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A new study from the University of Pittsburgh School of Pharmacy provides light on the processes that contribute to liver fibrosis and proposes a unique therapy method for this prevalent and serious disorder.
The work, led by senior author Wen Xie, M.D., Ph.D., professor and Joseph Koslow endowed chair of the Department of Pharmaceutical Sciences, and co-first authors Hung-Chun Tung, graduate student, and Jong-Won Kim, Ph.D., postdoctoral associate, was published today in Science Translational Medicine. In this Q&A, Xie expands on the study's findings and discusses why new diagnostic tools and therapy options for liver fibrosis are critically needed. Liver fibrosis is the formation of tissue scars in the liver due to chronic inflammation and injury. Over time, fibrosis can impair liver function and may lead to cirrhosis or even liver cancer. Those at risk include individuals with chronic viral hepatitis, obesity, diabetes and excessive alcohol use. Early detection and intervention are crucial to prevent progression to more severe liver disease. Currently there are no FDA-approved drugs that specifically treat liver fibrosis. The only treatment option is to treat diseases that cause liver fibrosis in the first place, such as hepatitis, obesity, type 2 diabetes and alcoholic liver disease. Preventive measures include avoiding excessive alcohol, maintaining a healthy body weight and early screening for liver diseases to prevent fibrosis from advancing to cirrhosis or liver failure. HSCs are a unique cell type in the liver. When the liver is injured or inflamed, HSCs become activated and produce excess collagen and other extracellular matrix proteins. The accumulation of collagen and other extracellular matrix proteins leads to scar tissue formation and liver fibrosis. This study identified the enzyme CYP1B1 as a biomarker and predictor of HSC activation and liver fibrosis in both patients and mice. Inhibition of CYP1B1 led to the accumulation of a sugar called trehalose, which we showed for the first time that trehalose has anti-fibrotic activity. Moreover, treatment of mice with trehalose, its analog lactotrehalose or CYP1B1 inhibitor protected mice from getting liver fibrosis. It was surprising to identify a liver function of CYP1B1, an enzyme traditionally known for its functions outside the liver. Although the concentration of CYP1B1 in the whole liver is not high, this enzyme is uniquely and abundantly present in HSCs and thus plays an important role in HSC activation and liver fibrosis. Liver fibrosis is a common, potentially deadly and costly liver disease that lacks FDA-approved drugs. Our findings are clinically important because we identified CYP1B1 as a predictor of HSC and liver fibrosis in patients, which may help with the early diagnosis of this disease. More importantly, we found that trehalose and lactotrehalose are potential novel drugs that could be used to treat liver fibrosis in the future. (ANI)
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