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Metabolism. 2018 Aug;85:286-297. doi: 10.1016/j.metabol.2018.04.006. Epub 2018 Apr 15.

ChREBP deficiency leads to diarrhea-predominant irritable bowel syndrome.

Author information

1
Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, GAIHST, Gachon University College of Medicine, Incheon 21999, Republic of Korea.
2
CHA Cancer Prevention Research Center, CHA Bio Complex, CHA University, Seongnam 13488, Republic of Korea.
3
Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
4
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
5
Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, GAIHST, Gachon University College of Medicine, Incheon 21999, Republic of Korea; Gachon Medical Research Institute, Gil Medical Center, Incheon 21565, Republic of Korea. Electronic address: jycha1014@gachon.ac.kr.

Abstract

OBJECTIVE:

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.

METHODS:

Wild type (WT) and Chrebp 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 Slc2A5, which encodes the fructose transporter GLUT5.

RESULTS:

Chrebp 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, Chrebp 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 (fructokinase, aldolase B, triokinase, and lactate dehydrogenase), and gluconeogenesis (glucose-6-phosphatase and fructose-1,6-bisphosphatase) were observed in the intestine of WT but not of Chrebp KO mice. Moreover the Na+/H+ exchanger NHE3, which is involved in Na+ and water absorption in the intestine, was significantly decreased in HFrD-fed Chrebp KO mice. Consistent with this finding, the high-fructose diet-fed Chrebp KO mice developed severe diarrhea. Results of chromatin immunoprecipitation assays showed a direct interaction of ChREBP with the Glut5 promoter, but not the Nhe3 promoter, in the small intestine. Ectopic co-expression of ChREBP and its heterodimer partner Max-like protein X activated the Glut5 promoter in Caco-2BBE cells.

CONCLUSIONS:

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 Chrebp results in a severe diarrhea in mice fed a high-fructose diet, which is associated with the insufficient induction of GLUT5 in the intestine.

KEYWORDS:

ChREBP; Diarrhea; Fructose absorption; GLUT5; Intestine

PMID:
29669261
DOI:
10.1016/j.metabol.2018.04.006
[Indexed for MEDLINE]

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