Loss of intestinal ChREBP impairs absorption of dietary sugars and prevents glycemic excursion curves

Abstract

Increased sugar consumption is a risk factor for features of the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease. The gut epithelium, which plays a central role in dietary sugar digestion, absorption and metabolism has emerged a key actor of metabolic disorders. While the transcription factor ChREBP (Carbohydrate response element binding protein) has been established as a key player of the adaptive reprograming of cellular metabolism in various tissues upon glucose or fructose challenge, its specific contribution to the regulation of blood glucose upon dietary sugar intake was not previously addressed. We demonstrate here that ChREBP is abundantly expressed in the proximal gut epithelium, where carbohydrate digestion and absorption primarily occur and in particular L cells, which produce the glucoincretin GLP-1. The inducible deletion of ChREBP specifically in the mouse gut epithelium (Ch{Delta}GUT mice) resulted in the reduction of early glycemic excursion upon oral glucose load. Surprisingly, despite being associated with reduced GLP-1 production, loss of gut ChREBP activity significantly dampened glucose transepithelial flux, and thereby delayed glucose distribution to peripheral tissues. Among the underlying mechanisms, we unveil that Ch{Delta}GUT mice show an impaired expression of key intestinal hexose (glucose, galactose, fructose) transporters and metabolic enzymes as well as brush border dissacharidases. In agreement, intestinal ChREBP deficiency was accompanied by a precocious intolerance to both high-lactose and high-sucrose diets concomitant with mild galactose and severe fructose malabsorption syndromes. Altogether, our study demonstrates that, by transcriptionally orchestrating local digestion and absorption of dietary sugars, ChREBP activity in the mouse gut epithelium controls glucose appearance rate into systemic circulation and prevents against intolerance to mono- and disaccharides.