The molecular structure of thio-ether fatty acids influences PPAR-dependent regulation of lipid metabolism. Issue 6 (15th March 2016)

• Record Type: Journal Article
• Authors: Lund, Jenny; Stensrud, Camilla; Rajender, ; Bohov, Pavol; Thoresen, G. Hege; Berge, Rolf K.; Wright, Michael; Kamal, Ahmed; Rustan, Arild C.; Miller, Andrew D.; Skorve, Jon
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 6(2016)
• Page Start: 1191
• Page End: 1203
• Publication Date: 2016-03-15
• Subjects: THEFA thio-ether fatty acid -- FA fatty acid -- MUFA monounsaturated fatty acid -- SFA saturated fatty acid -- TTA 2-(tetradecylthio)acetic acid -- TTA-PC 1, 2-di-[2-(tetradecylthio)acetyl]-sn-glycero-3-phosphocholine -- TTA-MAG 1-[2-(tetradecylthio)acetyl]-sn-glycerol -- dTTA 2-(tetradec-[7-enyl]thio)acetic acid -- dTTA-PC 1, 2-di-[2-(tetradec-[7-enyl]thio)acetyl]-sn-glycero-3-phosphocholine -- lyso-dTTA-PC 1-[2-(tetradec-[7-enyl]thio)acetyl]-sn-glycero-3-phosphocholine -- dTTA-MAG 1-[2-(tetradec-[7-enyl]thio)acetyl]-sn-glycerol -- tTTA 2-(tetradec-[7-ynyl]thio)acetic acid -- tTTA-PC 1, 2-di-[2-(tetradec-[7-ynyl]thio)acetyl]-sn-glycero-3-phosphocholine -- lyso-tTTA-PC 1-[2-(tetradec-[7-ynyl]thio)acetyl]-sn-glycero-3-phosphocholine -- tTTA-MAG 1-[2-(tetradec-[7-ynyl]thio)acetyl]-sn-glycerol -- OA oleic acid -- ANGPTL4 angiopoietin-like 4 -- FABP3 fatty acid binding protein 3 -- CD36 fatty acid translocase -- CPT1A carnitine palmitoyltransferase 1A -- NR nuclear receptor -- CA cell-associated radioactivity; Metabolic syndrome -- β-Oxidation -- Diabetes type 2 -- PPAR receptors -- Glycerolipids -- TTA -- Thio-ether fatty acids -- THEFAs; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.01.045
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Thio-ether fatty acids (THEFAs), including the parent 2-(tetradecylthio)acetic acid (TTA), are modified fatty acids (FAs) that have profound effects on lipid metabolism given that they are blocked for β-oxidation, and able to act as peroxisome proliferator-activated receptor (PPAR) agonists. Therefore, TTA in particular has been tested clinically for its therapeutic potential against metabolic syndrome related disorders. Here, we describe the preparation of THEFAs based on the TTA scaffold with either a double or a triple bond. These are tested in cultured human skeletal muscle cells (myotubes), either as free acid or following esterification as phospholipids, lysophospholipids or monoacylglycerols. Metabolic effects are assessed in terms of cellular bioavailabilities in myotubes, by FA substrate uptake and oxidation studies, and gene regulation studies with selected PPAR-regulated genes. We note that the inclusion of a triple bond promotes THEFA-mediated FA oxidation. Furthermore, esterification of THEFAs as lysophospholipids also promotes FA oxidation effects. Given that the apparent clinical benefits of TTA administration were offset by dose limitation and poor bioavailability, we discuss the possibility that a selection of our latest THEFAs and THEFA-containing lipids might be able to fulfill the therapeutic potential of the parent TTA while minimizing required doses for efficacy, side-effects and adverse reactions.