CEACAM1: A Common Regulator of Fat Metabolism and Cell Proliferation

 
 
 
 

CEACAM1: A Common Regulator of Fat Metabolism and Cell Proliferation

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dc.contributor.advisor Najjar, Sonia en_US
dc.contributor.author Lee, Sang Jun en_US
dc.date.accessioned 2009-04-10T08:20:35Z
dc.date.available 2009-04-10T08:20:35Z
dc.date.created 2008 en_US
dc.date.issued 2009-04-10T08:20:35Z
dc.identifier.uri http://rave.ohiolink.edu/etdc/view?acc_num=mco1218146004 en_US
dc.identifier.uri http://hdl.handle.net/2374.OX/107957
dc.description CEACAM1 mediates insulin clearance in the liver as a substrate of the insulin receptor. Moreover, CEACAM1 appears to play a central role in regulating fat metabolism and cell proliferation. The L-SACC1 mice with inactivation of CEACAM1 in the liver developed hyperinsulinemia resulting from impaired insulin clearance and also developed visceral adiposity with elevated plasma FFA and plasma and hepatic triglyceride levels. Herein, we have shown that CEACAM1 is a substrate of the EGFR and reduces EGFR-mediated cell growth in response to EGF, and that the CEACAM1 effect on EGFdependent hepatocyte proliferation is mediated by its ability to bind to and sequester Shc, thus uncoupling EGFR signaling from the Ras/Raf/MAP kinase pathway. Thus, impaired CEACAM1 phosphorylation leads to a ligand-independent increase of EGFR-mediated cell proliferation in the L-SACC1 mice. Moreover, increased levels of output of free fatty acids and heparin-binding EGF-like growth factor from increased fat continuously activate EGFR. Furthermore, once lipid storage begins in L-SACC1 mice fed a high fat diet for 3 months, the typical hepatic lesions of NASH, namely steatosis, inflammation, and early fibrosis were reproduced. In addition, the L-SACC1 animals fed a high fat diet exhibit severely enhanced hepatic fatty acid oxidation and elevated hepatic inflammatory cytokines such as TNFα, all leading to a severe enhancement of the proinflammatory NF- κB pathway. Taken together, L-SACC1 mice provide a model for the mechanistic link between increased cell proliferations in states of impaired metabolism with visceral obesity and are a useful tool for further studies to understand and prevent human NASH. en_US
dc.format application/pdf en_US
dc.format 198p. en_US
dc.rights unrestricted en_US
dc.rights Copyright and permissions information available at the source archive en_US
dc.subject CEACAM1 en_US
dc.subject Cell proliferation en_US
dc.subject NASH en_US
dc.subject fatty liver en_US
dc.subject inflamation en_US
dc.title CEACAM1: A Common Regulator of Fat Metabolism and Cell Proliferation en_US
dc.type Electronic Thesis or Dissertation en_US
dc.degree.name PhD en_US
dc.degree.level doctoral en_US
dc.degree.discipline Graduate Studies en_US
dc.degree.grantor University of Toledo Health Science Campus en_US
dc.contributor.publisher University of Toledo Health Science Campus / OhioLINK en_US

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