An international team of researchers, led by Monash University, have made a breakthrough discovery by identifying an entirely new way in which metabolic diseases such as obesity, fatty liver disease and type 2 diabetes (T2D) may be triggered.
In the study, which involved both preclinical and human studies, the researchers have for the first time identified that a toxic lipid (fat) known as ‘C16 ceramide’ is produced inside the gut and, subsequently, exported out of the gut via the lymphatic system in response to a diet high in saturated fats.
Once outside the gut, C16 ceramide has been associated with a myriad of health issues and has even been flagged as a key biomarker for various metabolic diseases.
This discovery into how the human body both generates and transports lipids from the gut when triggered by high-fat diets opens up a new target site for drug developers, who can work to design drugs that block the toxic lipid before it has a chance to leave the gut and wreak havoc on metabolic organs such as the liver.
Senior author and Research Fellow from the Monash Institute of Pharmaceutical Sciences (MIPS), Dr Sarah Turpin-Nolan, said the team is excited by the potential implications of the new discovery.
“Ceramides are a family of waxy lipid molecules, with the C16 ceramide considered to be ‘bad’ due to its direct link to fatty liver disease and T2D,” Dr Turpin-Nolen said.
“In this study we have, for the first time, uncovered that in humans this toxic lipid increases when there is more fat in the gut which makes more C16 ceramide available to be transported out of the gut, via the lymphatic system, to metabolic organs such as the liver.
“This information is critical in paving the way for research into new drugs that target C16 ceramide and, consequently, block it from leaving the gut and progressing into a metabolic disease like obesity, T2D or metabolic-associated fatty liver disease,” Dr Turpin-Nolan concluded.
Co-senior author and Head of the Cellular and Molecular Metabolism Laboratory at MIPS, Professor Mark Febbraio, said the team have also discovered a diverse new range of lipid species.
“Through screening of lipids derived in the gut we identified many more lipid species than were previously known to exist. All of these ‘behaved’ as you’d expect, except of course for the metabolically harmful C16 ceramide that increased in response to high-fat diets in both rats and humans,” Professor Febbraio said.
“We believe this exciting and promising new information supports the development of an updated model for how the human body generates and transports lipids from the gut via the lymphatic system when derived from high-fat diets.
“As far as next steps go, further research is now required to investigate exactly where these toxic fats go and if new medicines targeting lipids produced in the gut could reduce lipid accumulation in metabolic organs, including the liver, to treat metabolic diseases like obesity and metabolic-associated fatty liver disease.”
This study has been published in the prestigious journal, Science Advances.
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