Cholesterol modulates sorting of CEA -- implications for inflammatory bowel disease

In polarized Caco-2 cells, cholesterol was depleted by a combination of synthesis inhibition and plasma membrane extraction with complexing agents. This led to an increased sorting of CEA to the basolateral surface. Interestingly, polarity was not significantly affected by this approach. The association of CEA to lipid rafts, cholesterol, and sphingolipid-enriched microdomains was inhibited in parallel.

This study, performed by a team led by Dr. Robert Ehehalt, is described in a research article to be published on March 14, 2008, in the World Journal of Gastroenterology.

Carcinoembryonic antigen (CEA) is a GPI-anchored glycoprotein that has been suggested to have different functions depending on its expression at the apical or basolateral plasma membrane. Whereas at the apical membrane, it is possible for it to interact with bacteria, basolateral expression might be involved in the activation of suppressor T-cells and thus have anti-inflammatory properties. A decreased expression in the basolateral compartment has been attributed to the pathogenesis of inflammatory bowel disease (IBD).

The sorting of proteins to the apical or basolateral membrane in general is a precisely regulated mechanism. Part of this sorting is regulated by the dynamic interaction of proteins with lipid rafts. Influencing lipid-raft-dependent mechanisms by changing the lipid content of cells might therefore be a new lipid-based approach for influencing human diseases.

In the view of the authors, the interesting potential of influencing the lipid-raft-dependent sorting of CEA is that the protein changes its function from a potential pro-inflammatory to an anti-inflammatory. As the gut mucosa might be easily challenged by luminal agents, this could offer a new clinical treatment option.

A therapeutical approach for changing the lipid composition of cellular membranes has already been performed in studies for IBD. Lipid-based therapies with phospholipids have been shown to be successful in ulcerative colitis patients. In addition, animal experiments using ganglioside-enriched diets or short-chain fatty acids were shown to reduce intestinal inflammation. Interestingly, also reducing cholesterol by the systemic inhibition of HMG-CoA with pravastatin has been shown to reduce inflammation in a rat model of colitis.

However, whether a lipid-based therapy approach for IBD should include a reduction of the cholesterol content of enterocytes remains an open question. Further studies are also needed to estimate the clinical significance of the findings.

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Reference: Ehehalt R, Krautter M, Zorn M, Sparla R, Füllekrug J, Kulaksiz H Stremmel W. Increased basolateral sorting of CEA in a polarized colon carcinoma cell line after cholesterol depletion – Implications for treatment of IBD. World J Gastroenterol 2008; 14(10): 1528-1533

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