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

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.

Sterculic Acid: The Mechanisms of Action beyond Stearoyl-CoA Desaturase Inhibition and Therapeutic Opportunities in Human Diseases

“…Foam cell formation and lipid accumulation, are the first steps of atherosclerosis and many of these foam cells are derived from vascular smooth muscle cells (VSMCs) [78]. The role of SCD1 in the atherogenic inflammation is controverted.…”

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

“…Previous studies showed that despite the well-established essential role of monocyte-derived macrophages, vascular smooth muscle cells (VSMCs) were equipped with macrophage features, constituting a substantial source of foam cells and in ammatory response in plaques [5,6]. Basically, low density lipoprotein underwent oxidative modi cation beneath the vascular intimal, and could be ingested by VSMCs [7], which, promoted transition of VSMCs from the mature contractile state to the macrophage-like phenotype [8]. As a result, lipid accumulated in the VSMCs, and such VSMC-derived foam cells accelerated the progression of the atherosclerosis [9,10].…”

The Oncogene Transcription Factor EB Regulates Vascular Functions

“…In this cell type, oxidized lipoproteins inhibit the transcription of TFEB, which is counteracted by overexpression of stearoyl−coenzyme A desaturase−1, an integral protein anchored in the endoplasmic reticulum membrane. Overexpression of this enzyme inhibits the differentiation of VSMCs in foam cells and increases TFEB nuclear translocation (Pi et al, 2019). In mice maintained on a high-fat diet and subjected to partial carotid ligation, VSMCs undergo neointima formation, which is a hallmark of atherosclerotic plaques.…”