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Identification of dual PPARα/γ agonists and their effects on lipid metabolism

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dc.contributor.authorGao, Q.
dc.contributor.authorHanh, J.
dc.contributor.authorVáradi, L.
dc.contributor.authorCairns, R.
dc.contributor.authorSjöström, H.
dc.contributor.authorLiao, V.W.Y.
dc.contributor.authorWood, P.
dc.contributor.authorBalaban, S.
dc.contributor.authorOng, J.A.
dc.contributor.authorLin, H.Y.J.
dc.contributor.authorLai, F.
dc.contributor.authorHoy, A.J.
dc.contributor.authorGrewal, T.
dc.contributor.authorGroundwater, P.W.
dc.contributor.authorHibbs, D.E.
dc.date.issued2015
dc.description.abstractThe 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.
dc.description.statementofresponsibilityQuanqing Gao, Jacky Hanh, Linda Váradi, Rose Cairns, Helena Sjöström ... Jennifer Ai Ong ... et al.
dc.identifier.citationBioorganic and Medicinal Chemistry, 2015; 23(24):7676-7684
dc.identifier.doi10.1016/j.bmc.2015.11.013
dc.identifier.issn0968-0896
dc.identifier.issn1464-3391
dc.identifier.orcidOng, J.A. [0000-0002-0958-460X]
dc.identifier.urihttp://hdl.handle.net/2440/123567
dc.language.isoen
dc.publisherElsevier
dc.relation.grantNHMRC
dc.rights© 2015 Elsevier Ltd. All rights reserved.
dc.source.urihttps://doi.org/10.1016/j.bmc.2015.11.013
dc.subjectType 2 diabetes; dyslipidemia; cholesterol and fatty acid metabolism; Pan PPAR agonists; virtual screening
dc.titleIdentification of dual PPARα/γ agonists and their effects on lipid metabolism
dc.typeJournal article
pubs.publication-statusPublished

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