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Publication
Macrophage SR-BI modulates autophagy via VPS34 complex and PPARa transcription
of Tfeb in atherosclerosis.
Authors Tao H, Yancey PG, Blakemore JL, Zhang Y, Ding L, Jerome WG, Brown JD, Vickers
KC, Linton MF
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal The Journal of clinical investigation
Year 2021
Date Published 4/1/2021
Volume : Pages 131 : Not Specified
PubMed Reference 33661763
Abstract Autophagy modulates lipid turnover, cell survival, inflammation, and
atherogenesis. Scavenger receptor class B type I (SR-BI) plays a crucial role in
lysosome function. Here, we demonstrate that SR-BI regulates autophagy in
atherosclerosis. SR-BI deletion attenuated lipid-induced expression of autophagy
mediators in macrophages and atherosclerotic aortas. Consequently, SR-BI
deletion resulted in 1.8- and 2.5-fold increases in foam cell formation and
apoptosis, respectively, and increased oxidized LDL-induced inflammatory
cytokine expression. Pharmacological activation of autophagy failed to reduce
lipid content or apoptosis in Sr-b1-/- macrophages. SR-BI deletion reduced both
basal and inducible levels of transcription factor EB (TFEB), a master regulator
of autophagy, causing decreased expression of autophagy genes encoding VPS34 and
Beclin-1. Notably, SR-BI regulated Tfeb expression by enhancing PPARa
activation. Moreover, intracellular macrophage SR-BI localized to
autophagosomes, where it formed cholesterol domains resulting in enhanced
association of Barkor and recruitment of the VPS34-Beclin-1 complex. Thus, SR-BI
deficiency led to lower VPS34 activity in macrophages and in atherosclerotic
aortic tissues. Overexpression of Tfeb or Vps34 rescued the defective autophagy
in Sr-b1-/- macrophages. Taken together, our results show that macrophage SR-BI
regulates autophagy via Tfeb expression and recruitment of the VPS34-Beclin-1
complex, thus identifying previously unrecognized roles for SR-BI and
potentially novel targets for the treatment of atherosclerosis.




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