Hepatocyte nuclear factor 1 binding element within the promoter of microsomal triglyceride transfer protein (MTTP) gene is crucial for MTTP basal expression and insulin responsiveness.
Insulin inhibits the transcription of the microsomal triglyceride transfer protein (MTTP), which plays a pivotal role in lipoprotein assembly and secretion. Here, we provide evidence that a hepatocyte nuclear factor 1 binding element (HNF1A element) within the MTTP promoter serves as a novel negative insulin-responsive element. Deletion/mutation mapping of the MTTP gene promoter identified a modified HNF1A element that is crucial to the negative insulin effect. Chimeric promoter containing this HNF1A element and minimal TEAD1 promoter also responded negatively toward insulin treatment. Gel shift assay demonstrated that HNF1A but not HNF1B binds to this element. Enforced expression of HNF1A was sufficient to reconstitute the negative insulin responsiveness of MTTP promoter in TM4SF1 myocytes that are HNF1A negative. Furthermore, replacing this element with consensus HNF1A element preserved the negative insulin response, suggesting that negative insulin responsiveness is a generic characteristic of HNF1A element. Given that many genes implicated in diabetes contain HNF1A element, the potential regulation of these genes by insulin via HNF1A element may provide important clues for the manifestation and treatment of diabetic metabolic syndromes.
Au
Wo-Shing
WS
Department of Chemistry, Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Room 8N-11, Kadoorie Biological Science Building, Pokfulam Road, Hong Kong, China.
Lu
Liwei
L
Yeung
Chung-Man
CM
Liu
Ching-Chiu
CC
Wong
Oscar G
OG
Lai
Lihui
L
Kung
Hsiang-Fu
HF
Lin
Marie C
MC
D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression / Q000187:drug effects; D051537:Hepatocyte Nuclear Factor 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007328:Insulin / Q000494:pharmacology*; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D020218:Response Elements / Q000235:genetics
D002352:Carrier Proteins; D007328:Insulin; C106092:microsomal triglyceride transfer protein; D051537:Hepatocyte Nuclear Factor 1