The transcription factor BMAL1 (aryl hydrocarbon receptor nuclear translocator-like protein 1) is an essential regulator of the circadian clock, which controls the 24-hr cycle of physiological processes such as nutrient absorption. To examine the role of BMAL1 in small intestinal glucose absorption, we used differentiated human colon adenocarcinoma cells (Caco-2 cells). Here, we show that BMAL1 regulates glucose uptake in differentiated Caco-2 cells and that this process is dependent on the glucose transporter SGLT1. Mechanistic studies show that BMAL1 regulates glucose uptake by controlling the transcription of SGLT1 involving the paired-homeodomain transcription factor 4 (PAX4), a transcriptional repressor. This is supported by the observation that CRISPR-Cas9-knock down of PAX4 increases SGLT1 and glucose uptake. ChIP and ChIP-qPCR assays show that the knock down or overexpression of BMAL1 decreases or increases the binding of PAX4 to the HNF1a binding site of the SGLT1 promoter, respectively. These findings identify BMAL1 as a critical mediator of small intestine carbohydrate absorption and SGLT1.

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