SREBP-1 integrates the actions of thyroid hormone, insulin, cAMP, and medium-chain fatty acids on ACCalpha transcription in hepatocytes.
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.
Zhang
Yanqiao
Y
Department of Biochemistry and Molecular Pharmacology, School of Medicine, P.O. Box 9142, West Virginia University, Morgantown, WV, USA.
Yin
Liya
L
Hillgartner
F Bradley
FB
D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002208:Caproates / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D000242:Cyclic AMP / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D051780:Sterol Regulatory Element Binding Protein 1; D013347:Subcellular Fractions / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000378:metabolism* / Q000494:pharmacology
D022762:CCAAT-Enhancer-Binding Proteins; D002208:Caproates; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D007328:Insulin; D009687:Nuclear Proteins; D020033:Protein Isoforms; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014284:Triiodothyronine; C037652:hexanoic acid; D000242:Cyclic AMP; D000103:Acetyl-CoA Carboxylase