Lipid peroxidation, stellate cell activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis.
OBJECTIVE
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.
George
Jacob
J
Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Westmead Hospital, New South Wales, Sydney, Australia. jacob_george@wmi.usyd.edu.au
Pera
Natasha
N
Phung
Nghi
N
Leclercq
Isabelle
I
Yun Hou
Jing
J
Farrell
Geoffrey
G
D000818:Animals; D002794:Choline / Q000008:administration & dosage; D004032:Diet; D005234:Fatty Liver / Q000150:complications* / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008103:Liver Cirrhosis / Q000209:etiology*; D008297:Male; D008715:Methionine / Q000008:administration & dosage; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000235:genetics; D015854:Up-Regulation
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D008715:Methionine; D002794:Choline