4.6 Article

Defining the transcriptional regulation of the intestinal sodium-glucose cotransporter using RNA-interference mediated gene silencing

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SURGERY
卷 144, 期 2, 页码 168-173

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MOSBY-ELSEVIER
DOI: 10.1016/j.surg.2008.03.010

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  1. NIDDK NIH HHS [R01 DK047326-10S1, R01 DK047326, P30-DK040561, 5 R01 DK047326, P30 DK040561] Funding Source: Medline

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Background. The sodium glucose cotransporter (SGLT1) is responsible for all active intestinal glucose uptake. Hepatocyte nuclear factors 1 alpha and beta (HNF1 alpha and HNF1 beta) activate the SGLT1 promoter, whereas GATA-binding protein 5 (GATA-5) and caudal-type homeobox protein 2 (CDX2) regulate transcription of other intestinal genes. We investigated SGLT1 regulation by these transcription factors using promoter studies and RNA interference. Methods. Chinese hamster ovary (CHO) cells were transiently cotransfected with an SGLT1-luciferase promoter construct and combinations of expression vectors for HNF1 alpha HNF1 beta, CDX2, and GATA-5. Caco-2 cells were stably transfected with knockdown vectors for either HNF1 alpha or HNF1 beta. mRNA levels of HNF1 alpha, HNF1 beta; and SGLT1 were determined using quantitative polymerise chain reaction (qPCR). Results. HNF1 alpha, GATA-5, and HNF1 beta significantly activated the SGLT1 promoter (P < .05). Co-transfection of GATA-5 with HNF1 alpha had an additive effect, whereas HNF1 beta and CDX2 antagonized HNF1 alpha and GATA-5. SGLT1 expression was significantly reduced in HNF1 alpha or HNF1 beta knockdowns (P < .001). HNF1 alpha knockdown significantly reduced HNF1 beta expression and vice versa (P < .005). Conclusions. HNF1 alpha and HNF1 beta are important transcription factors for endogenous SGLT1 expression by cultured enterocytes. GATA-5 and CDX2 also regulate SGLT1 promoter activity and show cooperativity with the HNF1s. We, therefore, propose a multifactorial model for SGLT1 regulation, with interactions between HNF1, GATA-5, and CDX2 modulating intestinal glucose absorption.

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