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J Hepatol. 2003 Nov;39(5):756-64.

Lipid peroxidation, stellate cell activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis.

Author information

1
Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Westmead Hospital, New South Wales, Sydney, Australia. jacob_george@wmi.usyd.edu.au

Abstract

BACKGROUND/AIMS:

We explored the involvement of cell types, cytokines and lipid peroxidation in a rat dietary model of fibrosing steatohepatitis.

METHODS:

Male rats were fed a high fat diet deficient in methionine and choline (MCD) for up to 17 weeks. Whole liver, hepatocytes and non-parenchymal cells were analysed for reduced glutathione (GSH) levels, products of lipid peroxidation (thiobarbituric acid reactive substances, TBARS), liver injury, and fibrosis.

RESULTS:

MCD diet-fed rats developed hepatic steatosis at week 2 and focal necroinflammatory change by week 5, while pericellular fibrosis evolved and progressed between weeks 12 and 17. Collagen alpha(1)(1) gene expression was upregulated by week 5 and increased fivefold by week 17. Stellate cells were the unique source of collagen gene expression. TIMP-1 and -2 were increased at week 12. Livers of MCD diet-fed rats exhibited lowered levels of GSH and elevated TBARS. Hepatocytes were the source of lipid peroxidation, and mRNA levels for TGFbeta1 were increased only in this cell type.

CONCLUSIONS:

The MCD model of 'fibrosing steatohepatitis' replicates the histologic features of human steatohepatitis, and the sequence of steatosis, inflammatory cell injury and fibrogenesis. The temporal sequence is consistent with a concept for involvement of oxidative injury in inflammatory recruitment and pathogenesis of hepatic fibrogenesis.

PMID:
14568258
DOI:
10.1016/s0168-8278(03)00376-3
[Indexed for MEDLINE]

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