A new use for anti-fungal medicines
Non-alcoholic fatty liver disease is the most common chronic liver disease worldwide and affects 30% of the adult population in Hong Kong. It is also a leading trigger for liver cancer. However, the mechanism of the disease remains poorly understood and no therapeutic drug is currently available for the prevention or treatment of non-alcoholic fatty liver disease.
Squalene epoxidase is an essential enzyme for cholesterol biosynthesis in humans. Professor Jun Yu (Croucher Senior Research Fellowship 2016) of the Chinese University of Hong Kong and her team sequenced 18 pairs of infected and normal liver tissues and found out that squalene epoxidase was highly expressed in the infected sample. In three independent liver cancer patient groups, the enzyme was also overexpressed in tumor tissues.
In cell line and mouse models, Yu found that the enzyme promoted cholesteryl ester accumulation and induced reactive oxygen stress, which in turn increased cell proliferation.
Yu was the first to construct a genetically-engineered mouse model that overexpressed this enzyme in liver cells, and study its impact on liver cancer. The results suggest that the enzyme is an oncogenic factor that promotes non-alcoholic fatty liver disease in liver cancer.
Terbinafine is drug used for treating fungal infections. It has been known for some time that Terbinafine also has an impact on squalene epoxidase-induced cholesteryl ester and oxidative stress accumulation. In further studies, Yu and her team experimented with the use of terbinafine using a mouse model and found that the treatment inhibited tumor growth and extended survival. The treatment also effectively reduced the incidence of liver cancer. These results indicate that terbinafine might be useful for the prevention and treatment of the disease in humans.
The study is published in medical journal Science Translational Medicine as a cover story.
“Our study showed that the cholesterol biosynthesis gene is essential for the pathogenesis of non-alcoholic fatty liver. Our work also showed that Terbinafine can be repurposed for treating the disease. We will continue to investigate its efficacy, and to translate our findings to the clinic to benefit patient care,” said Yu.
Professor Andrew Brown of the University of New South Wales suggested that the results might lay groundwork for future research in understanding the role of squalene epoxidase in liver, and possibly other cancers.
Jun Yu is a professor in Department of Medicine and Therapeutics, Faculty of Medicine at The Chinese University of Hong Kong (CUHK). She completed her MD and PhD at Tongji Medical University and then she embarked on gastrointestinal specialist in Beijing University in 1994-1998, followed by a postdoctoral fellowship in the Department of Gastroenterology at the University of Dresden, Germany, University of Magdeburg, Germany and CUHK, Hong Kong, respectively in 1998-2002. She worked as a Senior Research Officer at University of Sydney in 2003-2005. She has been a CUHK faculty member since 2005 and currently as a Professor at Department of Medicine and Therapeutics, director of the Research Laboratory of Institute of Digestive Disease, and associate director of State Key Laboratory of Digestive Disease, CUHK.
To view Professor Yu's Croucher profile, please click here.