Madrid. The Growth Factors, Nutrients and Cancer Group of the National Cancer Research Center (CNIO), led by Nabil Djouder, created the first genetically modified mouse that develops liver cirrhosis comparable to that of humans, and identified the molecular mechanisms of this disease.
“Understanding these molecular mechanisms will help us understand how cirrhosis progresses to liver cancer,” said Djouder, whose work was published in the Journal of Hepatology.
In cirrhosis the liver hardens and becomes fibrotic, like scar tissue. This is due to the activation of cells called fibroblasts. The new work explains how they come into play: when the liver’s predominant cells, hepatocytes, don’t produce a protein called MCRS1, bile acids (liver products and components of bile) accumulate in the organ and activate fibroblasts, which end up producing fibrosis.
The first animal model recapitulating human liver cirrhosis was obtained in an unintended way. The Growth Factors, Nutrients and Cancer group has been studying the MCRS1 protein for almost a decade.
Several years ago he discovered its relationship with metabolism and with various types of cancer. Since the main organ responsible for metabolism is the liver, they also wanted to analyze the role of MCRS1 in liver cells.
Amanda Garrido and Eunjeong Kim, first signatories of the work, created a genetically modified mouse so that its hepatocytes did not express MCRS1, and observed that it developed alterations equivalent to human liver cirrhosis.
“It was a surprise that opened an opportunity to study the molecular mechanisms of cirrhosis and its progression to cancer, and thus try to reverse the disease,” said Djouder.
“Indeed, understanding why the lack of MCRS1 in hepatocytes generates cirrhosis has meant revealing a hitherto unknown process as the origin of the disease, and opens the door to the development of new pharmacological strategies,” Garrido said.
Fibroblast activation
Until now, it was known that liver fibrosis involved the transformation of hepatic stellate cells into fibroblasts, which synthesize the substance that forms scar tissue or fibrosis. However, the mechanisms that triggered this change and the consequent activation of the fibroblasts were unknown.
The lack of MCRS1 in hepatocytes alters the flow of bile acids, which activate a molecular receptor called FXR in fibroblasts, which acts as the switch that starts the cirrhosis process.
“This chain of events is central and universal in the development of liver cirrhosis. Acting on this pathway would have important implications for the treatment of the disease”, specified Djouder.
Furthermore, this reveals an unknown role of MCRS1 in regulating gene expression in hepatocytes and in normal liver function.
A drug against several liver diseases that is being tested in the United States, the semi-synthetic bile acid Ocaliva, acts on the FXR receptor. However, recent clinical data have raised the alarm about possible adverse effects: its use caused severe fibrosis and fulminant liver damage in some patients.
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