| First Author | Farrell GC | Year | 2014 |
| Journal | Liver Int | Volume | 34 |
| Issue | 7 | Pages | 1084-93 |
| PubMed ID | 24107103 | Mgi Jnum | J:354089 |
| Mgi Id | MGI:7719160 | Doi | 10.1111/liv.12335 |
| Citation | Farrell GC, et al. (2014) Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype. Liver Int 34(7):1084-93 |
| abstractText | 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-alpha, IL-12, IL-4, IL-10 was increased (but not IFN-gamma, IL-1beta, IL-17A), and IL-4:IFN-gamma 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-beta was unaltered but PDGFalpha and CTGF were increased in association with enhanced alpha-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, PDGFalpha, not TGF-beta) mobilized in the resultant hepatic necroinflammatory change may contribute to strain differences in NASH fibrosis. |
