PER1 modulates SGLT1 transcription in vitro independent of E-box status

Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
Digestive Diseases and Sciences (Impact Factor: 2.61). 04/2012; 57(6):1525-36. DOI: 10.1007/s10620-012-2166-8
Source: PubMed


The intestine demonstrates profound circadian rhythmicity in glucose absorption in rodents, mediated entirely by rhythmicity in the transcription, translation, and function of the sodium glucose co-transporter SGLT1 (Slc5a1). Clock genes are rhythmic in the intestine and have been implicated in the regulation of rhythmicity of other intestinal genes; however, their role in the regulation of SGLT1 is unknown. We investigated the effects of one clock gene, PER1, on SGLT1 transcription in vitro.
Caco-2 cells were stably transfected with knockdown vectors for PER1 and mRNA expression of clock genes and SGLT1 determined using quantitative polymerase chain reaction (qPCR). Chinese hamster ovary (CHO) cells were transiently cotransfected with combinations of the PER1 expression vectors and the wild-type SGLT1-luciferase promoter construct or the promoter with mutated E-box sequences.
Knockdown of PER1 increased native SGLT1 expression in Caco-2 enterocytes, while promoter studies confirmed that the inhibitory activity of PER1 on SGLT1 occurs via the proximal 1 kb of the SGLT1 promoter. E-box sites exerted a suppressive effect on the SGLT1 promoter; however, mutation of E-boxes had little effect on the inhibitory activity of PER1 on the SGLT1 promoter suggesting that the actions of PER1 on SGLT1 are independent of E-boxes.
Our findings suggest that PER1 exerts an indirect suppressive effect on SGLT1, possibly acting via other clock-controlled genes binding to non-E-box sites on the SGLT1 promoter. Understanding the regulation of rhythmicity of SGLT1 may lead to new treatments for the modulation of SGLT1 expression in conditions such as malabsorption, diabetes, and obesity.

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Available from: David Rhoads, Jan 27, 2014
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    ABSTRACT: Many physiological functions exhibit a diurnal rhythmicity that is influenced by biological clocks and feeding rhythms. In this review, we discuss the growing evidence showing the important role of circadian rhythms in regulating intestinal mucosa. First, we introduce the molecular timing system and the interrelationship between the master biological clock in the suprachiasmatic nuclei of the brain and the peripheral intestinal clock and provide evidence that the intestinal clock is entrained with the external environment. Second, we review the circadian rhythmicity of enterocyte proliferation and the largely unknown regulatory mechanisms behind these rhythms. Finally, we focus on the circadian clock control of food processing that functions by regulating the expression of digestive enzymes and intestinal nutrient and salt transporters. The concepts to be discussed highlight the ability of the intestinal epithelium to utilize self-sustained clock signals together with signals associated with changes in the cellular environment and to use endogenous temporal control of the gastrointestinal functions to meet varying physiological and pathophysiological demands. The fact that internal de-synchronizations within the body, such as those that occur in shift workers or with changes in food intake behavior, are often associated with malfunctions of the gastrointestinal tract indicates that more information about the connections between the circadian clock and intestinal mucosa/transporting enterocytes could provide clues for future therapies. Acta Physiologica © 2013 Scandinavian Physiological Society.
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