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Journal of Lipid Research, Vol. 44, 356-368, February 2003
Copyright © 2003 by Lipid Research, Inc.

SREBP-1 integrates the actions of thyroid hormone, insulin, cAMP, and medium-chain fatty acids on ACC transcription in hepatocytes

Yanqiao Zhang, Liya Yin and F. Bradley Hillgartner¹

Department of Biochemistry and Molecular Pharmacology, School of Medicine, P.O. Box 9142, West Virginia University, Morgantown, WV

¹ To whom correspondence should be addressed. e-mail: fbhillgartner{at}hsc.wvu.edu

In chick embryo hepatocytes, activation of acetyl-CoA 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). SREBP-1 directly interacts with TR on the ACC 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 ACC 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 ACC transcription by cAMP or hexanoate is mediated by ACC 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 ACC transcription.

Abbreviations: ACC, acetyl-CoA carboxylase-; CAT, chloramphenicol acetyltransferase; CEH, chick embryo hepatocyte; ChREBP, carbohydrate response element binding protein; HNF-4, hepatocyte nuclear factor-4; LXR, liver X receptor; PUFA, polyunsaturated fatty acid; RXR, retinoid X receptor; SRE, sterol regulatory element; SREBP, sterol regulatory element binding protein; T3, 3,5,3'-triiodothyronine; T3RE, T3 response element; TK, thymidine kinase; TR, nuclear T3 receptor

Supplementary key words lipogenesis • hexanoate • nuclear T3 receptor • liver X receptor • chicken • fatty acid synthesis • liver • sterol regulatory element binding protein • adenosine 3',5'-cyclic monophosphate • acetyl-CoA carboxylase-

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