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Tyrosine Agonists Reverse the Molecular Defects Associated with Dominant-Negative Mutations in Human Peroxisome Proliferator-Activated Receptor

Departments of Medicine (M.A., M.G., D.B.S., E.M.W., A.G.S., O.R., S.O., K.C.) and Clinical Biochemistry (D.B.S., S.O.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom; GlaxoSmithKline (K.T.G., S.H.L.), Isotope Chemistry, Upper Merion, Pennsylvania 19406; GlaxoSmithKline (H.E.X., T.M.W.), Nuclear Receptor Discovery Research, Research Triangle Park, North Carolina 27709; and Medical Research Council Laboratory of Molecular Biology (J.W.R.S.), Addenbrooke’s Hospital, Cambridge CB2 2QH, United Kingdom

Address all correspondence and requests for reprints to: V. K. Chatterjee, Department of Medicine, University of Cambridge, Level 5, Box 157, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom. E-mail: kkc1{at}mole.bio.cam.ac.uk.

Loss-of-function mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor (PPAR) are associated with a novel syndrome characterized by partial lipodystrophy and severe insulin resistance. Here we have further characterized the properties of natural dominant-negative PPAR mutants (P467L, V290M) and evaluated the efficacy of putative natural ligands and synthetic thiazolidinedione (TZD) or tyrosine-based (TA) receptor agonists in rescuing mutant receptor function. A range of natural ligands failed to activate the PPAR mutants and their transcriptional responses to TZDs (e.g. pioglitazone, rosiglitazone) were markedly attenuated, whereas TAs (e.g. farglitazar) corrected defects in ligand binding and coactivator recruitment by the PPAR mutants, restoring transcriptional function comparable with wild-type receptor. Transcriptional silencing via recruitment of corepressor contributes to dominant-negative inhibition of wild type by the P467L and V290M mutants and the introduction of an artificial mutation (L318A) disrupting corepressor interaction abrogated their dominant-negative activity. More complete ligand-dependent corepressor release and reversal of dominant-negative inhibition was achieved with TA than TZD agonists. Modeling suggests a structural basis for these observations: both mutations destabilize helix 12 to favor receptor-corepressor interaction; conversely, farglitazar makes more extensive contacts than rosiglitazone within the ligand-binding pocket, to stabilize helix 12, facilitating corepressor release and transcriptional activation. Farglitazar was a more potent inducer of PPAR target gene (aP2) expression in peripheral blood mononuclear cells with the P467L mutation. Having shown that rosiglitazone is of variable and limited efficacy in these subjects, we suggest that TAs may represent a more rational therapeutic approach.

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