A mutant thyroid hormone receptor alpha antagonizes peroxisome proliferator-activated receptor alpha signaling in vivo and impairs fatty acid oxidation.
Thyroid hormone regulates the balance between lipolysis and lipogenesis. We previously reported that male mice with a dominant-negative P398H mutation introduced into the TRalpha gene have visceral obesity, hyperleptinemia, and reduced catecholamine-stimulated lipolysis in white adipose tissue. Based on our observation of hepatic steatosis in the TRalpha P398H male mice, we used in vitro and in vivo models to investigate the influence of the TRalpha P398H mutant on peroxisome proliferator-activated receptor-alpha (PPARalpha) signaling. Wild-type TRalpha and the P398H mutant significantly reduced PPARalpha-mediated transcription in transient transfection assays. T(3) reversed the inhibition of PPARalpha action by wild-type TRalpha but not the P398H mutant. Chromatin immunoprecipitation assays demonstrated that the P398H mutant reduces PPARalpha binding to peroxisome proliferator receptor elements. In gel shift assays, the P398H mutant directly bound the peroxisome proliferator-activated receptor response element and inhibited PPARalpha binding, which was not reversed by addition of retinoid X receptor. The TRalpha R384C and PV dominant-negative mutants are not associated in vivo with a metabolic phenotype and had reduced (PV) or absent (R384C) PPARalpha 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 PPARalpha signaling. The P398H mutant is a potential probe to characterize the physiological role of thyroid hormone receptor/PPARalpha interactions.
Liu
Yan-Yun
YY
Molecular Endocrinology Laboratory, Department of Pathology, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA.
Heymann
Robert S
RS
Moatamed
Farhad
F
Schultz
James J
JJ
Sobel
Daniel
D
Brent
Gregory A
GA
D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics; D006003:Glycogen / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000502:physiology*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000037:antagonists & inhibitors*; D050436:Regulatory Elements, Transcriptional; D015398:Signal Transduction; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation
D005227:Fatty Acids; D050505:Mutant Proteins; D047493:PPAR alpha; D037021:Thyroid Hormone Receptors alpha; D006003:Glycogen