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Degree

Doctor of Philosophy in Medical Sciences (Ph.D.), University of Toledo Health Science Campus, Graduate School, 2005.

Abstract

CEACAM1 is a transmembrane glycoprotein highly expressed in liver. It downregulates the mitogenic effect of insulin, and contributes to circulating insulin level by regulating hepatic insulin clearance. We have proposed that CEACAM1 exerts its effect by taking part of the insulin endocytosis complex, and have identified Shc as an adaptor between CEACAM1 and IR. In the current studies, we explored the role of Shc/CEACAM1 complex in receptor-mediated insulin endocytosis and insulin-stimulated mitogenesis. Disruption of Shc/CEACAM1 or Shc/Grb2 interaction by overexpression the SH2 domain of Shc or of Grb2, respectively, revealed that CEACAM1 binding to Shc partitions it to the endocytosis rather than mitogenesis pathways. CEACAM1-mediated partitioning of Shc may provide a highly efficient method to regulate insulin signaling. In agreement with the role of CEACAM1 in hepatic insulin clearance, LSACC1 mice with liver-specific overexpression of the dominant-negative phosphorylation-defective CEACAM1 developed hyperinsulinemia primarily due to impaired insulin clearance. Noteworthy, there is a consistent correlation between obesity and loss of function/expression of CEACAM1 in rodent models. Herein we investigated the role of CEACAM1 in fat metabolism, and observed both in vitro and in vivo that CEACAM1 mediates an acute downregulatory effect of insulin on fatty acid synthase. We performed thorough analysis on CEACAM1/FAS interaction, and identified that it requires the phosphorylation of

Subject Headings

Health Sciences, Pharmacology

Keywords

CEACAM1; Insulin; FAS; insulin receptor; insulin resistance; Shc

Advisor

Sonia Najjar, Ph.D

Pages

167p.

Document number: mco1115060085
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=mco1115060085

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