PI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling

Abstract

Cytotoxic stress activates stress-activated kinases, initiates adaptive mechanisms, including the unfolded protein response (UPR) and autophagy, and induces programmed cell death. Fatty acid unsaturation, controlled by stearoyl-CoA desaturase (SCD)1, prevents cytotoxic stress but the mechanisms are diffuse. Here, we show that 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) [PI(18:1/18:1)] is a SCD1-derived signaling lipid, which inhibits p38 mitogen-activated protein kinase activation, counteracts UPR, endoplasmic reticulum-associated protein degradation, and apoptosis, regulates autophagy, and maintains cell morphology and proliferation. SCD1 expression and the cellular PI(18:1/18:1) proportion decrease during the onset of cell death, thereby repressing protein phosphatase 2 A and enhancing stress signaling. This counter-regulation applies to mechanistically diverse death-inducing conditions and is found in multiple human and mouse cell lines and tissues of Scd1-defective mice. PI(18:1/18:1) ratios reflect stress tolerance in tumorigenesis, chemoresistance, infection, high-fat diet, and immune aging. Together, PI(18:1/18:1) is a lipokine that links fatty acid unsaturation with stress responses, and its depletion evokes stress signaling.

Proteome coverage after simultaneous proteo-metabolome liquid-liquid extraction

“…Polar metabolites and lipids were analyzed and quantified by IC-SIM-MS and LC-MRM-MS 14 15 16 , respectively. Details of IC-SIM-MS and LC-MRM-MS analysis and bioinformatics data processing are described in the supplemental experimental section.…”

The MTORC1-AHR pathway sustains translation and autophagy in tumours under tryptophan stress

“…Sphingolipids were extracted from LN-18 cell pellets by successive addition of PBS pH 7.4, methanol, chloroform, and saline to a final ratio of 14:34:35:17 (Koeberle et al, 2010;Thurmer et al, 2022). The organic phase was evaporated to dryness using an Eppendorf Concentrator Plus System (Eppendorf, 5305000509; high vapor pressure application mode), and the remaining lipid film was dissolved in methanol, centrifuged twice at 21,100×g, 4°C for 5 min, and subjected to In variation to the procedure described above, sphingosine-1-phosphate (S1P) was separated on an Acquity UPLC CSH C18 column (130Å, 1.7 μm, 2.1 × 50 mm, Waters, 186005296) at 55°C.…”

Roles of Palmitoleic Acid and Its Positional Isomers, Hypogeic and Sapienic Acids, in Inflammation, Metabolic Diseases and Cancer

“…Finally, a significant part of the 16:1 fatty acids released by macrophages are incorporated into another phospholipid species, namely PI(18:0/16:1) (1-stearoyl-2-hexadecenoyl- sn -glycero-3-phosphoinositol) [ 86 ]. In analogy with other inositol phospholipid species that are formed upon cell activation and exert defined biological functions [ 90 , 91 , 92 , 93 ], it seems likely that the regulated formation of PI(18:0/16:1) may also be physiologically or pathophysiologically relevant ( Figure 4 ).…”

“…This is fully consistent with recent data demonstrating the accumulation of 16:1n-7 (and also the 16:1n-9 isomer) in selected inositol phospholipid species of activated cells, suggesting novel modes of cell regulation [ 86 ]. While this interesting role for 16:1n-7 as a mitogenic signal on its own will require further confirmation and characterization, it adds to the growing notion that individual phospholipid species play specific biological roles in cells [ 90 , 91 , 92 , 93 , 124 , 125 , 126 , 127 , 128 ].…”