In macrophages, lipophagy is selectively activated in response to pro-atherogenic lipoproteins (oxidized low-density lipoprotein (LDL) and aggregated LDL), as shown by lipid droplet tagging with ubiquitin and the recruitment of the autophagy marker LC3 and several canonical SARs (sequestome 1 (also known as p62), NBR1 and optineurin) at the lipid droplet surface1,4. In these cells, inhibition of LAL or genetic ablation of autophagy by deletion of Atg5 reduces lipid droplet catabolism and ABCA1-mediated cholesterol efflux by ~50% (ref. 4), calling into question the central dogma that cytoplasmic neutral lipases are solely responsible for macrophage lipolysis and reverse cholesterol transport. Indeed, reverse cholesterol transport from Atg5–/– macrophages is markedly reduced in vivo4. Consistent with this finding, macrophage-specific deletion of Atg5 in Ldlr–/– or Apoe–/– hypercholesterolaemic mice promotes atherosclerosis and results in increased accumulation of lipids in plaques, apoptosis and necrosis, impaired plaque efferocytosis and inflammasome hyperactivation5,6. Conversely, increasing macrophage autophagy and lysosome biogenesis in mice reduces atherogenesis7.

Autophagic markers (such as LC3 and p62) are ubiquitously expressed in the vascular wall. Autophagy flux is active in nascent atheroma but becomes progressively blunted during the progression of atherosclerosis5. Although lipophagy has been known for over a decade to operate in several cell types, including macrophage foam cells, the mechanisms underlying lipophagy and its physiological functions are still poorly understood. Even less is known about the lipophagic capacity of vascular smooth muscle cell (VSMC) foam cells, which comprise the majority of foam cells in atherosclerotic plaques. First, the capacity and extent to which plaque VSMC foam cells undergo lipid droplet biogenesis is unclear, given their intrinsically low LAL activity and consequent inability to process lipoprotein-derived cholesterol esters in lysosomes8. However, increased expression of the lipid droplet marker perilipin 2 in modulated VSMCs during atherosclerosis progression suggests some degree of lipid droplet accumulation in VSMCs at later stages of atherosclerosis9. Interestingly, direct comparisons between macrophage and VSMC foam cells in vitro and in vivo revealed that VSMC foam cells cannot initiate autophagy and induce autophagic lipid droplet catabolism, unlike macrophage foam cells9. The autophagy activator metformin helps to overcome this deficiency and increases ABCG1-mediated cholesterol efflux to high-density lipoprotein9, suggesting that targeting VSMC foam cell lipophagy is an important therapeutic intervention in atherosclerosis.

In an effort to identify the protein machinery that targets lipid droplets for lipophagy, one preliminary study investigated spartin as a potential lipophagy receptor. Through its ubiquitin-binding region, lipid droplet-localized spartin recruited LC3 to lipid droplets to promote lysosomal lipid droplet degradation in SUM159 cells3. A second study identified hepatic ORP8 as an AMPK-regulated lipophagy receptor that mediates autophagic recognition and degradation of lipid droplets by recruiting either LC3 or GABA receptor-associated proteins2. A third study in macrophage foam cells identified 37 proteins that were enriched on lipid droplets after inhibition of autophagic lipid droplet degradation, several of which contained predicted LC3-interacting region motifs and predicted ubiquitin-associated motifs that are typical of SARs1. Yeast lipophagy assays revealed a genetic requirement for several candidate lipophagy factors, including HSPA5, UBE2G2 and AUP1 (ref. 1). Intriguingly, several lipophagy factors are dysregulated in atherosclerosis1, suggesting that alterations in lipophagy flux contribute to atherogenesis. Together, these findings have important biological and therapeutic implications. First, targeting lipophagy receptors and factors to selectively inhibit lipophagy will allow the role of lipophagy in the development of atherosclerosis to be directly tested. Conversely, increasing lipophagy in arterial foam cells could promote reverse cholesterol transport, slow atherogenesis and even drive the regression of pre-existing atherosclerotic plaques.