Fructose is a simple sugar which, beside natural fruits, can be found in high quantities in soft drinks, sauces and fast foods. With the advent of modern biochemistry and metabolic analysis, in recent times scientists have discovered that fructose is up to three times more potent than glucose in increasing liver fat. Excessive fructose consumption has been linked to the recent surge in NAFLD – one of the most common metabolic disorders – and its associated co-morbidities, which include liver failure, cirrhosis, and cancer. The intestine is an organ that makes up part of the gastrointestinal system (more commonly known as the gut). In recent years it’s become evident that excessive fructose metabolism in the gut reduces the production of proteins that maintain the gut barrier, which can lead to a chronic inflammation condition called leaky gut syndrome, as documented in animal studies and pediatric NAFLD patients.
A team of international researchers including Monash University academics has discovered that, contrary to previous belief, fructose causes liver toxicity by changing the barrier function of the intestine. This new discovery not only deepens our understanding of how fructose affects the liver, it could also protect it from numerous life-threatening diseases. The new study, published this week, shows that fructose affects the liver only after it causes intestinal barrier disruption, therefore treatments that prevent barrier disruption could protect the liver from fructose-induced diseases including fatty liver disease, fibrosis and cancer. The international team of researchers found that by adding a cytokine called ‘tumor necrosis factor’ (TNF) to hepatocytes, stimulates the metabolism of fructose and increases the production of the enzymes that convert the molecule ‘acetyl CoA’ to fatty acids.
A large increase in the expression of these enzymes was also detected in livers of fructose-fed mice. Conversely, genetic modification that reduced TNF production was found to protect mice from fructose-provoked NAFLD, which is a very exciting step forward for the treatment of diseases which can evolve from this all too common liver disorder. The findings from this study make it clear that fructose does its damage in the intestine and if intestinal barrier deterioration is prevented, the fructose does little harm to the liver Although education and increased awareness are the best solutions to the problem of fructose-induce liver disease, for those individuals who progress to the severe form of NAFLD, known as non-alcoholic steatohepatitis (NASH), the findings described in this study offer some hope of a future therapy based on gut barrier restoration.
This study clearly demonstrates that maintaining gut barrier integrity is a therapeutic target to treat liver disease associated with high fructose consumption. The Toll receptor agonists produced by bacteria decomposition may promote gut permeabilization and trigger fatty liver (hepatosteathosis) through a pattern of cytokine-induced gene expression in liver. The researchers will now focus on screening drug candidates that target key proteins in the maintenance of gut barrier integrity. Leading Australian metabolic disease expert, Professor Mark Febbraio from Monash’s Institute of Pharmaceutical Sciences, was part of the international team of researchers led by Professor Michael Karin from The University of California San Diego, School of Medicine.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Todoric J et al., Febbraio M, Karin M. Nature Metabolism 2020 Aug 24.
Davey JR, Estevez E et al. FASEB J. 2020; 34(4):5697-5714.
Whitham M et al. Am J Physiol Endocrinol Metab 2019; 317:E597-E604.
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