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CEACAM1: A Common Regulator of Fat Metabolism and Cell Proliferation

Lee, Sang Jun
http://rave.ohiolink.edu/etdc/view?acc_num=mco1218146004

Abstract Details

2008, Doctor of Philosophy in Medical Sciences (Ph.D.), University of Toledo, College of Graduate Studies.
CEACAM1 mediates insulin clearance in the liver as a substrate of the insulinreceptor. 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.
Sonia Najjar, PhD (Committee Chair)
Han-Fei Ding, PhD (Committee Member)
Kam Yeung, PhD (Committee Member)
Manohar Ratnam, PhD (Committee Member)
William Gunning, PhD (Committee Member)
Randall Ruch, PhD (Committee Member)
Cynthia Smas, PhD (Committee Member)
198 p.
Health
CEACAM1; Cell proliferation; NASH; fatty liver; inflamation

Recommended Citations

Citations

  • Lee, S. J. (2008). CEACAM1: A Common Regulator of Fat Metabolism and Cell Proliferation [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1218146004

    APA Style (7th edition)

  • Lee, Sang Jun. CEACAM1: A Common Regulator of Fat Metabolism and Cell Proliferation. 2008. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1218146004.

    MLA Style (8th edition)

  • Lee, Sang Jun. "CEACAM1: A Common Regulator of Fat Metabolism and Cell Proliferation." Doctoral dissertation, University of Toledo, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=mco1218146004

    Chicago Manual of Style (17th edition)

mco1218146004
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© 2008, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.