1. Biochemistry and Chemical Biology
  2. Cell Biology
Download icon

Metabolism: Keeping tabs on fructose

  1. Anath Shalev  Is a corresponding author
  1. University of Alabama at Birmingham, United States
Insight
  • Cited 26
  • Views 1,564
  • Annotations
Cite this article as: eLife 2016;5:e21263 doi: 10.7554/eLife.21263

Abstract

Too much fructose in the diet can worsen metabolic problems via a process that involves thioredoxin-interacting protein.

Main text

Fructose is a simple sugar that is found in many fruits and plants. Its strong sweetness and minimal effect on blood glucose levels make fructose a more attractive sweetener than other naturally occurring sugars. As a result, high-fructose corn syrup is often added to a variety of foods and drinks to make them sweeter (Figure 1). This has lead to people consuming much more fructose than in previous decades, especially in the United States and other westernized countries (Cox, 2002; Goran et al., 2013). Along with this trend, more and more evidence suggests that consuming too much fructose could detrimentally affect our metabolism. In particular, excess fructose consumption has been linked to an increased risk of insulin resistance, obesity, type 2 diabetes and non-alcoholic fatty liver disease (Elliott et al., 2002; Kolderup and Svihus, 2015). However, it remains controversial whether the fructose itself actually causes these metabolic problems, and different studies have reported conflicting results (Campos and Tappy, 2016).

Fructose in food and drink.

High fructose corn syrup – which is synthetically manufactured from broken down cornstarch – is added to many soft drinks to increase their sweetness, palatability and taste.

Image credit: “high fructose water color” by Laura Taylor (CC BY-NC-ND 2.0)

After we eat or drink fructose it is transported through the cells that line our small intestine with the help of sugar-transporting proteins called GLUT5 and GLUT2 (Gould et al., 1991; Burant et al., 1992). Once in the bloodstream, it is taken to the liver via the hepatic portal vein. The liver then removes some of the fructose in the blood; this ensures that fructose levels in the blood remain at least 10 times lower than glucose levels (Douard and Ferraris, 2008). However, the liver also converts fructose into a number of metabolites that can be used to increase stores of glucose and fat, and this might contribute to the detrimental effects on metabolism that are linked to eating fructose. The uptake of fructose by the small intestine is limited to control how much fructose gets into the blood and liver, but relatively little is known about this process.

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. However, too much TXNIP can detrimentally affect how the body manages its glucose levels (referred to as glucose homeostasis) in a number of ways (Minn et al., 2005; Parikh et al., 2007; Chutkow et al., 2008; Xu et al., 2013).

The gene that encodes TXNIP is itself activated by sugars like glucose and fructose (Minn et al., 2005; Stoltzman et al., 2008; Cha-Molstad et al., 2009), and Dotimas et al. – who are based at Harvard and the Massachusetts General Hospital – confirmed that fructose promotes the production of TXNIP in the small intestine. They also went on to show that fructose actually promotes the interactions between TXNIP and GLUT5 and GLUT2 in the small intestine, and that TXNIP in turn increases fructose uptake.

By using mutant mice and radioactively labeled fructose, Dotimas et al. could show that mice fed fructose via a tube ended up with high levels of fructose in their blood and tissues, but only if they had a working copy of the gene for TXNIP. 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).

Previous studies have shown that diabetes leads to increased production of TXNIP and that deleting the gene for TXNIP (or otherwise inhibiting the protein) can prevent diabetes, improve glucose tolerance and have a beneficial effect on glucose metabolism (Chen et al., 2008). Dotimas et al. found that mice without the gene for TXNIP were also protected against the detrimental effects of a high fructose diet on metabolism.

The researchers also found that triggering diabetes in mice (by killing their insulin-producing cells with a toxin called streptozotocin) led to more TXNIP being produced in the small intestine. This in turn resulted in more fructose being absorbed by the small intestine. Since deleting the gene for TXNIP diminished this effect, they propose that diabetes increases fructose absorption and that TXNIP is involved in this process. Indeed, the data show that TXNIP links fructose absorption to both glucose homeostasis and diabetes.

Though Dotimas et al. clearly demonstrate a new protein-protein interaction between TXNIP and the fructose transporters; it remains to be shown that this interaction actually causes the increase in fructose absorption. If indeed it does, the next challenge will be to work out exactly how this happens. Other challenges include determining how diabetes affects the levels of fructose circulating in the blood in humans, and to tease apart whether any changes in fructose levels are caused by the diabetes itself or by differences in diet.

In addition to supporting the notion that too much fructose in the diet is bad for metabolic control, at least in mice, the work of Lee, Dotimas, Lee and co-workers might also help explain why different studies have come to different conclusions and suggests that the context in which fructose is consumed is important. Just by itself – that is, without glucose being present and in the absence of diabetes or elevated TXNIP levels – very little fructose might be absorbed. In contrast, high levels of glucose will lead to an increase in TXNIP levels, which will promote the absorption of fructose and exacerbate existing problems with metabolism. In any case, the latest work is consistent with the overall concept that inhibiting TXNIP is beneficial for metabolism, and reveals yet another reason why this might be. Another interesting future research direction would be to ask how the gut microbiome might affect the way TXNIP regulates fructose uptake and any resulting metabolic sequelae or complications.

References

    1. Burant CF
    2. Takeda J
    3. Brot-Laroche E
    4. Bell GI
    5. Davidson NO
    (1992)
    Fructose transporter in human spermatozoa and small intestine is GLUT5
    Journal of Biological Chemistry 267:14523–14526.
    1. Elliott SS
    2. Keim NL
    3. Stern JS
    4. Teff K
    5. Havel PJ
    (2002)
    Fructose, weight gain, and the insulin resistance syndrome
     American Journal of Clinical Nutrition 76:911–922.

Article and author information

Author details

  1. Anath Shalev

    Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States
    For correspondence
    Shalev@uab.edu
    Competing interests
    The author declares that no competing interests exist.

Publication history

  1. Version of Record published: October 11, 2016 (version 1)

Copyright

© 2016, Shalev

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,564
    Page views
  • 199
    Downloads
  • 26
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Biochemistry and Chemical Biology
    Hui Huang et al.
    Research Article Updated

    To assure complete tumor removal, frozen section analysis is the most common procedure for intraoperative pathological assessment of resected tumor margins. However, during one operation, multiple biopsies may be sent for examination, but only few of them are made into cryosections because of the complex preparation protocols and time-consuming pathological analysis, which potentially increases the risk of overlooking tumor involvement. Here, we propose a fluorescence-based pre-screening strategy that allows high-throughput, convenient, and fast gross assessment of resected tumor margins. A dual-activatable cationic fluorescent molecular rotor was developed to specifically illuminate live tumor cells’ cytoplasm by emitting two different fluorescence signals in response to elevations in hypoxia-induced nitroreductase (a biochemical marker) and cytoplasmic viscosity (a biophysical marker), two characteristics of cancer cells. The ability of the fluorescent molecular rotor in detecting tumor cells was evaluated in mouse and human specimens of multiple tissues by comparing with hematoxylin and eosin staining. Importantly, the fluorescent molecular rotor achieved 100 % specificity in discriminating lung and liver cancers from normal tissue, allowing pre-screening of the tumor-free surgical margins and promoting clinical decision. Altogether, this type of fluorescent molecular rotor and the proposed strategy may serve as a new option to facilitate intraoperative assessment of resected tumor margins.

    1. Biochemistry and Chemical Biology
    2. Cancer Biology
    E Josue Ruiz et al.
    Research Article Updated

    Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient’s 5-year survival rate is less than 5%. The ubiquitin-specific protease 28 (USP28) has been implicated in tumourigenesis through its stabilization of the oncoproteins c-MYC, c-JUN, and Δp63. Here, we show that genetic inactivation of Usp28-induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN, and Δp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumours and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma.