Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype

Geoffrey Farrell, Auvro Mridha, Matthew Yeh, Todor Arsov, Derrick Van Rooyen, John Brooling, Tori Nguyen, Deborah HEYDET, Viviane Delghingaro-Augusto, Christopher Nolan, Nicholas Shackel, Susan McLennan, Narci Teoh, Claire Larter

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34 Citations (Scopus)

Abstract

Background & Aims: Obese Alms1 mutant (foz/foz) NOD.B10 mice develop diabetes and fibrotic NASH when fed high-fat(HF) diet. To establish whether diabetes or obesity is more closely associated with NASH fibrosis, we compared diabetic foz/foz C57BL6/J with non-diabetic foz/foz BALB/c mice. We also determined hepatic cytokines, growth factors and related profibrotic pathways. Methods: Male and female foz/foz BALB/c and C57BL6/J mice were fed HF or chow for 24 weeks before determining metabolic indices, liver injury, cytokines, growth factors, pathology/fibrosis and matrix deposition pathways. Results: All foz/foz mice were obese. Hepatomegaly, hyperinsulinemia, hyperglycaemia and hypoadiponectinaemia occurred only in foz/foz C57BL6/J mice, whereas foz/foz BALB/c formed more adipose. Serum ALT, steatosis, ballooning, liver inflammation and NAFLD activity score were worse in C57BL6/J mice. In HF-fed mice, fibrosis was severe in foz/foz C57BL6/J, appreciable in WT C57BL6/J, but absent in foz/foz BALB/c mice. Hepatic mRNA expression of TNF-α, IL-12, IL-4, IL-10 was increased (but not IFN-γ, IL-1β, IL-17A), and IL-4:IFN-γ ratio (indicating Th-2 predominance) was higher in HF-fed foz/foz C57BL6/J than BALB/c mice. In livers of HF-fed foz/foz C57BL6/J mice, TGF-β was unaltered but PDGFα and CTGF were increased in association with enhanced α-SMA, CD147and MMP activity. Conclusions: In mice with equivalent genetic/dietary obesity, NASH development is linked to strain differences in hyperinsulinaemia and hyperglycaemia inversely related to lipid partitioning between adipose and liver. Diabetes-mediated CTGF-regulation of MMPs as well as cytokines/growth factors (Th-2 cytokine predominant, PDGFα, not TGF-β) mobilized in the resultant hepatic necroinflammatory change may contribute to strain differences in NASH fibrosis.

Original languageEnglish
Pages (from-to)1084-1093
Number of pages10
JournalLiver International
Volume34
Issue number7
DOIs
Publication statusPublished - 2014
Externally publishedYes

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Farrell, G., Mridha, A., Yeh, M., Arsov, T., Van Rooyen, D., Brooling, J., ... Larter, C. (2014). Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype. Liver International, 34(7), 1084-1093. https://doi.org/10.1111/liv.12335