Investigating fibrosis and inflammation in an ex vivo NASH murine modelGore, E., Bigaeva, E., Oldenburger, A., Jansen, Y. J. M., Schuppan, D., Boersema, M., Rippmann, J. F., Broermann, A. & Olinga, P., Feb-2020, In : American Journal of Physiology. Gastrointestinal and Liver Physiology. 318, 2, p. G336-G351 16 p.
Research output: Contribution to journal › Article › Academic › peer-review
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, characterized by excess fat accumulation (steatosis). Nonalcoholic steatohepatitis (NASH) develops in 15-20% of NAFLD patients, and frequently progresses to liver fibrosis and cirrhosis. We aimed to develop an ex vivo model of inflammation and fibrosis in steatotic murine precision-cut liver slices (PCLS). NASH was induced in C57Bl/6 mice using amylin and choline-deficient L-amino acid-defined (CDAA) diet. PCLS were prepared from steatohepatitic (sPCLS) and control (cPCLS) livers and cultured for 48h with LPS, TGFβ1 or elafibranor. Additionally, C57Bl/6 mice were placed on CDAA diet for 12 weeks, to receive elafibranor or vehicle from week 7-12. Effects were assessed by transcriptome analysis and pro-collagen Iα1 protein production. The diets induced features of human NASH. Upon culture, all PCLS showed an increased gene expression of fibrosis and inflammation related markers, but decreased lipid metabolism markers. LPS and TGFβ1 affected sPCLS more pronouncedly than cPCLS. TGFβ1 increased pro-collagen Iα1 solely in cPCLS. Elafibranor ameliorated fibrosis and inflammation in vivo, but not ex vivo, where it only increased the expression of genes modulated by PPARα. sPCLS culture induced inflammation, fibrosis and lipid metabolism related transcripts, explained by spontaneous activation. sPCLS remained responsive to pro-inflammatory and profibrotic stimuli on gene expression. We consider that PCLS represent a useful tool to reproducibly study NASH progression. sPCLS can be used to evaluate potential treatments for NASH, as demonstrated in our elafibranor study, and serves as a model to bridge results from rodent studies to the human system.
|Number of pages||16|
|Journal||American Journal of Physiology. Gastrointestinal and Liver Physiology|
|Early online date||6-Jan-2020|
|Publication status||Published - Feb-2020|