ChREBP-Knockout Mice Show Sucrose Intolerance and Fructose Malabsorption

Abstract

Abstract:We have previously reported that 60% sucrose diet-fed ChREBP knockout mice (KO) 13showed body weight loss resulting in lethality. We aimed to elucidate whether sucrose and 14 fructose metabolism are impaired in KO. Wild type mice (WT) and KO were fed a diet containing 1530% sucrose with/without 0.08% miglitol, an α-glucosidase inhibitor, and these effects on 28

ChREBP-Mediated Regulation of Lipid Metabolism: Involvement of the Gut Microbiota, Liver, and Adipose Tissue

“…Recent studies have revealed that gut microbiota-derived acetate also represents an important source of acetyl CoA for hepatic lipogenesis ( 29 ). Dietary fructose is absorbed and metabolized to glucose in the intestine, whereas unabsorbed fructose is fermented by the gut microbiota to produce acetate ( 26 , 27 , 29 , 40 – 42 ). Glucose induces the expression of both ChREBP - β and SREBP-1c, whereas fructose only induces the expression of SREBP-1c in the liver ( 28 ).…”

“…Glucose induces the expression of both ChREBP - β and SREBP-1c, whereas fructose only induces the expression of SREBP-1c in the liver ( 28 ). Our group and others have recently reported that ChREBP regulates intestinal fructose absorption by inducing the expression of Glut5 , Khk , and Aldob in the intestine and that Chrebp knockout mice consuming a sucrose-based diet show an irritable bowel syndrome-like phenotype, which develops because of fructose malabsorption and an increase in the numbers of acetate-producing bacteria in the intestine ( 26 , 27 ). These findings suggest that the inhibition of intestinal ChREBP increases microbial acetate production by increasing the entry of unabsorbed fructose into the colon.…”

“…ChREBP also induces Acss2 expression ( Figure 1 ) ( 14 , 29 , 33 ). Thus, inhibition of hepatic ChREBP is likely to prevent fructose-induced triglyceride accumulation by suppressing lipogenic gene expression and hepatic acetyl CoA production from gut microbial acetate, while the inhibition of intestinal ChREBP may increase acetate production in the intestine ( 27 ).…”

Fructose and irritable bowel syndrome

“…Therefore, one possible mechanism of fructose malabsorption in IBS could be the inhibition of GLUT2 translocation in response to stress. However, so far GLUT2 has not been identified as a major player in fructose malabsorption (84,85) or as an IBS marker. Carbohydrate responsive element-binding protein (ChREBP) is a transcription factor regulated by sugar intake.…”

“…Carbohydrate responsive element-binding protein (ChREBP) is a transcription factor regulated by sugar intake. ChREBP-KO mice fed with a high-fructose diet developed fructose malabsorption with diarrhoea and caecum distension in association with decrease in expression of genes involved in fructose transport and metabolism (85,86) . More specifically, ChREBP-KO mice were associated with insufficient induction of GLUT5 in response to fructose, which could potentially explain fructose malabsorption (87) .…”