TY - JOUR A1 - Amatobi, Kelechi M. A1 - Ozbek-Unal, Ayten Gizem A1 - Schäbler, Stefan A1 - Deppisch, Peter A1 - Helfrich-Förster, Charlotte A1 - Mueller, Martin J. A1 - Wegener, Christian A1 - Fekete, Agnes T1 - The circadian clock is required for rhythmic lipid transport in Drosophila in interaction with diet and photic condition JF - Journal of Lipid Research N2 - Modern lifestyle is often at odds with endogenously driven rhythmicity, which can lead to circadian disruption and metabolic syndrome. One signature for circadian disruption is a reduced or altered metabolite cycling in the circulating tissue reflecting the current metabolic status. Drosophila is a well-established model in chronobiology, but day-time dependent variations of transport metabolites in the fly circulation are poorly characterized. Here, we sampled fly hemolymph throughout the day and analyzed diacylglycerols (DGs), phosphoethanolamines (PEs) and phosphocholines (PCs) using LC-MS. In wild-type flies kept on sugar-only medium under a light-dark cycle, all transport lipid species showed a synchronized bimodal oscillation pattern with maxima at the beginning and end of the light phase which were impaired in period01 clock mutants. In wild-type flies under constant dark conditions, the oscillation became monophasic with a maximum in the middle of the subjective day. In strong support of clock-driven oscillations, levels of the targeted lipids peaked once in the middle of the light phase under time-restricted feeding independent of the time of food intake. When wild-type flies were reared on full standard medium, the rhythmic alterations of hemolymph lipid levels were greatly attenuated. Our data suggest that the circadian clock aligns daily oscillations of DGs, PEs, and PCs in the hemolymph to the anabolic siesta phase, with a strong influence of light on phase and modality. KW - hemolymph lipids KW - lipidomics KW - circadian rhythm KW - feeding KW - locomotor activity KW - light-driven metabolism Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-349961 VL - 64 IS - 10 ER - TY - JOUR A1 - Peck, Barrie A1 - Schug, Zachary T. A1 - Zhang, Qifeng A1 - Dankworth, Beatrice A1 - Jones, Dylan T. A1 - Smethurst, Elizabeth A1 - Patel, Rachana A1 - Mason, Susan A1 - Jian, Ming A1 - Saunders, Rebecca A1 - Howell, Michael A1 - Mitter, Richard A1 - Spencer-Dene, Bradley A1 - Stamp, Gordon A1 - McGarry, Lynn A1 - James, Daniel A1 - Shanks, Emma A1 - Aboagye, Eric O. A1 - Critchlow, Susan E. A1 - Leung, Hing Y. A1 - Harris, Adrian L. A1 - Wakelam, Michael J. O. A1 - Gottlieb, Eyal A1 - Schulze, Almut T1 - Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments JF - Cancer & Metabolism N2 - Background Enhanced macromolecule biosynthesis is integral to growth and proliferation of cancer cells. Lipid biosynthesis has been predicted to be an essential process in cancer cells. However, it is unclear which enzymes within this pathway offer the best selectivity for cancer cells and could be suitable therapeutic targets. Results Using functional genomics, we identified stearoyl-CoA desaturase (SCD), an enzyme that controls synthesis of unsaturated fatty acids, as essential in breast and prostate cancer cells. SCD inhibition altered cellular lipid composition and impeded cell viability in the absence of exogenous lipids. SCD inhibition also altered cardiolipin composition, leading to the release of cytochrome C and induction of apoptosis. Furthermore, SCD was required for the generation of poly-unsaturated lipids in cancer cells grown in spheroid cultures, which resemble those found in tumour tissue. We also found that SCD mRNA and protein expression is elevated in human breast cancers and predicts poor survival in high-grade tumours. Finally, silencing of SCD in prostate orthografts efficiently blocked tumour growth and significantly increased animal survival. Conclusions Our data implicate lipid desaturation as an essential process for cancer cell survival and suggest that targeting SCD could efficiently limit tumour expansion, especially under the metabolically compromised conditions of the tumour microenvironment. KW - SCD KW - lipidomics KW - prostate cancer KW - breast cancer KW - lipid desaturation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145905 VL - 4 IS - 6 ER - TY - JOUR A1 - Segerer, Gabriela A1 - Hadamek, Kerstin A1 - Zundler, Matthias A1 - Fekete, Agnes A1 - Seifried, Annegrit A1 - Mueller, Martin J. A1 - Koentgen, Frank A1 - Gessler, Manfred A1 - Jeanclos, Elisabeth A1 - Gohla, Antje T1 - An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation JF - Scientific Reports N2 - Mammalian phosphoglycolate phosphatase (PGP) is thought to target phosphoglycolate, a 2-deoxyribose fragment derived from the repair of oxidative DNA lesions. However, the physiological role of this activity and the biological function of the DNA damage product phosphoglycolate is unknown. We now show that knockin replacement of murine Pgp with its phosphatase-inactive Pgp\(^{D34N}\) mutant is embryonically lethal due to intrauterine growth arrest and developmental delay in midgestation. PGP inactivation attenuated triosephosphate isomerase activity, increased triglyceride levels at the expense of the cellular phosphatidylcholine content, and inhibited cell proliferation. These effects were prevented under hypoxic conditions or by blocking phosphoglycolate release from damaged DNA. Thus, PGP is essential to sustain cell proliferation in the presence of oxygen. Collectively, our findings reveal a previously unknown mechanism coupling a DNA damage repair product to the control of intermediary metabolism and cell proliferation. KW - cell proliferation KW - DNA metabolism KW - lipidomics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181094 VL - 6 ER -