Researchers from the University of South Carolina, Duke University, University of Alabama at Birmingham, and Metabolon Inc. Research Triangle Park have discovered a new pathway in the liver that opens the door to treat non-alcoholic fatty liver disease, a condition that affects up to 25 percent of the population and may lead to cirrhosis and eventually liver cancer or failure, and likely other liver diseases. The study was published in Free Radical Biology & Medicine, one of the leading scientific journals in the field of oxidative stress and medicine.
The team found that an ion channel protein (TRPV4), which can rapidly permeate calcium ions into liver cells where calcium functions as a “switch” inside the cells, which in turn leads to release of a gas, nitric oxide. This gas then blocks one of the liver enzymes (CYP2E1) that is a major contributor to non-alcoholic liver disease and its progression. Nitrous oxide, released by activation of TRPV4 in the liver thus acts hepato-protective, (i.e., shielding the liver from harm caused by excessive action of CYP2E1).
Now that TRPV4’s capacity to block the development of non-alcoholic fatty liver disease has been discovered, the next step is to harness its preventive and treatment perspective. According to the authors, a new generation of TRPV4 activating chemicals or other measures such as gene-therapy will have to be developed and implemented via clinical trials to prevent/treat non-alcoholic fatty liver disease, oftentimes associated with diabesity—a metabolic dysfunction.
“There are currently no clinically proven drugs to treat non-alcoholic fatty liver disease,” says Dr. Saurabh Chatterjee, an associate professor of environmental health sciences at USC’s Arnold School of Public Health and the director of the Environmental Health and Disease Laboratory where the research was led. “Our goal is to find novel pathways in the liver that will result in a road to a cure, and this novel internal defense mechanism within the liver offers a very promising route.”
In addition to revealing the benefits of activating TRPV4, the researchers also warn against the consequences of inhibiting the TRPV4 ion channel, an approach that can enhance hepatotoxicity (i.e., liver damage caused by chemicals), which can result from acetaminophen or alcohol over-consumption.
“This means that one has to be careful when aiming to inhibit TRPV4 for therapeutic purposes, such as when treating pain, inflammation or itching, or other conditions, in particular when inhibiting TRPV4 by systemic application of TRPV4-blockers,” says Dr. Wolfgang Liedtke, a professor of neurology, anesthesiology and neurobiology at Duke University School of Medicine who first described TRPV4 16 years ago.