Txnip Deficiency in the Intestinal Epithelial Cells Prevents against the High-Fat Diet-Induced Fructose Uptake

Abstract

Thioredoxin interacting protein (Txnip) has emerged as a key player in nutrient sensing and carbohydrate metabolism. Our lab 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 Txnip was required for the streptozotocin-induced diabetic mice to exhibit a significant increase in fructose absorption. In the present study, we explored the effects of high fat diet (HFD) on fructose uptake in mice with fasting euglycemia and elucidated the role of Txnip in this process. We hypothesized that jejunal uptake of fructose would increase in the HFD-fed mice as compared to the regular diet (RD)-fed controls, and this rise would be prevented in mice with intestinal epithelium knockout of Txnip, despite being on a HFD. To test this hypothesis, C57BL/6J wild type mice were kept on HFD for 16 weeks. At the end of this period, the HFD-fed mice not only exhibited a fasting euglycemia, but also displayed significantly higher fructose absorption (hepatic portal vein blood: p<0.01 and liver: p<0.vs. RD-fed mice, n=6-7 mice/group). Interestingly, gene and protein expressions of Txnip were also significantly higher in the jejunal samples from these mice. Since fructose absorption primarily occurs in the jejunum, 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. The preliminary data at one month post-diet shows a reduced trend of fructose absorption in both RD-fed and HFD-fed Txnip villin cre mice compared to the cre-controls. Thus, our data demonstrates that HFD facilitates fructose uptake by the intestine, and the targeted deletion of Txnip at the intestinal level can decrease the absorption of dietary fructose. This outcome implies a molecular mechanism by which high fat diet can promote excess hepatic lipid synthesis via enhanced fructose uptake. Disclosure A. Shah: None. S. Dagdeviren: None. H. Hundal: None. R. Lee: None.