Abstract
In chick embryo hepatocytes, activation of acetyl-CoA carboxylase-alpha (ACCalpha) transcription by 3,5,3'-triiodothyronine (T3) is mediated by a cis-acting regulatory unit (-101 to -71 bp) that binds the nuclear T3 receptor (TR) and sterol regulatory element-binding protein-1 (SREBP-1). SREBP-1 directly interacts with TR on the ACCalpha gene to enhance T3-induced transcription. Here, we show that treating hepatocytes with T3 or insulin stimulates a 4-fold increase in the concentration of the mature, active form of SREBP-1. When T3 and insulin are added together, a 7-fold increase in the mature SREBP-1 concentration is observed. Time course studies indicate that the T3-induced increase in mature SREBP-1 abundance is closely associated with changes in ACCalpha transcription and that the mechanism mediating the effect of T3 on mature SREBP-1 is distinct from that mediating the effect of insulin. Transfection analyses indicate that inhibition of ACCalpha transcription by cAMP or hexanoate is mediated by ACCalpha sequences between -101 and -71 bp. Treatment with cAMP or hexanoate suppresses the increase in mature SREBP-1 abundance caused by T3 and insulin. These results establish a new interaction between the SREBP-1 and TR signaling pathways and provide evidence that SREBP-1 plays an active role in mediating the effects of T3, insulin, cAMP, and hexanoate on ACCalpha transcription.
Highlights
In chick embryo hepatocytes, activation of acetylCoA carboxylase-␣ (ACC␣) transcription by 3,5,3-triiodothyronine (T3) is mediated by a cis-acting regulatory unit (؊101 to ؊71 bp) that binds the nuclear T3 receptor (TR) and sterol regulatory element-binding protein-1 (SREBP-1)
We have identified a new interaction between the sterol regulatory element binding protein (SREBP)-1 and TR signaling pathways
We showed that the mature form of SREBP-1 interacted with TR on the ACC␣ gene to enhance the stimulatory effect of T3 on ACC␣ transcription in chick embryo hepatocyte (CEH) [10]
Summary
Activation of acetylCoA carboxylase-␣ (ACC␣) transcription by 3,5,3-triiodothyronine (T3) is mediated by a cis-acting regulatory unit (؊101 to ؊71 bp) that binds the nuclear T3 receptor (TR) and sterol regulatory element-binding protein-1 (SREBP-1). Incubation of a 32P-labeled oligonucleotide probe containing the ACC␣ SRE-1 (Ϫ84 to Ϫ66 bp) with nuclear extracts from CEH resulted in the formation of three protein-DNA complexes (Fig. 1A, left panel). A: Gel mobility shift assays were per formed using nuclear extracts from hepatocytes or in vitro synthesized mature SREBP-1 (amino acids 1 to 464) and an oligonucleotide probe containing the acetyl-CoA carboxylase-␣ (ACC␣) sterol regulatory element (SRE)-1 (Ϫ84 to Ϫ66 bp).
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