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UCSD Protein Research Could Lead To Preventing Liver Damage

Attacking a protein that causes inflammation could be the key to treating a form of liver disease that's increasing in prevalence as Americans grow heavier, according to researchers at the UC San Diego School of Medicine.

The scientists found that the development of non-alcoholic steatohepatitis, or NASH, which can lead to cirrhosis and liver cancer, can be inhibited by interfering with a particular inflammatory protein.

Photo credit: UC San Diego

Multicolor stained micrograph of liver biopsy showing hepatocellular carcinoma. Blue staining depicts collagen fibrosis.

The researchers conducted their study in mice. It's been difficult to perform such experiments in the past because of a limited quantity of mouse models, the scientists said.

The protein, which doctors are seeing more often because of increased obesity among patients, has become the No. 1 cause of liver transplantation.

"These findings strongly call for clinical testing of relevant drugs in human NASH and its complications," said senior author Michael Karin, a distinguished professor of pharmacology in UCSD's Laboratory of Gene Regulation and Signal Transduction. "Our research has shown that, at least in this mouse model, chemical compounds that include already clinically approved drugs that inhibit protein aggregation can also be used to prevent NASH caused by a high fat diet."

The disease is characterized by inflammation and fibrosis, which damage the liver and can lead to cirrhosis, hepatocellular carcinoma — the major form of liver cancer — and loss of function. Often, the only remedy is organ transplantation, according to UCSD.

Using the new mouse model, the researchers showed that a protein called tumor necrosis factor, which is involved in the body's inflammatory response, plays a critical role in both protein development and progression to fibrosis and cancer.

By interfering with the protein's synthesis or its binding to its receptor, using genetic tools or an anti-psoriasis and rheumatoid arthritis drug called Enbrel, the researchers inhibited both the diseases's development and its progression to cancer in the mouse model.

"Given the dramatic and persistent increase in the incidence of obesity and its consequences in the United States and elsewhere, these studies have a high impact on a major public health problem," Karin said. "In addition to developing a more suitable model for the study of NASH, this new work suggests some immediate targets for prevention and therapeutic intervention."

The results of the study, in which Karin was assisted by researchers at the Sanford-Burnham Medical Research Institute, University of Tokyo and Universitat Autonoma de Barcelona in Spain, were published online in the journal Cancer Cell.

Their research was funded by grants from, among others, the National Institutes of Health, the Daiichi Sankyo Foundation of Life Science and Grant- in-Aid for Scientific Research, The Rotary Foundation, the Japan Society for Promotion of Science, the California Institute for Regenerative Medicine and the American Liver Foundation.

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