Resolving liver fibrosis with nutritional and therapeutic interventions.
Resolving fibrosis in non-alcoholic steatohepatitis.
Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), leading to fibrosis and potentially cirrhosis, and it is one of the most common causes of liver disease worldwide. Currently no therapeutic intervention strategy is accepted, dramatically enhancing the need for liver transplantation. Progression of fibrosis plays a crucial role in this process, leading to organ dysfunction. Therefore reducing progression or even resolving of fibrosis are major pharmaceutical targets. It is unknown whether therapeutic intervention allows resolution of fibrosis at all, and little is known about which processes are involved in formation and resolution of fibrosis.
The project aimed at obtaining a better understanding of the process of hepatic fibrosis formation and investigating whether it is possible to attenuate further progression or even resolve liver fibrosis with nutritional or therapeutic interventions.
One of the reasons for the absence of good therapies is the lack of good translational preclinical models. Recently, TNO has developed a mouse model, in which NASH and mild fibrosis is induced upon high fat diet feeding. The etiology of disease is comparable to NASH patients who develop NASH from metabolic dysregulation. The partner in this LSH project, Kinemed Inc., has developed a technology platform based on deuterated water, which allows analysis of newly synthesized proteins. The major protein involved in fibrosis is collagen, and prevention or reduction of collagen is regarded as the main challenge in treatment of fibrosis. Using this deuterated water technology (which can also be used in humans) we were able to study the process of collagen formation and resolving of collagen in the translational mouse model.
The findings of this project showed that in this setting hepatic fibrosis was not resolved, but newly formed collagen was reduced by nutritional and pharmacological intervention, resulting in reduced progression of fibrosis.