TY - JOUR TI - Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity AU - Ruiz, Mario AU - Bodhicharla, Rakesh AU - Ståhlman, Marcus AU - Svensk, Emma AU - Busayavalasa, Kiran AU - Palmgren, Henrik AU - Ruhanen, Hanna AU - Boren, Jan AU - Pilon, Marc A2 - Walther, Tobias C A2 - Malhotra, Vivek A2 - Walker, Amy VL - 8 PY - 2019 DA - 2019/11/26 SP - e47733 C1 - eLife 2019;8:e47733 DO - 10.7554/eLife.47733 UR - https://doi.org/10.7554/eLife.47733 AB - 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. KW - phospholipids KW - cell membrane KW - acyl-coA synthetase KW - adiponectin receptor KW - forward genetics KW - lipidomics JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -