Research results call for clinical trials of appropriate medicines to prevent NASH -
non-alcoholic fatty liver disease (NAFLD) is a common condition, affecting nearly 30 percent of Americans, with a significant number of suffering its most severe form, called NASH or NASH, which can lead to cirrhosis and liver cancer. In recent years, NASH has become the leading cause of liver transplantation.
Development of new effective therapies for preventing or treating NASH has been stymied by limited small animal models for the disease. In an article published online in Cancer Cell , the University of California scientists, San Diego School of Medicine describe a new mouse model that closely resembles human NASH and use it to demonstrate that interference with a key inflammatory protein inhibits both the development of NASH and its progression to liver cancer.
"These results strongly call for clinical trials of drugs relevant human NASH and its complications," said lead author Michael Karin, Ph.D., professor emeritus of pharmacology in the Laboratory of UC San Diego of Gene Regulation and signal transduction. "Our research has shown that, at least in this mouse model, chemical compounds that already include clinically approved drugs that inhibit the aggregation of proteins can also be used to prevent NASH caused by a high fat diet. "
The increasing prevalence of NAFLD is linked to being the nation's obesity epidemic. In the last decade, the rate of obesity has doubled in adults and tripled in children, largely due to a common diet rich in simple carbohydrates and saturated fats. NASH is characterized by inflammation and fibrosis, which can damage the liver and lead to cirrhosis, hepatocellular carcinoma (HCC), the main form of liver cancer, and loss of function. Often, the only cure is the transplantation of organs.
"The development of new strategies for NASH that block successful progression to cirrhosis or HCC necessary for the creation of appropriate small animal models that are amenable to genetic analysis and therapeutic intervention," said said first author Hayato Nakagawa, PhD, member of the Karin lab who led the research effort and is currently Assistant Professor at the University of Tokyo school of medicine.
new model mouse resulting advantage of an existing strain of mice called MUP-uPA that develops hepatic lesions similar to humans when fed a diet high in fat (60 percent of calories are derived from the fat) similar to the so-called "American cafeteria plan." The mice show clinical signs characteristic of NASH in 24 weeks and full HCC after 40 weeks. "The pathological characteristics of these tumors are almost identical to those of human HCC," Nakagawa said.
By using the new mouse model, Nakagawa and colleagues showed that a factor called tumor necrosis of the protein (TNF), involved in the body's inflammatory response plays an essential role in both NASH pathogenesis and progression of fibrosis and HCC. by interfering with the synthesis of TNF, or of its binding to its receptor using genetic tools or anti-psoriasis drug against rheumatoid arthritis called Enbrel, the researchers inhibited both the development of NASH and its progression to HCC in the mouse model.
"given the dramatic rise and persistent incidence of obesity and its consequences in the United States and elsewhere, these studies have a high impact on a major public health problem. in addition to developing a more appropriate model for the study of NASH, this new work suggests some immediate targets for prevention and therapeutic intervention, "said Karin, who is a research professor of American Cancer Society and holder of the Chair and Ben Wanda Hildyard for mitochondrial and metabolic diseases.
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