Regulation of Tight Junction Formation by Fatty Acids

Fatty acids are major constituents of the phospholipid bilayer of the epithelial cell membrane, and there have been a few reports on the effects of fatty acids on tight junction permeability; fatty acids have been shown to affect occludin protein expression in the umbilical vein endothelial cell line ECV304 and in brain capillary ECs. It has been demonstrated that the TER and the level of occludin mRNA were increased by fatty acids in capillary ECs isolated from brain, and the expression of occludin protein paralleled the change in the pattern of its mRNA expression. The first reported such finding was that the changes in tight junction permeability induced by EPA and gamma LA (GLA) in brain capillary ECs are due to the increase in TER and expression of occludin protein, respectively. Subsequent reports demonstrated the effect of a range of oleic acids, LA, GLA, alpha LA, arachidonic acids, eicosatrienoic acids, and EPA on the permeability of tight junctions and the protein level of occludin in the human umbilical vein endothelial cell line ECV304. GLA, alpha LA, and EPA significantly increased the TER and protein expression, whereas LA significantly decreased the TER of ECV304 cells. These changes in TER were related to alterations in paracellular permeability, which was significantly reduced by EPA and GLA, and significantly increased by LA in ECV304. Furthermore, it was recently shown that PUAC induces tight junctions to form in brain capillary ECs. In brain capillary ECs, the effects of GLA, EPA, and LA on tight junctions were studied in cell monolayers. In those studies the mRNA expression of occludin and the involvement of tyrosine phosphorylation, protein kinase C, and PI 3-kinase were investigated. In vitro studies have shown that fatty acids, EPA, and GLA affect TER and apical-basol permeability. The effect of LA, however, was different from that reported in the umbilical vein endothelial cell line ECV304. Namely, in the in vitro study using ECV304 cells, it was demonstrated that LA decreased the TER. This finding suggests that the difference in the effect of LA is due to a difference of response to fatty acids between umbilical vein ECs and brain capillary ECs, although the mechanism of the response remains unknown. In addition, the rise in TER induced by EPA and GLA was inhibited by tyrosine kinase inhibitors and protein kinase C inhibitor in brain capillary ECs. In contrast, the rise in TER induced by EPA and GLA was not inhibited by the PI 3-kinase inhibitor. EPA and GLA have the ability to increase the TER and the expression of occludin mRNA in brain capillary ECs. This GLA- and EPA- induced assembly of tight junctions is likely to be regulated by protein kinase C and tyrosine kinase activity. The tight junction barrier is regulated by phosphorylation. Various reports have shown that phosphorylation of occludin is a key step in tight junction assembly, which in turn affects the localization of occludin in the cell. The high-molecular-weight forms of occludin are the functional forms that participate in the formation of the tight-junction barrier. The localization of different phospho-rylated forms of tight junction-associated proteins in the cell may be especially important. It has been demonstrated that in Madin-Darby canine kidney (MDCK) cells, the less phosphorylated low-molecular-weight forms of occludin are found in the basolateral membrane and cytosol, whereas the more highly phosphorylated high-molecular-weight forms are concentrated exclusively in the tight junction. Differential phosphorylation of occludin might be important for generating tight junctions with different permeability properties. Indeed tyrosine phosphorylation of occludin is known to occur during the assembly of the tight junctions in MDCK cells. Recently the effects of tyrosine kinase inhibitors, genistein, and PP2 on the response to polyunsaturated fatty acids have been reported. It was found that tyrosine kinase inhibitors inhibited the EPA- and GLA-induced increases in TER in brain capillary ECs. The data suggested that EPA and GLA stimulated the tyrosine phosphorylation of multiple proteins. Furthermore, the results indicated that GLA and EPA act through the phosphorylation of protein tyrosine residues. On the other hand, the absorption-enhancing effects of the sodium salts of two medium-chain fatty acids, capric acid and lauric acid, have been studied in monolayers of intestinal epithelial Caco-2 cells derived from colonic carcinoma. Both fatty acids induced a rapid increase in epithelial permeability to the hydrophilic marker molecule sodium fluorescein in the Caco-2 cell line. These reports showed that diverse reactions of free fatty acid depend on differences of the organization. However, the role of fatty acids in tight junction assembly in brain capillary ECs in vivo is not yet well understood.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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