# Regulation of Fructose Transport by Thioredoxin-Interacting Protein

> **NIH NIH R01** · HARVARD UNIVERSITY · 2020 · $380,250

## Abstract

Fructose consumption has increased in modern America, and fructose consumption may play a role
in metabolic diseases including obesity and diabetes. Fructose transport is regulated by a protein family of
glucose transporters (GLUTs), and the fructose transporter GLUT5 is expressed in enterocytes from the
small intestine. Thioredoxin-Interacting Protein (Txnip) is a member of a mammalian protein superfamily
that contains arrestin-like domains. Here, we present new preliminary data showing that Txnip interacts with
the fructose transporter GLUT5. We also show that overexpression of Txnip increases cellular fructose
uptake in vitro, while deletion of Txnip inhibits fructose uptake. Our preliminary in vivo experiments further
demonstrate that a high fructose diet causes non-alcoholic fatty liver disease in wild type mice, while mice
deficient in Txnip have reduced intestinal fructose transport and hepatic fat deposition following a fructose
diet. These data support a new overall theory that Txnip enhances fructose transport through specific
molecular interactions with GLUT5. The experiments proposed here will likely reveal the molecular basis
for a new pathway in fructose metabolism. Our Specific Aims are:
 Specific Aim 1 will test the hypothesis that a specific molecular interaction through an alpha
arrestin-domain in Txnip regulates GLUT5 and GLUT2 functions. Here we will dissect the molecular
specificity of this interaction by structure-function analysis.
 Specific Aim 2 will test the hypothesis that enterocyte Txnip regulates intestinal fructose
transport and promotes hepatic steatosis in vivo. Targeted loss of function of Txnip will be used to test
this hypothesis in vivo. We will generate intestine-specific Cre-mediated deletion of Txnip in mice, by
crossing the Txnip flox/flox mouse that we engineered with a transgenic mouse bearing a Cre recombinase
expressed under the control of the villin promoter.
 Specific Aim 3 will test the hypothesis that Txnip increases intestinal fructose transport
through a redox-mediated mechanism in vivo. In this aim, we will test if GLUT5 regulation is controlled
by Txnip through a thioredoxin-dependent redox-mediated mechanism, using a novel mouse with a “knock-
in” mutation of Txnip that we have just generated. This mouse has a single amino acid change that
eliminates binding of Txnip to thioredoxin, and thus renders Txnip function independent of thioredoxin redox
state.

## Key facts

- **NIH application ID:** 9947924
- **Project number:** 5R01DK107396-05
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** RICHARD T LEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,250
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9947924

## Citation

> US National Institutes of Health, RePORTER application 9947924, Regulation of Fructose Transport by Thioredoxin-Interacting Protein (5R01DK107396-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9947924. Licensed CC0.

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