Molecular Bases of Disease
Glycolaldehyde is an endogenous source of lysine N-pyrrolationLysine N-pyrrolation converts lysine residues to Nϵ-pyrrole-l-lysine (pyrK) in a covalent modification reaction that significantly affects the chemical properties of proteins, causing them to mimic DNA. pyrK in proteins has been detected in vivo, indicating that pyrrolation occurs as an endogenous reaction. However, the source of pyrK remains unknown. In this study, on the basis of our observation in vitro that pyrK is present in oxidized low-density lipoprotein and in modified proteins with oxidized polyunsaturated fatty acids, we used LC–electrospray ionization–MS/MS coupled with a stable isotope dilution method to perform activity-guided separation of active molecules in oxidized lipids and identified glycolaldehyde (GA) as a pyrK source.
α-Synuclein structural features inhibit harmful polyunsaturated fatty acid oxidation, suggesting roles in neuroprotectionα-Synuclein (aS) is a protein abundant in presynaptic nerve terminals in Parkinson disease (PD) and is a major component of intracellular Lewy bodies, the pathological hallmark of neurodegenerative disorders such as PD. Accordingly, the relationships between aS structure, its interaction with lipids, and its involvement in neurodegeneration have attracted great interest. Previously, we reported on the interaction of aS with brain polyunsaturated fatty acids, in particular docosahexaenoic acid (DHA).
Group X Secreted Phospholipase A2 Releases ω3 Polyunsaturated Fatty Acids, Suppresses Colitis, and Promotes Sperm FertilityWithin the secreted phospholipase A2 (sPLA2) family, group X sPLA2 (sPLA2-X) has the highest capacity to hydrolyze cellular membranes and has long been thought to promote inflammation by releasing arachidonic acid, a precursor of pro-inflammatory eicosanoids. Unexpectedly, we found that transgenic mice globally overexpressing human sPLA2-X (PLA2G10-Tg) displayed striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages, accompanied by marked elevation of free ω3 polyunsaturated fatty acids (PUFAs) and their metabolites.
Nuclear Factor of Activated T Cells-dependent Down-regulation of the Transcription Factor Glioma-associated Protein 1 (GLI1) Underlies the Growth Inhibitory Properties of Arachidonic AcidNumerous reports have demonstrated a tumor inhibitory effect of polyunsaturated fatty acids (PUFAs). However, the molecular mechanisms modulating this phenomenon are in part poorly understood. Here, we provide evidence of a novel antitumoral mechanism of the PUFA arachidonic acid (AA). In vivo and in vitro experiments showed that AA treatment decreased tumor growth and metastasis and increased apoptosis. Molecular analysis of this effect showed significantly reduced expression of a subset of antiapoptotic proteins, including BCL2, BFL1/A1, and 4-1BB, in AA-treated cells.
Excess Linoleic Acid Increases Collagen I/III Ratio and “Stiffens” the Heart Muscle Following High Fat DietsBackground: Dietary n-6 polyunsaturated fats (n-6 PUFA) like linoleic acid (LA) may worsen cardiac remodeling after injury.Results: Excess LA increased cardiac collagen I/III ratio and lysyl oxidase causing early diastolic dysfunction. In vitro experiments in fibroblasts with genetic manipulation confirmed such mechanisms.Conclusion: LA promotes noncompliant collagen and cardiac stiffening.Significance: This study demonstrates a novel, cardiac-specific lipotoxic pathway of n-6 PUFAs.