SCD1 activation impedes foam cell formation by inducing lipophagy in oxLDL-treated human vascular smooth muscle cells.

Huifeng Pi,Zhen Wang,Feng Gao,Ping Deng,Mengyu Liu,Zhou Zhou,Zhengping Yu

doi:10.1111/jcmm.14401

Abstract

The formation of fat‐laden foam cells, which contributes to the fatty streaks in the plaques of atheromas, is an important process in atherosclerosis. Vascular smooth muscle cells (VSMCs) are a critical origin of foam cells. However, the mechanisms that underlie VSMC foam cell formation are not yet completely understood. Here, we demonstrated that oxidized low‐density lipoprotein (oxLDL) inhibited lipophagy by suppressing lipid droplet (LD)‐lysosome fusion and increased VSMC foam cell formation. Moreover, although oxLDL treatment inhibited lysosomal biogenesis, it had no significant effect on lysosomal proteolysis and lysosomal pH. Notably, through TMT‐based quantitative proteomic analysis and database searching, 94 differentially expressed proteins were identified, of which 54 were increased and 40 were decreased in the oxLDL group compared with those in the control group. Subsequently, SCD1, a protein of interest, was further investigated. SCD1 levels in the VSMCs were down‐regulated by exposure to oxLDL in a time‐dependent manner and the interaction between SCD1 and LDs was also disrupted by oxLDL. Importantly, SCD1 overexpression enhanced LD‐lysosome fusion, increased lysosomal biogenesis and inhibited VSMC foam cell formation by activating TFEB nuclear translocation and its reporter activity. Modulation of the SCD1/TFEB‐mediated lipophagy machinery may offer novel therapeutic approaches for the treatment of atherosclerosis.

Highlights

Considering the profound impact of Stearoyl‐coenzyme A desaturase‐1 (SCD1) on lipophagy, we examined whether SCD1 overexpression could rescue oxidized low‐density lipoprotein (oxLDL)‐in‐ duced Vascular smooth muscle cells (VSMCs) foam cell formation and lipophagic flux inhibition
Our current work, based on TMT‐based quantitative proteomic analysis, is the first to show that (a) oxLDL inhibited lipophagy by suppressing lipid droplet (LD)‐lysosome fusion and further increased VSMC foam cell formation; (b) al‐ though oxLDL treatment inhibited lysosomal biogenesis, it had no significant effect on lysosomal proteolysis and lysosomal pH; (c) oxLDL decreased SCD1 expression and inhibited SCD1 and LD interaction; and (d) overexpression of SCD1 attenuated oxLDL‐in‐ duced VSMC proliferation and foam cell formation by enhancing
Our study confirms that SCD1 signalling pathway activation inhibits VSMC foam cell formation by increasing lipophagy

Summary

Introduction

SCD1 is essential for autophagosome formation and autophagosome‐lysosome fusion.[30] Based on a previous study, we postulated that SCD1 is engaged in oxLDL‐induced lipophagy in VSMCs. Western blot analysis and RT‐PCR showed that the SCD1 levels in the VSMCs were decreased by oxLDL treatment in a time‐dependent manner (Figure 5A‐B).

Results

Conclusion