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Molecular drivers of non-alcoholic steatohepatitis are sustained in mild-to-late fibrosis progression in a guinea pig model

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Abstract

Hepatic fibrosis increases mortality in humans with non-alcoholic steatohepatitis (NASH), but it remains unclear how fibrosis stage and progression affect the pathogenic mechanisms of NASH. This study investigates the transcriptional regulation and the impact of fibrosis stage, of pathways relating to hepatic lipid and cholesterol homeostasis, inflammation and fibrosis using RT-qPCR in the guinea pig NASH model. Animals were fed a chow (4% fat), a high-fat (20% fat, 0.35% cholesterol) or high-fat/high-sucrose (20% fat, 15% sucrose, 0.35% cholesterol) diet for 16 or 25 weeks (n = 7/group/time point). High-fat diets induced NASH. In NASH, markers of hepatic de novo lipogenesis were enhanced (e.g. FASN, > twofold, p < 0.05) while markers of mitochondrial, peroxisomal and cytochrome fatty acid oxidation were reduced (e.g. CPT1A > twofold, p < 0.05). Markers of fatty acid uptake were unaltered or decreased. Likewise, expression of cholesterol uptake and synthesis markers were decreased, whereas genes relating to lipid and cholesterol export were unaltered. Inflammatory and chemotactic cytokines were enhanced alongside fibrogenic pathways including increased hepatic stellate cell activation and migration, matrix deposition (e.g. MCP1, TNFα, β-PDGF and Col1a1, > threefold, p < 0.05) and decreased matrix degradation. Fibrosis stage (mild vs. severe) and progression did generally not affect the expression of the investigated pathways. This suggests that liver dysfunction at the transcriptional level is induced early and maintained throughout fibrosis progression, allowing potential treatments to target dysregulated pathways already at early disease stages. As the guinea pig NASH model mimics several aspects of human molecular pathophysiology, these results may be used to increase the current understanding of NASH pathology and explore future treatment targets.

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Funding

This study was funded by the LifePharm Centre of In Vivo Pharmacology.

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Authors and Affiliations

  1. Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Thorvaldsensvej 57, 1871, Frederiksberg C, Denmark

    David Højland Ipsen, Josephine Skat-Rørdam, Maria Malvina Tsamouri, Jens Lykkesfeldt & Pernille Tveden-Nyborg

  2. Liver Disease Research, Global Research, Novo Nordisk, Novo Nordisk Park 1, 2760, Måløv, Denmark

    Markus Latta

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  1. David Højland Ipsen
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  2. Josephine Skat-Rørdam
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  3. Maria Malvina Tsamouri
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  5. Jens Lykkesfeldt
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  6. Pernille Tveden-Nyborg
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Correspondence to Pernille Tveden-Nyborg.

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Ipsen, D.H., Skat-Rørdam, J., Tsamouri, M.M. et al. Molecular drivers of non-alcoholic steatohepatitis are sustained in mild-to-late fibrosis progression in a guinea pig model. Mol Genet Genomics 294, 649–661 (2019). https://doi.org/10.1007/s00438-019-01537-z

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