Macrophage SR-BI modulates autophagy via VPS34 complex and PPARα transcription of Tfeb in atherosclerosis
Huan Tao, … , Kasey C. Vickers, MacRae F. Linton
Huan Tao, … , Kasey C. Vickers, MacRae F. Linton
Published March 4, 2021
Citation Information: J Clin Invest. 2021;131(7):e94229. https://doi.org/10.1172/JCI94229.
View: Text | PDF
Research Article Cardiology Vascular biology

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

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.

Authors

Huan Tao, Patricia G. Yancey, John L. Blakemore, Youmin Zhang, Lei Ding, W. Gray Jerome, Jonathan D. Brown, Kasey C. Vickers, MacRae F. Linton

×

Figure 1

The effects of macrophage SR-BI deficiency on autophagy.

Options: View larger image (or click on image) Download as PowerPoint
The effects of macrophage SR-BI deficiency on autophagy. (A–D) WT and Sr...
(A–D) WT and Sr-b1–/– macrophages were exposed to different levels of starvation (A), oxidized LDL (B), free cholesterol (FC) enrichment (C), or rapamycin (D). (A) For starvation, the cells were incubated for 12 or 24 hours in DMEM without serum. (B) Cells were incubated for 24 hours in DMEM containing 50 or 100 μg/mL oxidized LDL. (C) Cells were incubated for 24 hours in DMEM containing 50 or 100 μg/mL acetylated LDL and 5 μg/mL Sandoz 58035 (ACAT inhibitor). (D) Cells were incubated for 24 hours with 150 or 300 nM rapamycin. In A–D, also shown are basal levels for cells that were incubated for 24 hours with DMEM containing 10% FBS. The levels of VPS34, Beclin-1, and LC3II were analyzed by Western blotting and dot quantitation. The blots are representative, and the numbers are the mean of 3 experiments, in which the values are normalized to either basal WT (green, regular font) or basal Sr-b1–/– levels (red, italic font).