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 Sahai*, Padmini Malladi, Xiaomin Pan, Rachelle Paul, Hector Melin-Aldana, Richard M. Green, Peter F. Wittington

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

Obesity and type 2 diabetes are associated with nonalcoholic steatohepatitis (NASH), but an obese/diabetic animal model that mimics human NASH remains undefined. We examined the induction of steatohepatitis and liver fibrosis in obese and type 2 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 nondiabetic db/m mice were fed a diet deficient in methionine and choline (MCD diet) or control diet for 4 wk. 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 alanine aminotransferase 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-α, TGF-β, 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 Ob-Ra and OPN in the pathogenesis of NASH.

Original languageEnglish (US)
Pages (from-to)G1035-G1043
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume287
Issue number5 50-5
DOIs
StatePublished - Nov 1 2004

Keywords

  • Diabetes
  • Fibrosis
  • Insulin resistance
  • Obesity
  • Osteopontin

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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