Thyroid Hormone Stimulates Acetyl-CoA Carboxylase-α Transcription in Hepatocytes by Modulating the Composition of Nuclear Receptor Complexes Bound to a Thyroid Hormone Response Element

Yanqiao Zhang,Liya Yin,F Bradley Hillgartner

doi:10.1074/jbc.m005894200

Abstract

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.

Highlights

When the intake of dietary carbohydrate exceeds the immediate energy needs of the animal, excess carbohydrate is converted to triacylglycerols, which can be used for energy during periods of fasting
Chick embryo hepatocytes were transfected with a series DNA constructs containing 5Ј-deletions of acetyl-CoA carboxylase (ACC)␣ promoter 2 linked to the chloramphenicol acetyltransferase (CAT) gene
Unlabeled ACC␣-T3 response elements (T3REs), ACC␣-T3RE mut 1, and ACC␣-T3RE mut 3 were more effective than ACC␣-T3RE mut 2 and acetyl-CoA carboxylase-␣ (ACC␣)T3RE mut 4 in competing for the binding of complexes 1 and 2 in nuclear extracts from hepatocytes incubated in the absence of T3 and complex 3 in nuclear extracts from hepatocytes incubated in the presence of T3 (Fig. 6A)

Summary

Introduction

When the intake of dietary carbohydrate exceeds the immediate energy needs of the animal, excess carbohydrate is converted to triacylglycerols, which can be used for energy during periods of fasting. In nuclear extracts from hepatocytes incubated in the absence of T3, ACC␣-T3RE bound protein complexes (complexes 1 and 2) containing the liver X receptor (LXR) and the retinoid X receptor (RXR).

Results

Conclusion