Development of nonalcoholic steatohepatitis in insulin-resistant liver-specific S503A carcinoembryonic antigen-related cell adhesion molecule 1 mutant mice.
OBJECTIVE
Liver-specific inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 causes hyperinsulinemia and insulin resistance, which result from impaired insulin clearance, in liver-specific S503A carcinoembryonic antigen-related cell adhesion molecule 1 mutant mice (L-SACC1). These mice also develop steatosis. Because hepatic fat accumulation precedes hepatitis, lipid peroxidation, and apoptosis in the pathogenesis of nonalcoholic steatohepatitis (NASH), we investigated whether a high-fat diet, by causing inflammation, is sufficient to induce hepatitis and other features of NASH in L-SACC1 mice.


METHODS
L-SACC1 and wild-type mice were placed on a high-fat diet for 3 months, then several biochemical and histologic analyses were performed to investigate the NASH phenotype.


RESULTS
A high-fat diet caused hepatic macrosteatosis and hepatitis, characterized by increased hepatic tumor necrosis factor alpha levels and activation of the NF-kappaB pathway in L-SACC1 but not in wild-type mice. The high-fat diet also induced necrosis and apoptosis in the livers of the L-SACC1 mice. Insulin resistance in L-SACC1 fed a high-fat diet increased the hepatic procollagen protein level, suggesting a role in the development of fibrosis.


CONCLUSIONS
A high-fat diet induces key features of human NASH in insulin-resistant L-SACC1 mice, validating this model as a tool to study the molecular mechanisms of NASH.
The Center for Diabetes and Endocrine Research and the Department of Physiology and Pharmacology, College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio 43614, USA.
Sang Jun
SJ
Lee
Garrett
G
Heinrich
Larisa
L
Fedorova
Qusai Y
QY
Al-Share
Kelly J
KJ
Ledford
Mats A
MA
Fernstrom
Marcia F
MF
McInerney
Sandra K
SK
Erickson
Cara
C
Gatto-Weis
Sonia M
SM
Najjar
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002272:Carcinoembryonic Antigen / Q000235:genetics* / Q000378:metabolism; D015815:Cell Adhesion Molecules; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D007333:Insulin Resistance; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D016133:Polymerase Chain Reaction
D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D015815:Cell Adhesion Molecules; D004247:DNA