Autophagy Regulates Cholesterol Efflux from Macrophage Foam Cells via Lysosomal Acid Lipase

By M. Ouimet, V. Franklin, E. Mak, Xianghai Liao, I. Tabas, Y. Marcel. Cell Metabolism, 2011

725 citations recorded by the source corpus.

SUMMARY The lipid droplet (LD) is the major site of cholesterol storage in macrophage foam cells and is a potential therapeutic target for the treatment of atherosclerosis. Cholesterol, stored as cholesteryl esters (CEs), is liberated from this organelle and delivered to cholesterol acceptors. The current paradigm attributes all cytoplasmic CE hydrolysis to the action of neutral CE hydrolases. Here, we demonstrate an important role for lysosomes in LD CE hydrolysis in cholesterol-loaded macrophages, in addition to that mediated by neutral hydrolases. Furthermore, we demonstrate that LDs are delivered to lysosomes via autophagy, where lysosomal acid lipase (LAL) acts to hydrolyze LD CE to generate free cholesterol mainly for ABCA1-dependent efflux; this process is specifically induced upon macrophage cholesterol loading. We conclude that, in macrophage foam cells, lysosomal hydrolysis contributes to the mobilization of LD-associated cholesterol for reverse cholesterol transport.

Subfields: Biochemistry, Epidemiology, Surgery

View Paper: https://www.semanticscholar.org/paper/0026feb938f29ae10def3c12a7a397dfe914db76

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biochemistry

1. I. Tabas
2. R. Kaufman
3. J. Malhotra

In Epidemiology

1. Jennifer Lippincott-Schwartz
2. H. Plun-Favreau
3. Paul Denny
4. David P. Hill
5. Jennifer Martinez
6. Marc Feuermann
7. Paola Roncaglia
8. Sarah Cohen

In Surgery

1. I. Tabas
2. R. Kaufman
3. J. Malhotra
4. G. Hotamışlıgil

Citations in the corpus

• Exploring autophagy with Gene Ontology (2016, background): “…macrophage foam cell formation and function, 70,71 and terms relevant to these processes also appear among enrichment results, such as ‘ regulation of macrophage-derived foam cell differentiation ’ and its positive and negative children, 70 or ‘ regulation of cholesterol storage ’ 71 (Table S5).”
• Macrophage Autophagy Plays a Protective Role in Advanced Atherosclerosis (2012, background): “A recent study revealed that autophagy can play a role in the hydrolysis of stored CE droplets in macrophages, thus facilitating cholesterol efflux (Ouimet et al., 2011), but the relevance of this finding to atherosclerosis remains to be determined.”
• Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy and mitochondrial fusion dynamics (2015, result): “By contrast, we found that conditions of serum depletion in the presence of amino acids and glucose led to upregulation of lipophagy, consistent with previous studies (Ouimet et al., 2011; Schulze et al., 2013; Singh et al., 2009a).”
• Macrophage Phenotype and Function in Different Stages of Atherosclerosis (2016, neutral): “For example, inhibition of autophagy by silencing the E3 ubiquitin ligase ATG5 (autophagy protein 5) results in increased macrophage apoptosis and NADPH oxidase–mediated oxidative stress and, in addition, renders the apoptotic cells less well recognized by efferocytes.123 Furthermore, defective auto”