached steady state during injection at this time.…”

Regulation of signal transduction by HDL

“…Using SR-BI-Q445A, it was further demonstrated that plasma membrane cholesterol sensing by SR-BI does not infl uence SR-BI-mediated RCT to the liver in mice. However, the plasma membrane cholesterol sensing does underlie apolipoprotein B intracellular traffi cking in response to postprandial micelles or methyl-␤ -cyclodextrin in cultured enterocytes, and it is required for HDL activation of eNOS and migration in cultured endothelial cells and HDL-induced angiogenesis in vivo ( 114 ). Thus, through interaction with cholesterol, SR-BI serves as a plasma membrane cholesterol sensor, and the resulting intracellular signaling governs processes in both enterocytes and endothelial cells.…”

High-Density Lipoprotein

“…47 SR-BI was also found to be important for sensing the cholesterol concentration in plasma membrane domains of endothelial cells and enterocytes, independent of its ability to bind HDL or mediate cholesterol efflux. 71 Other laboratories provided evidence both in vitro and in vivo that S1P carried by HDL induces eNOS phosphorylation by binding to S1P1 and S1P3 receptors and thereby activating PI3 kinase and Akt phosphorylation. In fact, mice lacking either S1P3 or the S1P-binding protein apoM and thereby S1P showed reduced NO production as well as NO-dependent vasodilation and junction closure.…”