Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice
Article first published online: 24 SEP 2009
© 2009 The Authors. Journal compilation © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Journal of Gastroenterology and Hepatology
Volume 24, Issue 10, pages 1658–1668, October 2009
How to Cite
Larter, C. Z., Yeh, M. M., Van Rooyen, D. M., Teoh, N. C., Brooling, J., Hou, J. Y., Williams, J., Clyne, M., Nolan, C. J. and Farrell, G. C. (2009), Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice. Journal of Gastroenterology and Hepatology, 24: 1658–1668. doi: 10.1111/j.1440-1746.2009.05996.x
- Issue published online: 24 SEP 2009
- Article first published online: 24 SEP 2009
- Accepted for publication 22 June 2009.
- lipid partitioning;
- metabolic syndrome;
- non-alcoholic fatty liver disease; non-alcoholic steatohepatitis
Background and Aims: We previously reported that steatohepatitis develops in obese, hypercholesterolemic, diabetic foz/foz mice fed a high-fat (HF) diet for 12 months. We now report earlier onset of steatohepatitis in relation to metabolic abnormalities, and clarify the roles of dietary fat and bodily lipid partitioning on steatosis severity, liver injury and inflammatory recruitment in this novel non-alcoholic steatohepatitis (NASH) model.
Methods: Foz/foz (Alms1 mutant) and wild-type (WT) mice were fed a HF diet or chow, and metabolic characteristics and liver histology were studied at 2, 6, 12 and 24 weeks.
Results: After 12 weeks HF-feeding, foz/foz mice were obese and diabetic with approximately 70% reduction in serum adiponectin. Hepatomegaly developed at this time, corresponding to a plateau in adipose expansion and increased adipose inflammation. Liver histology showed mild inflammation and hepatocyte ballooning as well as steatosis. By 24 weeks, HF-fed foz/foz mice developed severe steatohepatitis (marked steatosis, alanine aminotransferase elevation, ballooning, inflammation, fibrosis), whereas dietary and genetic controls showed only simple steatosis. While steatosis was associated with hepatic lipogenesis, indicated by increased fatty acid synthase activity, steatohepatitis was associated with significantly higher levels of CD36, indicating active fatty acid uptake, possibly under the influence of peroxisome proliferator-activated receptor-γ.
Conclusion: In mice genetically predisposed to obesity and diabetes, HF feeding leads to restriction of adipose tissue for accommodation of excess energy, causing lipid partitioning into liver, and transformation of simple steatosis to fibrosing steatohepatitis. The way in which HF feeding ‘saturates’ adipose stores, decreases serum adiponectin and causes hepatic inflammation in steatohepatitis may provide clues to pathogenesis of NASH in metabolic syndrome.