Mice with null mutation of Ceacam1 develop nonalcoholic steatohepatitis

Original Research

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Authors: Sumona Ghosh, Meenakshi Kaw, Payal R Patel, et al

Published Date May 2010 Volume 2010:2 Pages 69 - 78

DOI: http://dx.doi.org/10.2147/HMER.S8902

Sumona Ghosh^1,2,*, Meenakshi Kaw^1,2,*, Payal R Patel^1,2, Kelly J Ledford^1,2, Thomas A Bowman^1,2, Marcia F McInerney^1,4, Sandra K Erickson⁵, Raymond E Bourey^1,3, Sonia M Najjar^1,2

¹Center for Diabetes and Endocrine Research, ²Departments of Physiology and Pharmacology, and of ³Medicine at the University of Toledo College of Medicine, Health Science Campus, Toledo, OH, USA; ⁴Department of Medicinal and Biological Chemistry at the College of Pharmacy, University of Toledo, Main Campus, Toledo, OH, USA; ⁵Department of Medicine, University of California, and Veterans Affairs Medical Center, San Francisco, CA, USA; *These authors contributed equally to this work

Abstract: Transgenic liver-specific inactivation of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM1) impairs hepatic insulin clearance and causes hyperinsulinemia, insulin resistance, elevation in hepatic and serum triglyceride levels, and visceral obesity. It also predisposes to nonalchoholic steatohepatitis (NASH) in response to a high-fat diet. To discern whether this phenotype reflects a physiological function of CEACAM1 rather than the effect of the dominant-negative transgene, we investigated whether Ceacam1 (gene encoding CEACAM1 protein) null mice with impaired insulin clearance also develop a NASH-like phenotype on a prolonged high-fat diet. Three-month-old male null and wild-type mice were fed a high-fat diet for 3 months and their NASH phenotype was examined. While high-fat feeding elevated hepatic triglyceride content in both strains of mice, it exacerbated macrosteatosis and caused NASH-characteristic fibrogenic changes and inflammatory responses more intensely in the null mouse. This demonstrates that CEACAM1-dependent insulin clearance pathways are linked with NASH pathogenesis.

Keywords: nonalcoholic steatohepatitis, CEACAM1, high-fat diet, inflammation, apoptosis, fibrosis