Lipidomics in drug development

Dehairs, Jonas; Derua, Rita; Rueda-Rincón, Natalia; Swinnen, Johannes V.

doi:10.1016/j.ddtec.2015.03.002

Cited by 32 publications

(27 citation statements)

References 43 publications

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“…Lipidomics is an exciting new area 26 . It has been widely applied in several disciplines, including neuroblastoma 27 , mammalian cancer 28 , prostate cancer 29 , tetrahydrocannabinol addiction 30 , Alzheimer’s Disease 31 and drug development 32 .…”

Section: Discussionmentioning

confidence: 99%

Glycerophosphatidylcholine PC(36:1) absence and 3′-phosphoadenylate (pAp) accumulation are hallmarks of the human glioma metabolome

Jia

et al. 2018

Sci Rep

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Glioma is the most prevalent malignant brain tumor. A comprehensive analysis of the glioma metabolome is still lacking. This study aims to explore new special metabolites in glioma tissues. A non-targeted human glioma metabolomics was performed by UPLC-Q-TOF/MS. The gene expressions of 18 enzymes associated with 3’-phosphoadenylate (pAp) metabolism was examined by qRT-PCR. Those enzymes cover the primary metabolic pathway of pAp. We identified 15 new metabolites (13 lipids and 2 nucleotides) that were significantly different between the glioma and control tissues. Glycerophosphatidylcholine [PC(36:1)] content was high and pAp content was significantly low in the control brain (p < 0.01). In glioma tissues, PC(36:1) was not detected and pAp content was significantly increased. The gene expressions of 3′-nucleotidases (Inositol monophosphatase (IMPAD-1) and 3′(2′),5′-bisphosphate nucleotidase 1(BPNT-1)) were dramatically down-regulated. Meanwhile, the gene expression of 8 sulfotransferases (SULT), 2 phosphoadenosine phosphosulfate synthases (PAPSS-1 and PAPSS-2) and L-aminoadipate-semialdehyde dehydrogenase-phosphopante-theinyl transferase (AASDHPPT) were up-regulated. PC(36:1) absence and pAp accumulation are the most noticeable metabolic aberration in glioma. The dramatic down-regulation of IMPAD-1 and BPNT-1 are the primary cause for pAp dramatic accumulation. Our findings suggest that differential metabolites discovered in glioma could be used as potentially novel therapeutic targets or diagnostic biomarkers and that abnormal metabolism of lipids and nucleotides play roles in the pathogenesis of glioma.

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Section: Discussionmentioning

confidence: 99%

Glycerophosphatidylcholine PC(36:1) absence and 3′-phosphoadenylate (pAp) accumulation are hallmarks of the human glioma metabolome

Jia

et al. 2018

Sci Rep

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“…166 Replacement of the central ring by pyridine resulted in similar effects on potency and lipophilicity as for the terminal position. 166 Appending polar substituents resulted in the significantly less lipophilic and more polar compound TUG-488 (12). 167 Investigations of their ability to permeate mucus producing membranes indicated better penetration for 10 and 12 than for 11.…”

Section: Synthetic Ligands For Ffa1mentioning

confidence: 97%

Complex Pharmacology of Free Fatty Acid Receptors

et al. 2016

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G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond simple competitive agonism or antagonism by ligands interacting with the orthosteric binding site of the receptor to incorporate concepts of allosteric agonism, allosteric modulation, signaling bias, constitutive activity, and inverse agonism. Herein, we consider how evolving concepts of GPCR pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or "free" fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets for the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential.

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“…19, 20 Indeed, recent lipidomics studies revealed a dynamic alteration of the membrane lipid composition in human cancer tissues, 21 and distinct lipid profiles correlated with tumor grade. 22 Moreover, combination of molecular biology and lipidomics techniques revealed some of the mechanisms underlying deregulated lipid metabolism in cancer.…”

Section: Introductionmentioning

confidence: 99%

A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling

et al. 2017

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Here, by combining lipidomics with transcriptome analysis, we demonstrate that Rb depletion in mouse embryonic fibroblastss induces significant alterations in their lipid composition. We discovered that Rb depletion induced increase in lysophosphatidylserine, diacylglycerol (DAG), fatty acid (FA), acylcarnitine, phosphatidylcholine (PC), arachidonoyl ethanolamine, and decrease in phosphatidylglycerol, monoacylglycerol, without change in total lipid per protein levels. Analysis of the acyl chain composition of DAG, PC and phosphatidylserine revealed increase of saturated and mono-unsaturated acyl chains with specific carbon chain length. Consistently, we observed that Rb depletion increased the levels of fatty acids with the corresponding carbon chain length and number of carbon–carbon double bondssuch as myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0) and all forms of FA 18:1. Microarray analysis revealed that Rb depletion induced significant upregulation of enzymes involved in elongation and desaturation of fatty acids. Among these, we found that elongation of long chain fatty acid family member 6 (Elovl6) and stearoyl-CoA desaturase 1 (Scd1) are the most robustly controlled by Rb possibly through E2F and sterol regulatory element-binding protein transcription factors. Depletion of Elovl6 or Scd1 significantly suppressed colony formation, sphere formation and xenograft tumor growth of Rb-deficient tumor cells. Suppression of self-renewal by the SCD1 inhibitor was rescued upon supplementation of the mono-unsaturated fatty acids generated by this enzyme. This study suggests a novel role for Rb in suppressing the malignant progression of tumors by controlling the lipid composition.

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Lipidomics in drug development

Cited by 32 publications

References 43 publications

Glycerophosphatidylcholine PC(36:1) absence and 3′-phosphoadenylate (pAp) accumulation are hallmarks of the human glioma metabolome

Glycerophosphatidylcholine PC(36:1) absence and 3′-phosphoadenylate (pAp) accumulation are hallmarks of the human glioma metabolome

Complex Pharmacology of Free Fatty Acid Receptors

A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling

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