The liver is the vital organ responsible for processing the various substances we consume, including food, drink, alcohol, and drugs. When the liver malfunctions, the consequences can be fatal. Scarring, also called liver fibrosis, is the root cause of many liver diseases, such as hepatitis and Non-Alcoholic SteatoHepatitis (NASH), and there are currently no drugs that can treat this scarring.
Researchers are investigating the underlying causes of liver fibrosis in an effort to identify future drug targets. A U-M study has found the molecule that causes liver bile duct cells to grow out of control.
Liangyou Rui, Ph.D., the Louis G. D’Alecy Collegiate Professor of Physiology, stated, “Under disease conditions in the liver, bile duct cells are injured.” “The liver has to make new bile duct cells all the time, which can sometimes go wrong and cause inflammation and scarring.”
Rui explains that this excessive bile duct production has a specific name: ductular reaction. Patients with ductular reactions have a higher incidence of disease complications and a worse prognosis.
In the article published in Nature Communications, the authors describe a molecule called NIK that is highly activated in bile duct cells that are dysfunctional. Using a mouse model that had its genes changed, the NIK gene was taken out of the bile duct cells.
Rui stated, “By removing these obstacles, you prevent all of these negative events from occurring.” Also, normal mice with liver disease got better when they were given NIK inhibitors, which are molecules that can stop NIK from working.
How does NIK lead to illness? Under normal conditions, NIK promotes the regeneration of bile duct cells in response to the various toxic substances to which the liver is exposed while performing normal functions. Nevertheless, certain viruses, drugs, or other insults can hijack this normal restorative function and cause excessive growth, ductular reaction, and the secretion of inflammatory mediators that result in scarring.
The team intends to work with collaborators at the University of Michigan and elsewhere to create new NIK-inhibitors to stop the scarring process. The findings have the potential to be used as a therapy for cholangiocarcinoma, a type of liver cancer that accounts for one-third of all liver cancers and has very limited treatment options.
The paper liver fibrosis’s first authors are Zhiguo Zhang, Xiao Zhong, and Hong Shen of the Department of Molecular and Integrative Physiology at the University of Michigan Medical School. Dr. Rui is the corresponding author with seniority. Additional authors are Liang Sheng, Suthat Liangpunsakul, Anna S. Lok, M. Bishr Omary, and Shaomeng Wang. Liver fibrosis.
