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Using human liver cells to understand the impact of a high-sugar diet without the use of animals

Researcher: Dr Alan Heath

Location: FRAME Lab, University of Nottingham

High fructose diets have been associated with an increase in fat production in the liver, which can cause health issues such as diabetes. Much of the scientific research into this has been done using rodents. In his project Alan used a human cell-based model to investigate the effect of fructose on the liver and explore potential ways of limiting the negative effect of high fructose in the blood.

The problem

Fructose is a naturally occurring sugar found in fruit, vegetables, and honey. Fructose has a sweeter taste than glucose which means less of it is needed to make foods taste sweet. Fructose is commonly used as a sweetener in processed foods and consumption in developed countries has significantly increased over the past few decades.

Fructose is processed in a different way to glucose. Glucose is broken down and used by cells all over the body, whereas fructose is almost entirely broken down by the liver. And as the liver breaks down fructose, the production of fat increases.

Negative health effects have been linked to high fructose diets include obesity, diabetes, cardiovascular, and liver disease. In research, however, most negative effects have been investigated in studies where rodents are fed abnormally high amounts of fructose, levels not representative of the diets of most people (1). More relevant research is needed in human-based models, with fructose in quantities found in a normal diet.

The project

In his project Alan used primary liver cells obtained from human patients to investigate the effects of normal dietary levels of fructose and how reducing high blood fructose levels directly after a meal could reduce negative health effects.

Alan compared the effect of a high dose of fructose over a short time verses half that dose of fructose over twice the time period on the liver cells. Using this approach, he studied the effect on the liver cells by measuring, for example, fat released by the liver as triglycerides, a type of fat linked to an increase likelihood of heart disease.

Alan also measured:

  • Lipid and glycogen accumulation from the cells which can lead to liver disease.
  • Excessive lactate production which can lead to increased fat around internal organs
  • Effects on hormones that the liver cells release. This is a good indicator of harm to the cells and can affect a person’s perception of sweet tastes.

After looking at health effects of high fructose on liver cells, Alan investigated the possibility of controlling fructose absorption from the gut (i.e. slowing down absorption). Alan used a human gut cell line in his research. Immortalised cells have been mutated to continue dividing indefinitely, providing a long-term supply of cells for in vitro research. Using the immortalised human gut cell line, he applied fructose, glucose, and potential inhibitors to see if these chemicals prevented the transport of the sugars across the cells. Which would indicate the potential to slow down the transport of fructose into the blood and help reduce the risk of health problems associated with a high ‘spike’ in fructose levels.

‘‘Rats and mice are still widely used to research high-fructose diet-induced metabolic syndrome as seen in recent publications (2).

As an alternative approach, we are using cell culture methods to investigate the effects of normal dietary levels of fructose.’’ 

Dr Alan Heath

The potential

Alan found that decreasing the amount of fructose reaching the liver did lead to reduced fat release from the liver. This indicates that limiting high levels of fructose in the blood after eating could reduce the risk of conditions such as cardiovascular disease or liver disease.

His research showed that fructose at normal doses, relative to glucose, in liver cells increases:

  • triglyceride release
  • glycogen storage
  • lactate production
  • the release of a hormone known as FGF21.

These observations are consistent with those found in humans. As such, this project has shown that fresh human liver cells (primary hepatocytes) are potentially a useful model and a valid alternative to animals for similar studies.

Alan also hoped his project would discover substances that are natural inhibitors of fructose uptake from the gut that would have the potential to be used in consumer products such as soft drinks containing high sugar. Such findings would support further research such as clinical studies to demonstrate the effectiveness of fructose uptake inhibitors in consumer products.


  1. Health implications of fructose consumption: A review of recent data
  2. Recent Developments in Rodent Models of High-Fructose Diet-Induced Metabolic Syndrome: A Systematic Review

Dr Alan Heath completed his PhD at the FRAME Laboratory in 2022

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