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J. Biol. Chem., Vol. 278, Issue 10, 7964-7972, March 7, 2003

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A Thyroid Hormone Response Unit Formed between the Promoter and First Intron of the Carnitine Palmitoyltransferase-I Gene Mediates the Liver-specific Induction by Thyroid Hormone^*

Loretta Jackson-Hayes^§, Shulan Song, Eduard N. Lavrentyev, Michelle S. Jansen, F. Bradley Hillgartner^¶, Liquin Tian, Philip A. Wood, George A. Cook, and Edwards A. Park^**

From the  Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, the ^¶ Department of Biochemistry and Molecular Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia, 26506-9142, and the  Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294

Carnitine palmitoyltransferase-I (CPT-I) catalyzes the rate-controlling step of fatty acid oxidation. CPT-I converts long-chain fatty acyl-CoAs to acylcarnitines for translocation across the mitochondrial membrane. The mRNA levels and enzyme activity of the liver isoform, CPT-I, are greatly increased in the liver of hyperthyroid animals. Thyroid hormone (T3) stimulates CPT-I transcription far more robustly in the liver than in non-hepatic tissues. We have shown that the thyroid hormone receptor (TR) binds to a thyroid hormone response element (TRE) located in the CPT-I promoter. In addition, elements in the first intron participate in the T3 induction of CPT-I gene expression, but the CPT-I intron alone cannot confer a T3 response. We found that deletion of sequences in the first intron between +653 and +744 decreased the T3 induction of CPT-I. Upstream stimulatory factor (USF) and CCAAT enhancer binding proteins (C/EBPs) bind to elements within this region, and these factors are required for the T3 response. The binding of TR and C/EBP to the CPT-I gene in vivo was shown by the chromatin immunoprecipitation assay. We determined that TR can physically interact with USF-1, USF-2, and C/EBP. Transgenic mice were created that carry CPT-I-luciferase transgenes with or without the first intron of the CPT-I gene. In these mouse lines, the first intron is required for T3 induction as well as high levels of hepatic expression. Our data indicate that the T3 stimulates CPT-I gene expression in the liver through a T3 response unit consisting of the TRE in the promoter and additional factors, C/EBP and USF, bound in the first intron.

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