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

  • David Højland Ipsen
  • Josephine Skat-Rørdam
  • Maria Malvina Tsamouri
  • Markus Latta
  • Jens Lykkesfeldt
  • Pernille Tveden-NyborgEmail author
Original Article

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.

Keywords

Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis Animal model Guinea pig Fibrosis Molecular mechanisms 

Notes

Funding

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

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests in relation to the present work.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

438_2019_1537_MOESM1_ESM.docx (17 kb)
Supplementary material 1 (DOCX 16 KB)
438_2019_1537_MOESM2_ESM.docx (16 kb)
Supplementary material 2 (DOCX 16 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Veterinary and Animal Sciences, Faculty of Health and Medical SciencesUniversity of CopenhagenFrederiksberg CDenmark
  2. 2.Liver Disease Research, Global Research, Novo NordiskMåløvDenmark

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