Kazuo Yamagata 2Motoki Tagami 3Yasuo Nara 4Shingo Itoh 1Hidehiko Yokogoshi and 5Yukio Yamori

laboratory of Preventive Nutrition, Department of Food Science and Technology College of Bioresource Sciences, Nihon University,

Fujisawa-shi, Kanagawa-ken, Japan 2Department of Internal Medicine, Sanraku Hospital, Chiyoda-Ku, Tokyo, Japan 3Laboratory of Health Science, Department of Biological Pharmacy, School of Pharmacy, Shujitu University, Okayama-shi,

Okayama, Japan

4Laboratory of Food Science, Department of Food Science and Technology College of Bioresource Sciences, Nihon University,

Fujisawa-shi, Kanagawa-ken, Japan 5World Health Organization Collaborating Center for Research on Primary Prevention of Cardiovascular Diseases, Kyoto-shi,

Kyoto, Japan

Introduction

The brain is highly enriched in fatty acids such as docosahexaenoic acid (DHA) and arachidonic acid. These fatty acids are major constituents of the phospholipid bilayer of the cell membrane, and modulate the tight junction permeability and occludin protein expression in brain capillary endothelial cells (ECs). This review summarizes the main findings of the in vitro approach in blood-brain barrier (BBB) research, describes the unique tight-junction features of the brain endothelium, and provides a short overview on how these BBB characteristics can be induced by the fatty acids in cerebral ECs.

Overview: Tight Junction and Fatty Acids

Brain capillary ECs lining the cerebral microvasculature form the BBB. The BBB is a complex of tight junctions between brain ECs. This barrier between the blood and the central nervous system (CNS) is relatively impermeable to ions, many amino acids, small peptides, and proteins. The maintenance of such an efficient barrier between the blood and brain compartments is essential for normal brain function. The barrier formed by the tight junctions has the important function of protecting the brain from fluctuations in the composition of the plasma. Accordingly, disruption of the BBB can be a relatively major part of the pathology following cerebral ischemia. Physiological and morphological studies have indicated that the relationship between the transepithelial electrical resistance (TER) and intramembrane particle strand number is logarithmic. In fact, the TER across the BBB in vivo is believed to be 1,000 W cm2. In freeze-fracture electron micrographs, tight junctions appear as a set of continuous, anastomosing intramembrane particle strands in the cytoplasmic face with complementary grooves in the extracellular face. Various tight junction-associated proteins have been identified, including zonula occludens (ZO)-1, ZO-2, ZO-3, cingulin, 7H6 antigen, occluding, and claudin. It has been shown that ZO-1 binds to occludin in vitro and is colocalized with F-actin in cultured cells. In particular, occludin and claudin-5 are integral membrane proteins localized within tight junction strands that have been shown to serve as functional components of the tight junction of vascular ECs. Therefore, both occludin and claudin-5 contribute to the electrical barrier function of tight junctions and possibly to the formation of aqueous pores within tight junction strands in brain ECs. These proteins together with the actin cytoskeleton are major determinants of tight-junction structure and also play a role in the regulation of tight junctions. Tight-junction formation appears to be regulated in part by signal transduction pathways involving G proteins, release of intracellular Ca2+, and activation of protein kinase C. Fatty acids are the major constituents of the phospholipid bilayer of the epithelial cell membrane and reportedly modulate the permeability of the epithelial cells. Various reports have demonstrated the effects of fatty acids on tight junction permeability and occludin protein expression in an umbilical vein endothelial cell line. It has also been demonstrated that exposure to fatty acids significantly increased TER in ECs derived from the brain. On the other hand, the absorption-enhancing effects of the sodium salts of two medium-chain fatty acids have been studied in mono-layers of intestinal epithelial cell lines derived from colonic carcinoma. Medium fatty acids induced a rapid increase in epithelial permeability in the intestinal cell lines. These reports suggest that the fatty acids contribute to the regulation of tight junctions in ECs. Essential fatty acids are structural components of all tissues and are indispensable for cell membrane synthesis. Brain, retinal, and other neural tissues are particularly rich in long-chain polyunsaturated fatty acids (PUFAs). These fatty acids serve as specific precursors for eicosanoids, which regulate numerous cell and organ functions. It is generally accepted that PUFAs are essential for growth and development, and their crucial role in the development of the CNS has been the subject of many studies. The important role of fatty acids, including PUFAs, for tight junction assembly in brain capillary ECs is well established. Furthermore, tight junction formation appears to be regulated in part by the release of PUFA from astrocytes in vivo.

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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