Development of fatty liver disease as part of a healthy diet

A new study identifies two genes, previously reported to be involved in cancer, as regulators of the metabolic state of the liver. Alterations in these genes influence the likelihood of developing fatty liver disease.

The worldwide obesity epidemic has increased the risk of fat accumulation in the liver, a prelude to liver inflammation and liver disease. Yet a still intriguing paradox is the development of fatty liver disease in lean, normal-weight individuals and in individuals following a healthy diet. Scientists know that two genes, RNF43 and ZNRF3, are mutated in patients with liver cancer. However, their role in the development of liver cancer was until now unknown. Researchers at the Max Planck Institute for Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany, now describe that a loss or mutation of these genes causes lipid accumulation and inflammation in the liver in non-obese mice fed diet. These genetic alterations not only increase fat accumulation but also the number of proliferating liver cells (hepatocytes). In human patients, these alterations also increase the risk of developing NASH and fatty liver disease and reduce the patient’s survival time. These discoveries could facilitate the discovery of people at risk and could promote new therapeutic interventions and better management of the disease.

The liver is our central metabolic organ, which is vital for detoxification and digestion. Chronic liver diseases, such as cirrhosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH, inflamed liver), as well as liver cancer, are on the rise worldwide, with a combined mortality of two million people who die each year. It is therefore more important than ever to understand their causes and the underlying molecular mechanisms of liver disease in order to prevent, manage and treat these growing patient subgroups. Previous cancer genomics studies have identified RNF43 and ZNRF3 as mutated genes in colon and liver cancer patients. However, their role in liver disease has not been explored. Meritxell Huch’s research laboratory at MPI-CBG, in collaboration with colleagues from the Gurdon Institute (Cambridge, UK) and the University of Cambridge, has now investigated the mechanisms by which alterations in these two genes can affect the emergence of liver diseases. . Their study is published in the journal Communication Nature.

To pursue this goal, the researchers worked with mice as an animal model, data from human individuals, human tissues and cultures of liver organoids, which are 3D cellular microstructures consisting of liver-like hepatocytes in a box. Germán Belenguer, first author of the study and postdoctoral researcher in Meritxell Huch’s group, explains: “With the organoid, we were able to grow hepatocytes mutated only in these genes, and we saw that the loss of these ci activates a signal that regulates lipid metabolism. As a result, fat metabolism is no longer under control and lipids accumulate in the liver, which in turn leads to fatty liver disease. Another consequence of the activated signal is that the hepatocytes multiply uncontrollably. The two mechanisms combined facilitate progression to fatty liver disease and cancer.” The scientists then compared the results of the experiments with patient data in a publicly available dataset from the International Cancer Genome Consortium. They assessed the survival prognosis when both genes are mutated in liver cancer patients and found that patients with these mutated genes had fatty liver disease and had a worse prognosis than liver cancer patients whose the two genes had not mutated.

“Our results can help identify individuals who carry an RNF43/ZNRF3 mutation and therefore are at risk of developing fatty liver disease or liver cancer,” says Meritxell Huch. She continues, “With the alarming increase in fat and sugar consumption around the world, recognizing individuals already predisposed because they carry these genetic mutations could be important for therapeutic intervention and disease management, especially particular at very early stages or even before the We will need more studies to further characterize the roles of the two genes in human fatty liver disease, NASH and human liver cancer and to identify therapeutics that may help patients who are already inherently predisposed to developing the disease.

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