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This Article Accepted manuscript (PDF) All Versions of this Article: JME-08-0080v1 41/4/229    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Au, W.-S. Articles by Lin, M. C.-m. Search for Related Content PubMed PubMed Citation Articles by Au, W.-S. Articles by Lin, M. C.-m.

W Au, Chemistry, University of Hong Kong, Hong Kong, Hong Kong
L Lu, Pathology, University of Hong Kong, Hong Kong, Hong Kong
C Yeung, Chemistry, University of Hong Kong, Hong Kong, Hong Kong
C Liu, Chemistry, University of Hong Kong, Hong Kong, Hong Kong
O Wong, Chemistry, University of Hong Kong, Hong Kong, Hong Kong
L Lai, Institute of Molecular and Chemical Biology, East China Normal University, Shanghai, China
H Kung, Centre of Emerging Infectious Diseases, Chinese University of Hong Kong, Hong Kong, Hong Kong
M Lin, Chemistry, University of Hong Kong, Hong Kong, CSW, Hong Kong

Correspondence: Marie Chai-mi Lin, Email: mcllin{at}hkusua.hku.hk

Abstract

Insulin inhibits the transcription of the microsomal triglyceride transfer protein (MTP), which plays a pivotal role in lipoprotein assembly and secretion. Here we provide evidence that a hepatocyte nuclear factor 1 binding element (HNF-1 element) within the MTP promoter serves as a novel negative insulin responsive element. Deletion/mutation mapping of the MTP gene promoter identified a modified HNF-1 element that is crucial to the negative insulin effect. Chimeric promoter containing this HNF-1 element and minimal SV40 promoter also responded negatively towards insulin treatment. Gel shift assay demonstrated that HNF-1 but not HNF-1β binds to this element. Enforced expression of HNF-1 was sufficient to reconstitute the negative insulin responsiveness of MTP promoter in L6 myocytes which are HNF-1 negative. Furthermore, replacing this element with consensus HNF-1 element preserved the negative insulin response, suggesting that negative insulin responsiveness is a generic characteristic of HNF-1 element. Given that many genes implicated in diabetes contains HNF-1 element, the potential regulation of these genes by insulin via HNF-1 element may provide important clues for the manifestation and the treatment of diabetic metabolic syndrome.