Scavenger receptor class B type I is a plasma membrane cholesterol sensor

Circ Res. 2013 Jan 4;112(1):140-51. doi: 10.1161/CIRCRESAHA.112.280081. Epub 2012 Sep 28.


Rationale: Signal initiation by the high-density lipoprotein (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. The C-terminal transmembrane domain uniquely interacts with plasma membrane (PM) cholesterol.

Objective: The molecular basis and functional significance of SR-BI interaction with PM 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 PM cholesterol sensor.

Methods and results: In studies performed in COS-M6 cells, mutation of a highly conserved C-terminal transmembrane domain 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 also was 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 methyl-β-cyclodextrin in cultured enterocytes, and it is required for HDL activation of endothelial NO synthase and migration in cultured endothelial cells and HDL-induced angiogenesis in vivo.

Conclusions: Through interaction with PM cholesterol, SR-BI serves as a PM cholesterol sensor, and the resulting intracellular signaling governs processes in both enterocytes and endothelial cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine
  • Animals
  • Apolipoproteins B / metabolism
  • Caco-2 Cells
  • Cattle
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Cholesterol / metabolism*
  • Cholesterol, HDL / metabolism
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Enterocytes / drug effects
  • Enterocytes / metabolism*
  • Glutamine
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Liver / metabolism
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Neovascularization, Physiologic
  • Nitric Oxide Synthase Type III / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Scavenger Receptors, Class B / chemistry
  • Scavenger Receptors, Class B / genetics
  • Scavenger Receptors, Class B / metabolism*
  • Signal Transduction* / drug effects
  • Time Factors
  • Transfection
  • beta-Cyclodextrins / pharmacology


  • Apolipoproteins B
  • Cholesterol, HDL
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • PDZK1 protein, mouse
  • SCARB1 protein, human
  • Scarb1 protein, mouse
  • Scavenger Receptors, Class B
  • beta-Cyclodextrins
  • methyl-beta-cyclodextrin
  • Glutamine
  • Cholesterol
  • Nitric Oxide Synthase Type III
  • Alanine