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  • Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity.

Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity.

eLife (2019-11-27)
Mario Ruiz, Rakesh Bodhicharla, Marcus Ståhlman, Emma Svensk, Kiran Busayavalasa, Henrik Palmgren, Hanna Ruhanen, Jan Boren, Marc Pilon
ABSTRACT

The human AdipoR1 and AdipoR2 proteins, as well as their C. elegans homolog PAQR-2, protect against cell membrane rigidification by exogenous saturated fatty acids by regulating phospholipid composition. Here, we show that mutations in the C. elegans gene acs-13 help to suppress the phenotypes of paqr-2 mutant worms, including their characteristic membrane fluidity defects. acs-13 encodes a homolog of the human acyl-CoA synthetase ACSL1, and localizes to the mitochondrial membrane where it likely activates long chains fatty acids for import and degradation. Using siRNA combined with lipidomics and membrane fluidity assays (FRAP and Laurdan dye staining) we further show that the human ACSL1 potentiates lipotoxicity by the saturated fatty acid palmitate: silencing ACSL1 protects against the membrane rigidifying effects of palmitate and acts as a suppressor of AdipoR2 knockdown, thus echoing the C. elegans findings. We conclude that acs-13 mutations in C. elegans and ACSL1 knockdown in human cells prevent lipotoxicity by promoting increased levels of polyunsaturated fatty acid-containing phospholipids.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
6-Dodecanoyl-N,N-dimethyl-2-naphthylamine, suitable for fluorescence, ≥97.0% (HPLC)
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MISSION® esiRNA, targeting human ACSL5
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MISSION® esiRNA, targeting human ACSL6, CTB-127M13.1
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MISSION® esiRNA, targeting human ACSL1
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Monoclonal Anti-α-Tubulin antibody produced in mouse, ascites fluid, clone B-5-1-2