Fructose causes liver toxicity by first changing the barrier function of the intestine, a team of international researchers including Australians has found.
The study, published in Nature Metabolism, showed that a prolonged, high fructose diet induces barrier deterioration, a low-grade endotoxaemia, and intestinal epithelial endoplasmic reticulum (ER) stress in experimental animals.
Importantly, treatments that prevent barrier disruption could protect the liver from fructose-induced diseases including non-alcoholic fatty liver disease (NAFLD), fibrosis and cancer.
The study suggested that endotoxin neutralisation may be a potential preventative or therapeutic approach that deserves consideration .
One of the senior investigators on the study Professor Mark Febbraio, from Monash’s Institute of Pharmaceutical Sciences, said the findings make it clear that fructose does its damage via the intestine.
“… and if intestinal barrier deterioration is prevented, the fructose does little harm to the liver.”
The research showed a toxic pathway from a high fructose diet through to hepatosteatosis and, after 12 months, HCC nodules in the mice.
The research also found that adding tumour necrosis factor (TNF) to hepatocytes also stimulated fructose-drive steatosis.
“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,” Professor Febbraio said.
“Although our mouse model experiments, employing high amounts of fructose, may not be immediately extended to humans, most of whom rarely consume fructose without glucose, we suggest that barrier deterioration is likely to occur only after continuous and excessive consumption of fructose, and is probably influenced by other dietary and genetic factors or comorbidities,” the study said.
The study demonstrates that maintaining gut barrier integrity is a therapeutic approach to treat liver disease associated with high fructose consumption. The researchers will now focus on screening drug candidates that target key proteins in the maintenance of gut barrier integrity.
Other Australian investigators on the study included Professor Peter Meikle (Baker Heart and Diabetes Institute) and Dr Darren Henstridge (formerly at the Baker, now at the University of Tasmania).