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Am J Physiol Gastrointest Liver Physiol (July 15, 2004). doi:10.1152/ajpgi.00199.2004
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Submitted on April 29, 2004
Accepted on July 8, 2004

Obese and Diabetic db/db Mice Develop Marked Liver Fibrosis in a Model of Nonalcoholic Steatohepatitis: Role of Short-Form Leptin Receptors and Osteopontin

ATUL SAHAI1*, PADMINI MALLADI1, XIAOMIN PAN1, RACHELLE PAUL1, HECTOR MELIN-ALDANA2, RICHARD M. GREEN3, and PETER F. WHITINGTON1

1 Department of Pediatrics, The Feinberg School of Medicine, Northwestern University, the Children's Memorial Institute for Education and Research, Chicago, IL, USA
2 Department of Pathology, The Feinberg School of Medicine, Northwestern University, the Children's Memorial Institute for Education and Research, Chicago, IL, USA
3 Department of Medicine, The Feinberg School of Medicine, Northwestern University, the Children's Memorial Institute for Education and Research, Chicago, IL, USA

* To whom correspondence should be addressed. E-mail: a-sahai{at}northwestern.edu.

Obesity and type II diabetes are associated with nonalcoholic steatohepatitis (NASH), but the development of an obese/diabetic animal model that mimics human NASH remains undefined. We examined the induction of steatohepatitis and liver fibrosis in obese and type II diabetic db/db mice in a nutritional model of NASH and determined the relationship of the expressions of osteopontin (OPN) and leptin receptors to the pathogenesis of NASH. db/db mice and the corresponding lean and non-diabetic db/m mice were fed a diet deficient in methionine and choline (MCD diet) or control diet for 4 weeks. Leptin-deficient, obese and diabetic ob/ob mice fed similar diets were used for comparison. MCD diet-fed db/db mice exhibited significantly greater histological inflammation and higher serum ALT levels than db/m and ob/ob mice. Trichrome staining showed marked pericellular fibrosis in MCD diet-fed db/db mice, but no significant fibrosis in db/m or ob/ob mice. Collagen I mRNA expression was increased 10-fold in db/db mice, 4-fold in db/m mice, and was unchanged in ob/ob mice. mRNA expressions of OPN, TNF-{alpha}, TGF-{beta}, and short-form leptin receptors (Ob-Ra) were significantly increased in db/db mice compared with db/m or ob/ob mice. Parallel increases in OPN and Ob-Ra protein levels were observed in db/db mice. Cultured hepatocytes expressed only Ob-Ra, and leptin stimulated OPN mRNA and protein expression in these cells. In conclusion, our results demonstrate the development of an obese/diabetic experimental model for NASH in db/db mice, and suggest an important role for shortform leptin receptors and OPN in the pathogenesis of NASH.




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