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A Mutant Thyroid Hormone Receptor Antagonizes Peroxisome Proliferator-Activated Receptor Signaling in Vivo and Impairs Fatty Acid Oxidation

Molecular Endocrinology Laboratory (Y.-Y.L., R.S.H., J.J.S., G.A.B., D.S.), Department of Pathology (F.M.), Veterans Affairs Greater Los Angeles Healthcare System, Departments of Medicine and Physiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90073

Address all correspondence and requests for reprints to: Gregory A. Brent, Molecular Endocrinology Laboratory, Building 114, Room 230, 11301 Wilshire Boulevard, Los Angeles, California 90073. E-mail: gbrent{at}ucla.edu.

Thyroid hormone regulates the balance between lipolysis and lipogenesis. We previously reported that male mice with a dominant-negative P398H mutation introduced into the TR gene have visceral obesity, hyperleptinemia, and reduced catecholamine-stimulated lipolysis in white adipose tissue. Based on our observation of hepatic steatosis in the TR P398H male mice, we used in vitro and in vivo models to investigate the influence of the TR P398H mutant on peroxisome proliferator-activated receptor- (PPAR) signaling. Wild-type TR and the P398H mutant significantly reduced PPAR-mediated transcription in transient transfection assays. T₃ reversed the inhibition of PPAR action by wild-type TR but not the P398H mutant. Chromatin immunoprecipitation assays demonstrated that the P398H mutant reduces PPAR binding to peroxisome proliferator receptor elements. In gel shift assays, the P398H mutant directly bound the peroxisome proliferator-activated receptor response element and inhibited PPAR binding, which was not reversed by addition of retinoid X receptor. The TR R384C and PV dominant-negative mutants are not associated in vivo with a metabolic phenotype and had reduced (PV) or absent (R384C) PPAR inhibition compared with P398H. The metabolic phenotype of the P398H mutant mice is due, in part, to unique properties of the P398H mutant receptor interfering with PPAR signaling. The P398H mutant is a potential probe to characterize the physiological role of thyroid hormone receptor/PPAR interactions.

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