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The Role of OSTα/β as a Bile Acid and Drug Transporter in Obesity-Associated Chronic Liver Disease, Nonalcoholic Fatty Liver Disease

Periodic Reporting for period 1 - OSTtrans (The Role of OSTα/β as a Bile Acid and Drug Transporter in Obesity-Associated Chronic Liver Disease, Nonalcoholic Fatty Liver Disease)

Reporting period: 2018-09-01 to 2020-08-31

Obesity is increasing rapidly in EU, with about 50% of the population being obese. In addition to cardiovascular disease and type-2 diabetes, non-alcoholic fatty liver disease fatty liver disease (NAFLD) is a major obesity-associated chronic disease. The European Association for the Study of the Liver has estimated that up to 44% of obese people (116 million people) are likely to suffer from NAFLD. Some patients will develop non-alcoholic steatohepatitis (NASH), an advanced disease involving inflammation. Despite the high frequency of NAFLD, comprehensive research on its effects on hepatic biotransformation capacity of endogenous and exogenous compounds is lacking, especially in human subjects.
The project aimed to increase understanding of the emerging liver diseases NAFLD and NASH, particularly by evaluating the expression of transporter proteins in the liver of NAFLD and NASH patients. The information on the transporter expression in the diseases is essential for safe drug therapies and will benefit the development of new chemical entities for chronic metabolic and liver diseases. The project focus on the role of OSTα/β as a bile acid and drug transporter particularly in NAFLD. The hepatic expression of OSTα/β is normally low but dramatically increased in the conditions with elevated bile acid levels in the liver, even more than expression of other bile acid transporters. The scientific aims of the project are: 1) the proteomics of bile acid transporters in NAFLD and NASH liver, 2) regulation and mechanisms of OSTα/β transport, and 3) the role of OSTα/β as a bile acid and drug transporter in the human liver in comparison to other hepatic basolateral transporters.
The project was started by setting up protocols and methodologies to quantify proteins by mass spectroscopy technology (WP1). The newly established collaboration with clinicians gave us an opportunity to study selected bile acid transporters in the human liver tissue of NAFLD and NASH. The quantification of the membrane proteins from the human liver samples of limited size emerged to be challenging and requiring further technological optimization. The proteins were successfully quantified from the cell culture samples.

Secondly, we aimed to evaluate the function and activity of the bidirectional OSTα/β transporter in human cell line overexpressing human OSTα/β (WP2). Both modulation of OSTα/β transporter by endogenous compounds and interaction of OSTα/β transporter with drugs and endogenous compounds were evaluated. The results of this work package will be published shortly. The developed in vitro methodologies are further applied by our collaborators to reveal novel OSTα/β substrates and inhibitors and evaluate drug-drug interactions.

The work arising from this project has been presented at multiple scientific meetings, but also in the meeting of community pharmacists. I presented posters at ITTS Inaugural Conference - “The Transporter Transition” (2018) and Farmasian Päivät (2018), where I gave also a talk. The work has been presented as posters also at Gordon Research Conference - Drug Metabolism (2019) and BioParadigms - 11th BioMedical Transporters Conference (2019). In addition, posters planned to be presented in conferences both in Europe and in the United States (2020).

The project will yield publications that will be found on public databases. During the fellowship, I have continued collaboration with my previous laboratory and the collaborative work initiated prior the fellowship has gained multiple publications.
The results originating from this research programme add knowledge on the OSTα/β transporter in distribution of endogenous and exogenous compounds hereby benefiting academic researchers, clinicians, pharmaceutical industry and drug safety authorities. The methods established during this work are applied in new research projects. The quantified targeted absolute proteomics methodologies are applied to quantify proteins important in drug efficacy and safety, both wildtype proteins and their genetic variants. The protocols to specifically evaluate the function of OSTα/β protein complex are utilized to reveal the substrates, inhibitors and modulators of this important bidirectional transporter. Overall, the results and methodologies from the programme generated new knowledge supporting the drug efficacy and safety predictions.