mutated (right) mice in which lipids, i.e. fats, (in green) accumulate. If the two
genes RNF43 and ZNRF3 are mutated, the liver cells independently produce higher ones
Quantities of lipids that also accumulate as large droplets inside each cell
(Recognizable by the nuclei in blue and the surrounding cell membrane in white).
Microscopic recordings: Belenguer et al. Nature Communications 2022 / MPI-CBG
” data-image-caption=”
Image of organoids from liver cells from normal (left) and
mutated (right) mice in which lipids, i.e. fats, (in green) accumulate. If the two
genes RNF43 and ZNRF3 are mutated, the liver cells independently produce higher ones
Quantities of lipids that also accumulate as large droplets inside each cell
(Recognizable by the nuclei in blue and the surrounding cell membrane in white).
Microscopic recordings: Belenguer et al. Nature Communications 2022 / MPI-CBG
” data-medium-file=”https://oiger.de/wp-content/uploads/Bodipy-Wt-vs-RZ-Adult-Hep-Organoids-300×168.jpg” data-large-file=”https:/ /oiger.de/wp-content/uploads/Bodipy-Wt-vs-RZ-Adult-Hep-Organoids-600×335.jpg” loading=”lazy” class=”size-full wp-image-181869″ alt=”Image of organoids from liver cells of normal (left) and mutant (right) mice in which lipids, i.e. fats, (in green) accumulate. When both the RNF43 and ZNRF3 genes are mutated, the liver cells produce higher levels of lipids on their own, which also accumulate as large droplets inside each cell (recognizable by the nuclei in blue and the surrounding cell membrane in white). Micrographs: Belenguer et al. Nature Communications 2022 / MPI-CBG” width=”1000″ height=”559″ srcset=”https://oiger.de/wp-content/uploads/Bodipy-Wt-vs-RZ-Adult-Hep-Organoids.jpg 1000w, https://oiger.de/wp-content/uploads/Bodipy-Wt-vs-RZ-Adult-Hep-Organoids-300×168.jpg 300w, https://oiger.de/wp-content/uploads/Bodipy -Wt-vs-RZ-Adult-Hep-Organoids-600×335.jpg 600w, https://oiger.de/wp-content/uploads/Bodipy-Wt-vs-RZ-Adult-Hep-Organoids-150×84.jpg 150w , https://oiger.de/wp-content/uploads/Bodipy-Wt-vs-RZ-Adult-Hep-Organoids-768×429.jpg 768w” sizes=”(max-width: 1000px) 100vw, 1000px”/>
Image of organoids from liver cells of normal (left) and mutant (right) mice, in which lipids, i.e. fats, (in green) accumulate. If the two genes RNF43 and ZNRF3 are mutated, the liver cells independently produce higher amounts of lipids, which also accumulate as large droplets inside each cell. This can be recognized by the nuclei in blue and the surrounding cell membrane in white.
Microscopic recordings: Belenguer et al. Nature Communications 2022 / MPI-CBG
Dresden geneticists find “switches” for inflammation
Dresden, January 17, 2022. Even some slim people who eat a healthy diet suddenly develop fatty liver. The reason for this lies in the genome, as a team led by research group leader Dr. Meritxell Huch from the Max Planck Institute for Molecular Cell Biology and Genetics (MPI-CBG) in Dresden has now discovered that when the “RNF43” and “ZNRF3” genes mutate, more fat accumulates and the liver cells (“hepatocytes”) multiply. Inflammation up to fatty liver and a shrinking lifespan can be the consequences.
Dr. Meritxell Huch. Photo: MPI-CBG
Findings can help with diagnosis and early start of therapy
“Our results can help to identify people with an RNF43/ZNRF3 mutation who have an increased risk of developing fatty liver or liver cancer,” explained Meritxell Huch. “With the alarming increase in fat and sugar consumption worldwide, it could be important for therapeutic measures and management of the disease to identify those individuals who are predisposed to it because of their genetic mutations, especially at very early stages or even before the onset of the disease .” In addition, earlier studies had already shown an increased risk of liver cancer for people whose genes “RNF43” and “ZNRF3” were mutated. Obviously, these two genetic components are responsible for several liver diseases.
2 million people per year die worldwide from pathological changes in the liver
Around two million people worldwide die every year from cirrhosis, fatty liver, liver cancer or other abnormal liver changes. experts go according to the “Apotheken-Umschau” assumes “that approximately 20 to 30 percent of the population in western industrialized countries suffer from non-alcoholic fatty liver disease”. The sufferers notice little of this at first, but then often suffer from loss of appetite, feel tired and listless, get flatulence and a feeling of pressure in the upper right abdomen.
Organoids helped with experiments
However, the underlying mechanisms and underlying causes are not yet conclusively known. In order to clarify these connections, the Dresden Huch team teamed up with researchers from the “Gurdon Institute” in Cambridge, England, and the University of Cambridge. For their investigations, they used genetically modified mice, patient data, human tissue and so-called liver organoids: these are artificially generated 3D cell cultures that resemble a simplified liver. “Using the organoid, we were able to grow hepatocytes that were only mutated in these genes,” explained study lead author Germán Belenguer. “We saw that the loss of these genes triggers a signal that regulates lipid metabolism. As a result, the lipid metabolism is no longer under control and lipids accumulate in the liver, which in turn leads to fatty liver.” The activated signal also led to the liver cells (hepatocytes) multiplying uncontrollably. “Both mechanisms together promote the progression of fatty liver disease and cancer.”
Bad cards if both genes are mutated
The researchers also compared their findings with data sets from the International Cancer Genome Consortium. They found that patients in whom both signaling genes are mutated are more likely to develop fatty liver and have a poorer prognosis than liver cancer patients in whom both genes are not mutated.
Which: MPI-CBG
Scientific publication:
German Belenguer, Gianmarco Mastrogiovanni, Clare Pacini, Zoe Hall, Anna M. Dowbaj, Robert Arnes-Benito, Aleksandra Sljukic, Nicole Prior, Sofia Kakava, Charles R Bradshaw, Susan Davies, Michele Vacca, Kourosh Saeb-Parsy, Bon-Kyoung Koo, Meritxell Huch: „RNF43/ZNRF3 loss predisposes to Hepatocellular-carcinoma by impairing liver regeneration and altering liver lipid metabolic ground-state”, in: “Nature Communications”, 17. Januar 2022, doi: 10.1038/s41467-021-27923-z