title: Identification of dual PPARα/γ agonists and their effects on lipid metabolism.
abstract: The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPARα, PPARγ and PPARδ, play central roles in lipid metabolism and glucose homeostasis. Dual PPARα/γ agonists, which stimulate both PPARα and PPARγ isoforms to similar extents, are gaining popularity as it is believed that they are able to ameliorate the unwanted side effects of selective PPARα and PPARγ agonists; and may also be used to treat dyslipidemia and type 2 diabetes mellitus simultaneously. In this study, virtual screening of natural product libraries, using both structure-based and ligand-based drug discovery approaches, identified ten potential dual PPARα/γ agonist lead compounds (9-13 and 16-20). In vitro assays confirmed these compounds to show no statistically significant toxicity to cells, with the exception of compound 12 which inhibited cell growth to 74.5%±3.5 and 54.1%±3.7 at 50μM and 100μM, respectively. In support of their potential as dual PPARα/γ agonists, all ten compounds upregulated the expression of cholesterol transporters ABCA1 and ABCG1 in THP-1 macrophages, with indoline derivative 16 producing the greatest elevation (2.3-fold; 3.3-fold, respectively). Furthermore, comparable to the activity of established PPARα and PPARγ agonists, compound 16 stimulated triacylglycerol accumulation during 3T3-L1 adipocyte differentiation as well as fatty acid β-oxidation in HuH7 hepatocytes.
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Quanqing
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Jacky
authors.initials: J
authors.lastname: Hanh
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Váradi
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Rose
authors.initials: R
authors.lastname: Cairns
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Helena
authors.initials: H
authors.lastname: Sjöström
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Vivian W Y
authors.initials: VW
authors.lastname: Liao
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Peta
authors.initials: P
authors.lastname: Wood
authors.affiliation: Discipline of Physiology, School of Medical Sciences & Bosch Institute, The University of Sydney, 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Seher
authors.initials: S
authors.lastname: Balaban
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Jennifer Ai
authors.initials: JA
authors.lastname: Ong
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Hsuan-Yu Jennifer
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Felcia
authors.initials: F
authors.lastname: Lai
authors.affiliation: Discipline of Physiology, School of Medical Sciences & Bosch Institute, The University of Sydney, 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hoy
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Grewal
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Groundwater
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia. Electronic address: david.hibbs@sydney.edu.au.
authors.forename: David E
authors.initials: DE
authors.lastname: Hibbs
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D062105:Molecular Docking Simulation; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D054852:Small Molecule Libraries
keywords: Cholesterol and fatty acid metabolism; Dyslipidemia; Pan PPAR agonists; Type 2 diabetes; Virtual screening