Strain dependence of diet‐induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype. (25th October 2013)

• Record Type: Journal Article
• Authors: Farrell, Geoffrey C.; Mridha, Auvro R.; Yeh, Matthew M.; Arsov, Todor; Van Rooyen, Derrick M.; Brooling, John; Nguyen, Tori; Heydet, Deborah; Delghingaro‐Augusto, Viviane; Nolan, Christopher J.; Shackel, Nicholas A.; McLennan, Susan V.; Teoh, Narci C.; Larter, Claire Z.
• Is Part Of: Liver international. Volume 34:Number 7(2014:Sep.)
• Page Start: 1084
• Page End: 1093
• Publication Date: 2013-10-25
• Subjects: Liver -- Periodicals; Liver -- Diseases -- Periodicals; 616.362
• DOI: 10.1111/liv.12335
• Languages: English
• ISSNs: 1478-3223

Abstract

<abstract abstract-type="main" id="liv12335-abs-0001"> <title>Abstract</title> <sec id="liv12335-sec-0001" sec-type="section"> <title>Background & Aims</title> <p>Obese <italic>Alms1</italic> mutant (<italic>foz/foz</italic>) 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 <italic>foz/foz</italic> C57BL6/J with non‐diabetic <italic>foz/foz </italic>BALB/c mice. We also determined hepatic cytokines, growth factors and related profibrotic pathways.</p> </sec> <sec id="liv12335-sec-0002" sec-type="section"> <title>Methods</title> <p>Male and female <italic>foz/foz </italic>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.</p> </sec> <sec id="liv12335-sec-0003" sec-type="section"> <title>Results</title> <p>All <italic>foz/foz</italic> mice were obese. Hepatomegaly, hyperinsulinemia, hyperglycaemia and hypoadiponectinaemia occurred only in <italic>foz/foz</italic> C57BL6/J mice, whereas <italic>foz/foz</italic> 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 <italic>foz/foz</italic> C57BL6/J, appreciable in WT C57BL6/J, but absent in <italic>foz/foz</italic> 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 <italic>foz/foz</italic> C57BL6/J than BALB/c mice. In livers of HF‐fed <italic>foz/foz</italic> C57BL6/J mice, TGF‐β was unaltered but PDGFα and CTGF were increased in association with enhanced α‐SMA, CD147and MMP activity.</p> </sec> <sec id="liv12335-sec-0004" sec-type="section"> <title>Conclusions</title> <p>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.</p> </sec> </abstract>