Abstract
Dysregulation of hepatic gluconeogenesis contributes to the pathogenesis of diabetes, yet the detailed molecular mechanisms remain to be fully elucidated. Here we show that FOXP1, a transcriptional repressor, plays a key role in the regulation of systemic glucose homeostasis. Hepatic expression levels of FOXP1 are decreased in diabetic mice. Modest hepatic overexpression of FOXP1 in mice inhibited the expression of gluconeogenic genes, such as peroxisome proliferators-activated receptor γ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6PC), leading to a decrease in hepatic glucose production and fasting blood glucose levels in normal mice and different mouse models of diabetes, including db/db diabetic and high-fat diet-induced obese mice. FOXP1 physically interacted with FOXO1 in vivo and competed with FOXO1 for binding to the insulin response element in the promoter region of gluconeogenic genes, thereby interfering expression of these genes. These results identify a previously unrecognized role for FOXP1 in the transcriptional control of hepatic glucose homeostasis.
Highlights
In mammals, blood glucose levels are maintained within a relatively tight range through regulation of glucose uptake by peripheral tissues and glucose secretion by the liver, protecting the body from hypoglycemia during fasting conditions and from hyperglycemia after a high-carbohydrate meal [1]
FOXO1 has a well defined role in the regulation of hepatic gluconeogenesis and this transcription factor exerts its function by binding to the consensus sequence of insulin response element (IRE), T(G/ A)TTT(T/G)(G/T), in the promoters of phosphoenolpyruvate carboxykinase (PEPCK) and G6PC genes [8]
In this study we found that FOXP1 can bind to IRE in the promoters of PEPCK and G6PC in vitro and in vivo
Summary
F, 5Ј-CATTTGATGCACTGACAGATGGA-3Ј F, 5Ј-TGCAAGGGAGAACTCAGCAA-3Ј F, 5Ј-ACACACACACATGCTCACAC-3Ј F, 5Ј-CCAGCCTTCCTTCTTGGGTAT-3Ј F, 5Ј-CCTCGCTCAAGGCATGATTC-3Ј F, 5Ј-GGAGCCATGGATTGCACATT-3Ј F, 5Ј-GTAAGTTCTGTGGCTCCAGAG-3Ј F, 5Ј-AGGAAGATGGCGTCCGCTCTG-3Ј F, 5Ј-GAACCCCAACATCCCCAAAC-3Ј F, 5Ј-AACACTTACTATGCCTCGATTGCA-3Ј F, 5Ј-ACAAGGCCTCAGGGTACCA-3Ј. F, 5Ј-ATGATGCAAGAATCTGGGTCTGAG-3Ј; F, 5Ј-AGATCTCCACCATGATGCAAGAATCTG-3Ј F, 5Ј-ACGCGTAGACATGAGGCCAATACCAGG-3Ј F, 5Ј-ACGCGTACTCTGTCCTGTGTCTCTGG-3Ј F, 5Ј-ACGCGTCATCAACCTACTGGTGATGC-3Ј F, 5Ј-GATCCGGAGAAATCCCTGCCCTCA-3Ј. R, 5Ј-GTCAGGCATGGAGGAAGGAC-3Ј R, 5Ј-GGACCAAGGAAGCCACAATG-3Ј R, 5Ј-ATCACCGCATAGTCTCTGAA-3Ј R, 5Ј-TGCTGGAAGGTGGACAGTGAG-3Ј R, 5Ј-AGGACTTGGAAGGTGCCGAG-3Ј R, 5Ј-GGCCCGGGAAGTCACTGT-3Ј R, 5Ј-GCCCTCCCGTACACTCACTC-3Ј R, 5Ј-GGTGAGATGTGCTGGGTCAT-3ЈR R, 5Ј-TCCTGGCATTCTCCTGGAAT-3Ј R, 5Ј-CCATAGCCTCCGAAAATCTGAA-3Ј R, 5Ј-GCCGAAAGAAGCCCTTACAG-3Ј. FOXP1 can directly interact with FOXO1 in vivo and it competes with FOXO1 for binding to IRE mapped in the promoter of gluconeogenic genes, preventing FOXO1 binding to these genes, thereby modulating hepatic glucose metabolism
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