Recently, a collaborative study between German and British scientists found that deletions or mutations in the genes RNF43 and ZNRF3 trigger a regulatory signal for lipid metabolism, which in turn leads to lipid accumulation and inflammation in the liver. The findings could explain why some people are thin but still suffer from fatty liver. The results were published in the journal Nature Communications.
Previous cancer genomic studies have identified RNF43 and ZNRF3 as genes that are mutated in patients with colon and liver cancers. A research team led by Dr. Meritschel Hoch at the Max Planck Institute for Molecular Cell Biology and Genetics in Germany, together with scientists at the Gurdon Institute at the University of Cambridge in the United Kingdom, investigated the mechanisms by which changes in these two genes affect the development of liver disease and well explain a once puzzling paradox of how fatty liver can occur in lean and normal weight individuals as well as in individuals with a healthy diet.
It was found that deletions or mutations in the genes RNF43 and ZNRF3 in non-obese mice fed a normal diet lead to lipid accumulation and inflammation in the liver. These genetic changes lead not only to increased lipid accumulation but also to an increase in hepatocytes. In humans, these changes increase the risk of diseases such as fatty liver and liver cancer, and shorten the life expectancy of patients.
With the help of organoids, we were able to grow hepatocytes with mutations in only these genes, and we saw that the deletion of these genes triggered a regulatory signal for lipid metabolism,” explained Herman Berenger, first author of the paper and a postdoctoral fellow in Hoch’s research group. The result is that lipid metabolism is no longer under control and lipids accumulate in the liver, leading to a fatty liver. In addition, the activated signal leads to uncontrolled reproduction of hepatocytes. Together, these two mechanisms contribute to the progression of fatty liver disease and cancer.”
The scientists compared the experimental results with patient data publicly available from the International Cancer Genome Consortium. They examined the survival chances of patients with mutations in these two genes in liver cancer patients and found that patients with mutations in these genes had fatty liver and a worse prognosis.
