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Regulation of Expression of CEACAM1 and Functional Correlation in Metabolic Diseases

Khuder, Saja S.
http://rave.ohiolink.edu/etdc/view?acc_num=mco1455885773

Abstract Details

2016, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences.
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is highly conserved and ubiquitously expressed in many cell types and tissues such as brain, liver. CEACAM1 is not found at the protein level in skeletal and adipose tissue, however it is expressed in tissues line with an endothelium barrier. As a cell adhesion molecule, CEACAM1 mediates cell-cell interactions, however it is also known to be involved in numerous biological processes: cell morphogenesis, proliferation, migration, angiogenesis, tumor suppressor, thrombosis and insulin clearance. In hepatocytes, where its expression is most abundant, CEACAM1 regulates insulin action by promoting insulin uptake and clearance. Mice with null mutation of Ceacam1 (Cc1–/–) exhibit impaired insulin clearance with increased lipid production in the liver and redistribution to white adipose tissue. This consequently leads to visceral obesity, leptin and insulin resistance at 6 months of age. Mice generated with endothelial cell-specific deletion of Ceacam1 (+Cc1fl) allowed for the differentiation between peripheral and central leptin resistance. In contrast to Cc1–/–, +Cc1fl mice remain insulin sensitive up to 12 months of age, however, like Cc1–/–, they exhibit an increase in body weight, fat mass, hyperphagia and hyperleptinemia beginning at 3-4 months. The exhibited hyperphagia is associated with blunted hypothalamic leptin signaling in response to an intraperitoneal injection of leptin. However, central leptin signaling was found to be normal, suggesting that leptin resistance is likely to stem from altered leptin transport across the blood brain barrier (BBB) at the choroid plexus. Studies of leakage in the capillaries of the cortex of the choroid plexus using FITC-dextran perfusion and Evans Blue reveal BBB extravasation. Together, this indicates that endothelial CEACAM1 preserves leptin sensitivity by regulating vascular stability. CEACAM1 also mediates a negative acute effect of insulin on fatty acid synthase activity. Western blot analysis reveals lower hepatic CEACAM1 expression during fasting. However, CEACAM1 expression is lowered as a consequence of obesity, fasting conditions, and response to high fat feeding. High-fat diet results in insulin resistance by reducing CEACAM1 before the onset of inflammation. Peroxisome Proliferator Activated Receptor a (PPARa) and Peroxisome Proliferator ¿ (PPAR¿), are nuclear receptors that form heterodimers with retinoid x receptor alpha (RXRa) to bind to DNA at sites of target genes. Treating of rat hepatoma FAO cells with Wy14,643, an agonist of PPARa, reduces Ceacam1 mRNA and CEACAM1 protein levels within 1 and 2 hours, respectively. FA-induced PPARa activation results in direct transcriptional inhibition of Ceacam1. Like PPARa, preliminary data suggests that PPAR¿ binds to the Ceacam1 promoter at the same Proxisome Proliferator Response Element (PPRE) regions; however, functioning to upregulate CEACAM1 expression. Upregulation of CEACAM1 expression is to promote insulin sensitivity and lipid metabolism. Deletion and block mutation analyses of the Ceacam1 promoter identified a main site of PPAR/RXRa binding, providing substantial evidence for its direct regulation by PPARa and PPAR¿. Furthermore, our studies show that CEACAM1 expression is mediated by PPAR-dependent mechanisms. Ultimately, the test of our hypothesis is to create a mouse model, including PPRE mutations on the Ceacam1 promoter, in order to abolish regulation of PPAR on CEACAM1. The mutation mouse model along with our current studies will further provide understanding of the regulation of expression of CEACAM1 and its functional correlation in metabolic diseases.
Sonia Najjar, Ph.D. (Committee Chair)
Edwin Sanchez, Ph.D (Committee Member)
Abraham Lee, P.T. Ph.D. (Committee Member)
Ivana de la Serna , Ph.D. (Committee Member)
Nikolai Modyanov , Ph.D. D.SC. (Committee Member)
Jennifer Hill , Ph.D. (Committee Member)
188 p.
Biomedical Research

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Citations

  • Khuder, S. S. (2016). Regulation of Expression of CEACAM1 and Functional Correlation in Metabolic Diseases [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1455885773

    APA Style (7th edition)

  • Khuder, Saja. Regulation of Expression of CEACAM1 and Functional Correlation in Metabolic Diseases. 2016. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1455885773.

    MLA Style (8th edition)

  • Khuder, Saja. "Regulation of Expression of CEACAM1 and Functional Correlation in Metabolic Diseases." Doctoral dissertation, University of Toledo, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=mco1455885773

    Chicago Manual of Style (17th edition)

mco1455885773
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This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.