Nutrient Regulation of PFKFB3/iPFK2 and Its Role in Regulating Diet-Induced Inflammation in Intestinal Epithelial Cells

Abstract

The gene PFKFB3 encodes for inducible 6-phosphofructo-2-kinase (iPFK2), an important regulatory enzyme of glycolysis. It is shown that PFKFB3/iPFK2 links metabolic and inflammatory pathways in adipose tissue; however, whether it functions in the same manner within small intestine, where nutrients are assimilated and first interact with the body, is unknown. Therefore, the present study firstly investigated how diet, macronutrients, e.g. glucose and palmitate, and bacterial metabolites influence PFKFB3/iPFK2 expression, and secondly determined how altered gene expression relates to inflammatory responses in small intestinal epithelial cells (IECs).

HFD feeding and in vitro palmitate treatment were associated with reduced PFKFB3/iPFK2 but increased proinflammatory responses. LFD feeding and glucose treatment showed the opposite result. In vitro overexpression of PFKFB3/iPFK2 lead to reduced proinflammatory responses while inhibition of PFKFB3/iPFK2 was associated with increased inflammatory markers. Treatment with the bacterial metabolite indole stimulated PFKFB3/iPFK2 and reduced the generation of inflammation.

Together these findings indicate that macronutrients differentially regulate PFKFB3/iPFK2 expression in IECs, where carbohydrates stimulate PFKFB3/iPFK2 and saturated fats contribute to proinflammatory mechanisms. Further, results confirm an anti-inflammatory ability of PFKFB3/iPFK2 within IECs and suggest an additional anti-inflammatory mechanism of action of indole in regulating inflammation through PFKFB3/iPFK2.