Autophagy differentially regulates macrophage lipid handling depending on the lipid substrate (oleic acid vs. acetylated-LDL) and inflammatory activation state.
Biochim Biophys Acta Mol Cell Biol Lipids
; 1864(12): 158527, 2019 12.
Article
em En
| MEDLINE
| ID: mdl-31520777
The regulation of lipid droplet (LD) dynamics by autophagy in naïve macrophages is complex: Inhibiting autophagosome initiation steps attenuates oleic acid (OA) induced LD (OA-LD) biogenesis, whereas interfering with later-autophagosome maturation/lysosomal steps accelerates OA-LD biogenesis rate, but not OA-LD degradation. Here we hypothesized that regulation of macrophage lipid handling by autophagy may be lipid-substrate and activation-state-specific. Using automated quantitative live-cell imaging, initial LD biogenesis rate was ~30% slower when the lipid source was acetylated low density lipoprotein (acLDL) compared to OA. Yet, both were similarly affected by triacsin-C, an inhibitor of acyl-CoA synthase, which inhibited, and etomoxir, an inhibitor of acylcarnitine palmitoyl transferase (fatty acid oxidation), which augmented, LD biogenesis rates. An autophagy inducing peptide, Tat-Beclin1, enhanced the degradation, and inhibited (by 37%) the biogenesis of acLDL induced LD (acLDL-LD). Yet, Tat-Beclin1 increased OA-LD biogenesis rate by 70%. When macrophages were pre-activated with LPSâ¯+â¯INFG they exhibited increased autophagosome number and area, and reduced BECN1 and ATG14 protein levels, which associated with a markedly attenuated autophagic flux. Concomitantly, OA-LD and acLDL-LD biogenesis rates increased 3 and 7.4-fold, respectively, but could not be further modulated by Tat-Beclin1, as observed in non-activated/naïve macrophages. We propose that macrophage autophagy, and/or components of its machinery, differentially regulate LD/foam-cell biogenesis depending on the lipid-source, and that inflammatory activation uncouples autophagy from LD biogenesis.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Autofagia
/
Ácido Oleico
/
Lipoproteínas LDL
/
Ativação de Macrófagos
/
Macrófagos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article