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Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype.
Liver Int. 2014 Aug; 34(7):1084-93.LI

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.

Authors+Show Affiliations

Liver Research Group, Australian National University Medical School at The Canberra Hospital, Garran, ACT, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24107103

Citation

Farrell, Geoffrey C., et al. "Strain Dependence of Diet-induced NASH and Liver Fibrosis in Obese Mice Is Linked to Diabetes and Inflammatory Phenotype." Liver International : Official Journal of the International Association for the Study of the Liver, vol. 34, no. 7, 2014, pp. 1084-93.
Farrell GC, Mridha AR, Yeh MM, et al. Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype. Liver Int. 2014;34(7):1084-93.
Farrell, G. C., Mridha, A. R., Yeh, M. M., Arsov, T., Van Rooyen, D. M., Brooling, J., Nguyen, T., Heydet, D., Delghingaro-Augusto, V., Nolan, C. J., Shackel, N. A., McLennan, S. V., Teoh, N. C., & Larter, C. Z. (2014). Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype. Liver International : Official Journal of the International Association for the Study of the Liver, 34(7), 1084-93. https://doi.org/10.1111/liv.12335
Farrell GC, et al. Strain Dependence of Diet-induced NASH and Liver Fibrosis in Obese Mice Is Linked to Diabetes and Inflammatory Phenotype. Liver Int. 2014;34(7):1084-93. PubMed PMID: 24107103.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype. AU - Farrell,Geoffrey C, AU - Mridha,Auvro R, AU - Yeh,Matthew M, AU - Arsov,Todor, AU - Van Rooyen,Derrick M, AU - Brooling,John, AU - Nguyen,Tori, AU - Heydet,Deborah, AU - Delghingaro-Augusto,Viviane, AU - Nolan,Christopher J, AU - Shackel,Nicholas A, AU - McLennan,Susan V, AU - Teoh,Narci C, AU - Larter,Claire Z, Y1 - 2013/10/25/ PY - 2013/05/08/received PY - 2013/09/06/accepted PY - 2013/10/11/entrez PY - 2013/10/11/pubmed PY - 2015/5/29/medline KW - Non-alcoholic steatohepatitis KW - cytokines KW - fibrosis KW - growth factors KW - strain difference SP - 1084 EP - 93 JF - Liver international : official journal of the International Association for the Study of the Liver JO - Liver Int. VL - 34 IS - 7 N2 - 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. SN - 1478-3231 UR - https://www.unboundmedicine.com/medline/citation/24107103/Strain_dependence_of_diet_induced_NASH_and_liver_fibrosis_in_obese_mice_is_linked_to_diabetes_and_inflammatory_phenotype_ L2 - https://doi.org/10.1111/liv.12335 DB - PRIME DP - Unbound Medicine ER -