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Strain dependence of diet‐induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype
Author(s) -
Farrell Geoffrey C.,
Mridha Auvro R.,
Yeh Matthew M.,
Arsov Todor,
Van Rooyen Derrick M.,
Brooling John,
Nguyen Tori,
Heydet Deborah,
DelghingaroAugusto Viviane,
Nolan Christopher J.,
Shackel Nicholas A.,
McLennan Susan V.,
Teoh Narci C.,
Larter Claire Z.
Publication year - 2014
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12335
Subject(s) - fibrosis , steatosis , endocrinology , medicine , diabetes mellitus , biology
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 C57 BL 6/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 C57 BL 6/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 MMP s as well as cytokines/growth factors (Th‐2 cytokine predominant, PDGF α, not TGF ‐β) mobilized in the resultant hepatic necroinflammatory change may contribute to strain differences in NASH fibrosis.