Knockout of Txnip in the Intestinal Epithelial Cells Abrogates the High Fat Diet‐Induced Fructose Uptake in Mice

Abstract

Thioredoxin interacting protein (Txnip) was initially identified as a protein that can bind to and inhibit thioredoxin, but it is now recognized to participate in nutrient sensing and carbohydrate metabolism. We recently discovered that Txnip binds to the fructose transporters, Glut 2 and Glut 5, to increase the fructose uptake by enterocytes. Additionally, we demonstrated that mice with diabetes induced by streptozotocin exhibit significantly higher fructose absorption compared to their non‐diabetic counterparts. Interestingly, this increase of fructose absorption in the diabetic state requires Txnip. In the current study, we studied the effects of a high fat diet (HFD) on fructose uptake and the involvement of Txnip in this process while the mice were still euglycemic. We hypothesized that high fat diet (HFD) feeding would increase fructose absorption by the jejunum compared to the controls on standard chow diet (RD), and this increase would be prevented in mice with deletion of Txnip in the intestinal epithelium despite being on a HFD. To test this hypothesis, 8‐week‐old male C57BL/6J wild‐type mice were kept on HFD for 16 weeks. At the end of 16 weeks, HFD‐fed mice not only developed insulin resistance as expected, but also displayed significantly higher fructose absorption (hepatic portal vein blood: p<0.01 and liver: p<0.05 vs regular diet mice, n=6–7 mice/group) 20 minutes after the oral gavage of [14C‐(U)]‐D‐fructose. Interestingly, gene and protein expressions of Txnip were also significantly higher in the jejunal samples from these mice, suggesting a potential role of Txnip in fructose uptake by the HFD‐fed mice. Since fructose absorption primarily occurs in the jejunum, using a cre‐lox breeding strategy, we generated a Txnip villin‐cre mice that lacks Txnip in the intestinal epithelial cells; and then subjected these mice and their cre counterparts to RD/HFD at 7–9 weeks of age. The preliminary data at 1 month post‐diet shows a downward trend of fructose absorption in both RD‐fed and HFD‐fed Txnip villin cre mice compared to cre‐controls that exhibited a physiological level of Txnip in villi. Therefore, our data indicate that HFD facilitates fructose uptake by the intestine, and targeted deletion of Txnip at the intestinal level can decrease absorption of dietary fructose. This finding suggests a molecular mechanism by which a high fat diet can promote additional hepatic lipid synthesis through increased fructose absorption.Support or Funding InformationNational Institute of Health (RTL R01DK107396) and Canadian Diabetes Association (PF‐3‐16‐5176‐AS to AS)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.