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Macrophage SR-BI modulates autophagy via VPS34 complex and PPARα transcription of Tfeb in atherosclerosis.

Citation
Tao, H., et al. “Macrophage Sr-Bi Modulates Autophagy Via Vps34 Complex And Pparα Transcription Of Tfeb In Atherosclerosis.”. The Journal Of Clinical Investigation.
Center Vanderbilt University
Author Huan Tao, Patricia G Yancey, John L Blakemore, Youmin Zhang, Lei Ding, Gray Jerome, Jonathan D Brown, Kasey C Vickers, MacRae F Linton
Keywords atherosclerosis, Autophagy, Cardiology, macrophages, Vascular Biology
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 PPARα 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.

Year of Publication
2021
Journal
The Journal of clinical investigation
Volume
131
Issue
7
Date Published
04/2021
ISSN Number
1558-8238
DOI
10.1172/JCI94229
Alternate Journal
J Clin Invest
PMID
33661763
PMCID
PMC8011903
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