Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin

Am J Physiol Gastrointest Liver Physiol. 2004 Nov;287(5):G1035-43. doi: 10.1152/ajpgi.00199.2004. Epub 2004 Jul 15.

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-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 Ob-Ra and OPN in the pathogenesis of NASH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Choline Deficiency / complications
  • Deficiency Diseases / complications
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Disease Models, Animal*
  • Fatty Liver / etiology*
  • Female
  • Liver Cirrhosis / etiology*
  • Liver Cirrhosis / pathology
  • Methionine / deficiency
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / complications*
  • Obesity / genetics
  • Obesity / metabolism
  • Osteopontin
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / metabolism*
  • Receptors, Leptin
  • Sialoglycoproteins / metabolism

Substances

  • Receptors, Cell Surface
  • Receptors, Leptin
  • SPP1 protein, human
  • Sialoglycoproteins
  • Spp1 protein, mouse
  • leptin receptor, human
  • leptin receptor, mouse
  • Osteopontin
  • Methionine