Diabetes regulates fructose absorption through thioredoxin-interacting protein

Abstract

Metabolic studies suggest that the absorptive capacity of the small intestine for fructose is limited, though the molecular mechanisms controlling this process remain unknown. Here we demonstrate that thioredoxin-interacting protein (Txnip), which regulates glucose homeostasis in mammals, binds to fructose transporters and promotes fructose absorption by the small intestine. Deletion of Txnip in mice reduced fructose transport into the peripheral bloodstream and liver, as well as the severity of adverse metabolic outcomes resulting from long-term fructose consumption. We also demonstrate that fructose consumption induces expression of Txnip in the small intestine. Diabetic mice had increased expression of Txnip in the small intestine as well as enhanced fructose uptake and transport into the hepatic portal circulation. The deletion of Txnip in mice abolished the diabetes-induced increase in fructose absorption. Our results indicate that Txnip is a critical regulator of fructose metabolism and suggest that a diabetic state can promote fructose uptake.DOI: http://dx.doi.org/10.7554/eLife.18313.001

Intestinal Fructose and Glucose Metabolism in Health and Disease

“…Although the precise mechanisms remains elusive, TXNIP is upregulated in response to fructose consumption and co-immunoprecipitates with GLUT2 and GLUT5. It may be possible that the link between fructose transport and TXNIP may be mediated by phosphorylation of the protein mediated by AMPK, similar to what we described above for GLUT1 [65].…”

“…Glucose-induced TXNIP inhibits glucose transport through interaction with GLUT1 and inducing its internalization through clathrin-coated pits, as well as reducing the expression of GLUT1, whereas energy stress leads to TXNIP degradation through phosphorylation by AMP-dependent protein kinase (AMPK), resulting in increased GLUT1 function and mRNA expression [61,64]. Dotimas et al demonstrated that TXNIP regulates fructose absorption in the small intestine [65]. Although the precise mechanisms remains elusive, TXNIP is upregulated in response to fructose consumption and co-immunoprecipitates with GLUT2 and GLUT5.…”

Fructose metabolism and metabolic disease

“…Recent data showed that high-fructose feeding induces intestinal thioredoxin-interacting protein (TXNIP), which binds and regulates GLUT5-mediated intestinal fructose transport (36). Consistent with this, we recently showed that carbohydrate-responsive element-binding protein (ChREBP), a transcription factor that responds to intracellular jci.org Volume 128 Number 2 February 2018 glucose uptake and phosphorylation, leading to rapid glycogen accumulation (66).…”

Keeping tabs on fructose

“…To confirm that TXNIP was making the small intestine absorb more fructose, they then performed a similar experiment but injected a solution of fructose directly into the bloodstream rather than feeding the mice via a tube. As expected, when the small intestine was bypassed like this, all the mice showed the same elevated levels of fructose in their tissues regardless of whether they had TXNIP or not ( Dotimas et al, 2016 ).…”

“…Now, in eLife, Richard Lee and co-workers – including James Dotimas and Austin Lee as joint first authors – report that a protein referred to as TXNIP (which is short for thioredoxin-interacting protein) regulates fructose uptake via a previously unrecognized interaction with GLUT5 and GLUT2 ( Dotimas et al, 2016 ). Normally, TXNIP acts to regulate the cell’s redox state.…”