Thyroid hormone regulates carnitine palmitoyltransferase Ialpha gene expression through elements in the promoter and first intron.
Carnitine palmitoyltransferase I (CPT-I) catalyzes the transfer of long chain fatty acyl groups from CoA to carnitine for translocation across the mitochondrial inner membrane. CPT-Ialpha is a key regulatory enzyme in the oxidation of fatty acids in the liver. CPT-Ialpha is expressed in all tissues except skeletal muscle and adipose tissue, which express CPT-Ibeta. Expression of CPT-Ialpha mRNA and enzyme activity are elevated in the liver in hyperthyroidism, fasting, and diabetes. CPT-Ialpha mRNA abundance is increased 40-fold in the liver of hyperthyroid compared with hypothyroid rats. Here, we examine the mechanisms by which thyroid hormone (T3) stimulates CPT-Ialpha gene expression. Four potential T3 response elements (TRE), which contain direct repeats separated by four nucleotides, are located 3000-4000 base pairs 5' to the start site of transcription in the CPT-Ialpha gene. However, only one of these elements functions as a TRE. This TRE binds the T3 receptor as well as other nuclear proteins. Surprisingly, the first intron of the CPT-Ialpha gene is required for the T3 induction of CPT-Ialpha expression, but this region of the gene does not contain a TRE. In addition, we show that CPT-Ialpha is induced by T3 in cell lines of hepatic origin but not in nonhepatic cell lines.
Jansen
M S
MS
Department of Pharmacology, University of Tennessee, School of Medicine, Memphis, Tennessee 38163, USA.
Cook
G A
GA
Song
S
S
Park
E A
EA
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003850:Deoxyribonuclease I / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007438:Introns; D008099:Liver / Q000201:enzymology; D008156:Luciferases / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D020218:Response Elements; D017422:Sequence Analysis, DNA; D013963:Thyroid Hormones / Q000378:metabolism*; D014162:Transfection; D014284:Triiodothyronine / Q000378:metabolism
D005227:Fatty Acids; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013963:Thyroid Hormones; D014284:Triiodothyronine; D008156:Luciferases; D002334:Carnitine O-Palmitoyltransferase; D003850:Deoxyribonuclease I