ChREBP deficiency leads to diarrhea-predominant irritable bowel syndrome

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P><B>Objective</B></P> <P>Fructose malabsorption is a common digestive disorder in which absorption of fructose in the small intestine is impaired. An abnormality of the main intestinal fructose transporter proteins has been proposed as a cause for fructose malabsorption. However the underlying molecular mechanism for this remains unclear. In this study, we investigated whether carbohydrate response element-binding protein (ChREBP) plays a role in intestinal fructose absorption through the regulation of genes involved in fructose transport and metabolism and ion transport.</P> <P><B>Methods</B></P> <P>Wild type (WT) and <I>Chrebp</I> knockout (KO) mice (6 or 8 weeks old) were fed a control diet (55% starch, 15% maltodextrin 10) or high-fructose diet (HFrD, 60% fructose, 10% starch) for 3–12 days. Body weight and food intake were measured, signs of fructose malabsorption were monitored, and the expression of genes involved in fructose transport/metabolism and ion transport was evaluated. Furthermore, transient transfection and chromatin immunoprecipitation were performed to show the direct interaction between ChREBP and carbohydrate response elements in the promoter of <I>Slc2A5</I>, which encodes the fructose transporter GLUT5.</P> <P><B>Results</B></P> <P> <I>Chrebp</I> KO mice fed the control diet maintained a constant body weight, whereas those fed a HFrD showed significant weight loss within 3–5 days. In addition, <I>Chrebp</I> KO mice fed the HFrD exhibited a markedly distended cecum and proximal colon containing both fluid and gas, suggesting incomplete fructose absorption. Fructose-induced increases of genes involved in fructose transport (GLUT5), fructose metabolism (<I>fructokinase</I>, <I>aldolase B</I>, <I>triokinase</I>, and <I>lactate dehydrogenase</I>), and gluconeogenesis (<I>glucose</I>-<I>6</I>-<I>phosphatase</I> and <I>fructose</I>-<I>1</I>,<I>6</I>-<I>bisphosphatase</I>) were observed in the intestine of WT but not of <I>Chrebp</I> KO mice. Moreover the Na<SUP>+</SUP>/H<SUP>+</SUP> exchanger NHE3, which is involved in Na<SUP>+</SUP> and water absorption in the intestine, was significantly decreased in HFrD-fed <I>Chrebp</I> KO mice. Consistent with this finding, the high-fructose diet-fed <I>Chrebp</I> KO mice developed severe diarrhea. Results of chromatin immunoprecipitation assays showed a direct interaction of ChREBP with the <I>Glut5</I> promoter, but not the <I>Nhe3</I> promoter, in the small intestine. Ectopic co-expression of ChREBP and its heterodimer partner Max-like protein X activated the <I>Glut5</I> promoter in Caco-2BBE cells.</P> <P><B>Conclusions</B></P> <P>ChREBP plays a key role in the dietary fructose transport as well as conversion into lactate and glucose through direct transcriptional control of genes involved in fructose transport, fructolysis, and gluconeogenesis. Moreover, ablation of <I>Chrebp</I> results in a severe diarrhea in mice fed a high-fructose diet, which is associated with the insufficient induction of GLUT5 in the intestine.</P> <P><B>Highlights</B></P> <P> <UL> <LI> <I>Chrebp</I> knockout mice show intestinal fructose malabsorption upon high-fructose feeding. </LI> <LI> ChREBP deficiency leads to a severe diarrhea and weight loss upon high-fructose feeding. </LI> <LI> GLUT5 and intestinal fructolytic genes are not induced by fructose in <I>Chrebp</I> knockout mice. </LI> <LI> ChREBP directly regulates <I>Glut5</I> gene expression through binding to functional ChoREs. </LI> </UL> </P>