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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Carroll, RG; Zasłona, Z; Galván-Peña, S; Koppe, EL; Sévin, DC; Angiari, S; Triantafilou, M; Triantafilou, K; Modis, LK; O'Neill, LA.
An unexpected link between fatty acid synthase and cholesterol synthesis in proinflammatory macrophage activation.
J Biol Chem. 2018; 293(15): 5509-5521.
Doi: 10.1074/jbc.RA118.001921
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- Co-authors Med Uni Graz
- Angiari Stefano
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- Abstract:
- Different immune activation states require distinct metabolic features and activities in immune cells. For instance, inhibition of fatty acid synthase (FASN), which catalyzes the synthesis of long-chain fatty acids, prevents the proinflammatory response in macrophages; however, the precise role of this enzyme in this response remains poorly defined. Consistent with previous studies, we found here that FASN is essential for lipopolysaccharide-induced, Toll-like receptor (TLR)-mediated macrophage activation. Interestingly, only agents that block FASN upstream of acetoacetyl-CoA synthesis, including the well-characterized FASN inhibitor C75, inhibited TLR4 signaling, while those acting downstream had no effect. We found that acetoacetyl-CoA could overcome C75's inhibitory effect, whereas other FASN metabolites, including palmitate, did not prevent C75-mediated inhibition. This suggested an unexpected role for acetoacetyl-CoA in inflammation that is independent of its role in palmitate synthesis. Our evidence further suggested that acetoacetyl-CoA arising from FASN activity promotes cholesterol production, indicating a surprising link between fatty acid synthesis and cholesterol synthesis. We further demonstrate that this process is required for TLR4 to enter lipid rafts and facilitate TLR4 signaling. In conclusion, we have uncovered an unexpected link between FASN and cholesterol synthesis that appears to be required for TLR signal transduction and proinflammatory macrophage activation. © 2018 Carroll et al.
- Find related publications in this database (using NLM MeSH Indexing)
- Acyl Coenzyme A - metabolism
- Animals -
- Cholesterol - biosynthesis
- Fatty Acid Synthase, Type I - metabolism
- Inflammation - enzymology
- Macrophage Activation -
- Macrophages - enzymology
- Mice -
- Palmitic Acid - metabolism
- Signal Transduction -
- Toll-Like Receptor 4 - metabolism