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Papers In Press, published online ahead of print October 16, 2002
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Submitted on July 19, 2002
Department of Biochemistry and Molecular Pharmacology, West Virginia University, Health Sciences Center, Morgantown, WV 26506-9142
Corresponding Author: fbhillgartner{at}hsc.wvu.edu
In chick embryo hepatocyte cultures, 3,5,3'-triiodothyronine (T3) and insulin increase acetyl-CoA carboxylase-alpha (ACCalpha) transcription, whereas cAMP and medium-chain fatty acids inhibit ACCalpha transcription. The activation of ACCalpha transcription by T3 is mediated by a cis-acting regulatory unit (-101 and -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 ACCalpha transcription. In the present study, we further analyze the role of SREBP-1 in the hormonal and nutritional regulation of ACCalpha transcription. Addition of T3 or insulin to hepatocytes stimulates a 4.0 to 4.5-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 concentration of mature SREBP-1 is observed. Results from time course analyses 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 abundance is distinct from that mediating the effect of insulin. Data from transfection analyses indicate that optimal inhibition of ACCalpha transcription by cAMP or hexanoate is dependent on the presence of the T3 response element and sterol regulatory element between -101 and -71 bp. Incubating hepatocytes with cAMP or hexanoate suppresses the increase in mature SREBP-1 concentration caused by T3 and insulin. In conclusion, these data 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 in hepatocytes.
Revised on September 12, 2002
Accepted on October 15, 2002
Sterol regulatory element-binding protein-1 integrates the actions of thyroid hormone, insulin, cAMP, and medium-chain fatty acids on acetyl-CoA carboxylase-alpha transcription in hepatocytes
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