title: The molecular structure of thio-ether fatty acids influences PPAR-dependent regulation of lipid metabolism.
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.
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lund
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
authors.forename: Camilla
authors.initials: C
authors.lastname: Stensrud
authors.affiliation: Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Imperial College London, UK; Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad, India.
authors.lastname: Rajender
authors.affiliation: Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway.
authors.forename: Pavol
authors.initials: P
authors.lastname: Bohov
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Norway.
authors.forename: G Hege
authors.initials: GH
authors.lastname: Thoresen
authors.affiliation: Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Norway.
authors.forename: Rolf K
authors.initials: RK
authors.lastname: Berge
authors.affiliation: Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Imperial College London, UK; Institute of Pharmaceutical Science, Franklin-Wilkins Building, King's College London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Wright
authors.affiliation: Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
authors.forename: Arild C
authors.initials: AC
authors.lastname: Rustan
authors.affiliation: Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad, India; Institute of Pharmaceutical Science, Franklin-Wilkins Building, King's College London, UK; GlobalAcorn Ltd, London, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Miller
authors.affiliation: Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway. Electronic address: jon.skorve@k2.uib.no.
authors.forename: Jon
authors.initials: J
authors.lastname: Skorve
mesh_terms: D004305:Dose-Response Relationship, Drug; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005227:Fatty Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D015394:Molecular Structure; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004987:Ethers; D005227:Fatty Acids; D047492:Peroxisome Proliferator-Activated Receptors; D013438:Sulfhydryl Compounds
keywords: Diabetes type 2; Glycerolipids; Metabolic syndrome; PPAR receptors; THEFAs; TTA; Thio-ether fatty acids; β-Oxidation