02432nas a2200409   4500000000100000000000100001008004100002260001500043653001200058653002700070653001100097653002000108653000900128653003800137100002300175700001600198700002700214700001800241700001700259700001700276700002000293700001900313700001900332700002400351700001900375700001900394700002000413700001900433700001800452700001600470700001700486245011700503300000900620490000600629520137300635022001402008       2021                            d  c2021-09-1510aAnimals10aDisease Models, Animal10aHumans10aLiver Cirrhosis10aMice10aNon-alcoholic Fatty Liver Disease1 aTomasz Kostrzewski1 aSophie Snow1 aAnya Lindström Battle1 aSamantha Peel1 aZahida Ahmad1 aJayati Basak1 aManasa Surakala1 aAurelie Bornot1 aJulia Lindgren1 aMaria Ryaboshapkina1 aMaryam Clausen1 aDaniel Lindén1 aChristian Maass1 aLucy May Young1 aAdam Corrigan1 aLorna Ewart1 aDavid Hughes00aModelling human liver fibrosis in the context of non-alcoholic steatohepatitis using a microphysiological system  a10800 v43 aNon-alcoholic steatohepatitis (NASH) is a common form of chronic liver disease characterised by lipid accumulation, infiltration of immune cells, hepatocellular ballooning, collagen deposition and liver fibrosis. There is a high unmet need to develop treatments for NASH. We have investigated how liver fibrosis and features of advanced clinical disease can be modelled using an in vitro microphysiological system (MPS). The NASH MPS model comprises a co-culture of primary human liver cells, which were cultured in a variety of conditions including+/- excess sugar, fat, exogenous TGFβ or LPS. The transcriptomic, inflammatory and fibrotic phenotype of the model was characterised and compared using a system biology approach to identify conditions that mimic more advanced clinical disease. The transcriptomic profile of the model was shown to closely correlate with the profile of patient samples and the model displayed a quantifiable fibrotic phenotype. The effects of Obeticholic acid and Elafibranor, were evaluated in the model, as wells as the effects of dietary intervention, with all able to significantly reduce inflammatory and fibrosis markers. Overall, we demonstrate how the MPS NASH model can be used to model different aspects of clinical NASH but importantly demonstrate its ability to model advanced disease with a quantifiable fibrosis phenotype.  a2399-3642