Thyroid hormone stimulates acetyl-coA carboxylase-alpha transcription in hepatocytes by modulating the composition of nuclear receptor complexes bound to a thyroid hormone response element.
Triiodothyronine (T3) stimulates a 7-fold increase in transcription of the acetyl-CoA carboxylase-alpha (ACCalpha) gene in chick embryo hepatocytes. Here, we characterized an ACCalpha T3 response element (ACCalpha-T3RE) with unique functional and protein binding properties. ACCalpha-T3RE activated transcription both in the absence and presence of T3, with a greater activation observed in the presence of T3. In nuclear extracts from hepatocytes incubated in the absence of T3, ACCalpha-T3RE bound protein complexes (complexes 1 and 2) containing the liver X receptor (LXR) and the retinoid X receptor (RXR). In nuclear extracts from hepatocytes incubated in the presence of T3 for 24 h, ACCalpha-T3RE bound a different set of complexes. One complex contained LXR and RXR (complex 3) and another contained the nuclear T3 receptor (TR) and RXR (complex 4). Mutations of ACCalpha-T3RE that inhibited the binding of complexes 1 and 2 decreased transcriptional activation in the absence of T3, and mutations of ACCalpha-T3RE that inhibited the binding of complexes 3 and 4 decreased transcriptional activation in the presence of T3. The stimulation of ACCalpha transcription caused by T3 was closely associated with changes in the binding of complexes 1-4 to ACCalpha-T3RE. These data suggest that T3 regulates ACCalpha transcription by a novel mechanism involving changes in the composition of nuclear receptor complexes bound to ACCalpha-T3RE. We propose that complexes containing LXR/RXR ensure a basal level of ACCalpha expression for the synthesis of structural lipids in cell membranes and that complexes containing LXR/RXR and TR/RXR mediate the stimulation of ACCalpha expression caused by T3.
Zhang
Y
Y
Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, West Virginia 26506, USA.
Yin
L
L
Hillgartner
F B
FB
D000103:Acetyl-CoA Carboxylase / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D002642:Chick Embryo; D002645:Chickens; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D015698:Genomic Library; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000166:cytology; D000071518:Liver X Receptors; D016297:Mutagenesis, Site-Directed; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014284:Triiodothyronine / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014284:Triiodothyronine; D000103:Acetyl-CoA Carboxylase