Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin.
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.
Sahai
Atul
A
Department of Pediatrics, The Feinberg School of Medicine, Northwestern University, Children's Memorial Institute for Education and Research, Chicago, IL 60614, USA. a-sahai@northwestern.edu
Malladi
Padmini
P
Pan
Xiaomin
X
Paul
Rachelle
R
Melin-Aldana
Hector
H
Green
Richard M
RM
Whitington
Peter F
PF
D000818:Animals; D002460:Cell Line; D002796:Choline Deficiency / Q000150:complications; D003677:Deficiency Diseases / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology*; D005260:Female; D008103:Liver Cirrhosis / Q000209:etiology* / Q000473:pathology; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D053495:Osteopontin; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D054411:Receptors, Leptin; D012795:Sialoglycoproteins / Q000378:metabolism
C515448:LEPR protein, human; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; C515447:leptin receptor, mouse; D053495:Osteopontin; D008715:Methionine