Since it has been reported that dietary intakes of fish oil link to reduced rates of cardiovascular and inflammatory diseases in Greenland Eskimos, many studies have focused on the role of icosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the modulation of lipid metabolism. By the way, the number of patients with disease peculiar to the aged, such as senile dementia, has tended to increase in recent years. Studies specifically concerned with the modification of nervous system and the control of aging by EPA and DHA are now noteworthy. In this review, we have described recent studies in the following areas: metabolism of EPA and DHA, cardiovascular system, anti-inflammatory action, brain and retina, and aging.
The lipoproteins are globular particles which contain a non-polar core, triglyceride and cholesterol ester, surrounded by phospholipids, unesterified cholesterol and various apoproteins. Dietary triglycerides and cholesterol are incorporated into chylomicron, which are eventually hydrolyzed into chylomicron remnants by lipoprotein lipase. Remnants enriched with B-48 and E are taken up by hepatic cells. Endogenously synthesized triglyceride in the core of VLDL are secreted into the blood, subsequenly hydrolyzed into LDL, rich in cholesterol and B-100, via IDL. IDL and LDL are catabolized by the liver through LDL receptor. HDL, produced either by the hydrolysis of chylomicron and VLDL, or synthesized directly by the liver and intestinal cells, transports free cholesterol of the cell to the liver by LCAT. Various defects in apolipoproteins A- I, B, C- II and E are responsible for the development of hyper-lipoproteinemias, which are also produced by the abnormality by LDL receptor activity and lipid transfer protein.
Obesity is the condition where the lipid store of the body, adipose tissue, is enlarged. The main, functional unit of adipose tissue is the adipocyte. Enlargement of adipose tissue is accomplished first by enlargement of adipocyte contents of storage fat, triglyceride. At some point after the plateau in cell size is reached, an increase in obesity must be accompanied by an increase in number of adipocytes. It should be emphasized, that adipocytes have a unique ability to change their capacity for triglyceride storage. The fatty acid composition of triglyceride in the adipose tissue is affected by that of fat in a meal. However, the fatty acid composition of the adipose tissue do not differ between obese and non-obese subjects. In obesity, the excess depot fat is presumably accumulated in the available depots by principally the same regulatory mechanisms as in the physiological non-obese state. Triglyceride in adipocyte is synthesized from blood glucose and circulating fat in the form of chylomicron and very low density lipopretein, and hydrolyzed to glycerol and fatty acids by hormone-sensitive lipase. Recent work has demonstrated that lipid mobilization in the adipocyte were regurated by genetic, nervous, endocrine, and metabolic factors. Now, the description and risk of excess adipose tissue in obesity are fairly well establised. Accumulation of triglyceride in adipocytes in the end result of the balance between triglyceride synthesis and degradation. Therefore, lipid mobilization is of importance for the obesity. Clearly, more studies are needed in the area.
The Role of dietary fat and oils is very important in human nutrition. However, fats differ in their chemical characteristics and physiological effects. Recently fat consumption, especially animal fat, in our daily diet significantly increased in Japan. So it is very important to recognize all sources of fat in the diet, and to give careful consideration of both the quantity and the quality of fats intake. Phisiological effects and the way to intake of various fats are discussed in this report.
Although dietary carbohydrate, protein and fat contributed to the induction of lipogenic enzymes in a similar direction, the regulation mechanisms were individually different. Acetyl-CoA carboxylase and malic enzyme were carbohydrate-dependent, whereas glucose-6-phosphate dehydrogenase was rather protein-dependent. Both carbohydrate and protein were required for fatty acid synthetase induction. Concerning malic enzyme, the transcriptional rates were increased by feeding various diets to fasted rats, but the increases were not significantly different among the nutrients. On feeding a carbohydrate diet (without protein), the mRNA concentration was increased to the level in a carbohydrate/protein diet, while the enzyme induction was not so much increased. Dietary protein appeared to be involved in the translation.
Skin surface is covered with very thin lipid film called as skin surface lipids. Skin surface lipids are the mixture of sebum originated from sebaceous gland and epidermal lipids. Epidermal lipid is the minor component of skin surface lipids and occupies less than 5 % of skin surface lipids. However, the epidermal lipids, especially ceramide, play an important role in water barrier function of the skin.
Recent numerous studies have indicated that inositol phospholipids metabolism plays an important role in the signal trasduction of Ca2+ mobilizing hormones. The hydrolysis of phosphatidyl 4, 5-bisphosphate (PIP2) by phospholipase C has been considered to be initial event induced by receptor-activation. Breakdown of PIP2 leads to the formation of 1, 2-diacylglycerol (1, 2-DG) and inositol 1, 4, 5-triphosphate [Ins(1, 4, 5)P3] which apparently serve as intercellular 2nd-messengers 1, 2-DG is known to act as an activator for protein kinase C, and Ins(1, 4, 5)P3, another product, is able to release Ca2+ from intercellular store, which cause Ca2+-dependent enzyme activation. Thus activation of protein kinase C and mobilization of intercellular Ca2+ lead to various cellular response.
PAF (platelet-activating factor, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent phospholipid mediator of acute allergic and inflammatory reactions. PAF is synthesized from a variety of stimulated inflammatory cells and has a wide spectrum of biological activities. Recent studies have revealed that PAF is also generated from normal tissues (organs) and involved in a variety of normal physiological phenomena. It is plausible that 1-O-alkyl-2-arachidonoyl-GPC is a source of both PAF and bioactive arachidonate metabolites in various cells. The arachidonate products may lead to increased synthesis of PAF and they act synergistically with PAF. Recently, it was reported that the dietary enrichment with n-3 polyunsaturated fatty acids suppress PAF and arachidonate generation. Although the precise role of PAF in vivo has not yet been fully understood, it is becoming increasingly evident that PAF is important in physiological and pathological reaction. In this review, we describe the outline of PAF research based on biochemical and lipid chemical aspects.
Phospholipases are a class of ubiquitous enzymes and ditected either intracellularly or intercellularly over a wide variety of organisms. The functions of phospholipases are diverse: 1, The action of phospholipases in digestion (digestion of extracellular phospholipids in phagocytes and digestion of dietary phospholipids in the intestine), 2, Regulatory phospholipases. Some phospholipases may play an important role in the transmembrane control and also in the generation of bio-active lipids such as icosanoids and PAF, both of which may function as a mediator of various cell-cell communications. 3, Detoxication. 4, Remodeling of membrane phospholipids. The functional and structural aspects of various phospholipases will be reviewed in this article.
Lipids as drug carriers influence on parenteral absorption of drags, their intracorporeal distribution, metabolism, and elimination. Especially, lipid vesicles composed of polar lipids, surfactants, and the like, are expected to deliver drugs toward their target sites, and to control their releasing continually. The reason why is that the systems described above is relatively lymphatogenous, so they can aim at their target. Up to the present, various studies have been carried out on new drug carriers using lipids ; liposomes, lipid micro-sphere, lipid-surfactant mixed micelles, oleous constructive medium etc. These materials are bioerodible, biocompatible, and non-antigenic. For some of them, the clinical effects have been examined.
Lipid peroxidation in foods proceeds via autocatalytic oxidation, photosensitized oxidation and lipoxygenase reaction. Lipid peroxidation products including hydroperoxides and their secondary products accumulate in daily foods and foodstuffs, and are probably harmful to human body. Animal studies strongly suggest that lipid peroxidation products are partly absorbed into human body resulting in toxicity and carcinogenicity. Prooxidants and antioxidants present in foods, as well as lipid peroxidation products, seems to modify the sensitivity of biomembrane to lipid peroxidation which may be related to cancer and other pathological conditions.
Induction of lipid peroxidation in tissues or cells produces fluorescence, crosslinks and borohydride-reducible functions in the proteins. Fatty acid hydroperoxides, initial products of lipid peroxidation, produce fluorescence and cross-links by reacting with proteins, and the fluorescence characteristics of the products are similar to those of the products formed in cells and tissues. Malonaldehyde that may be generated to a little extent during lipid peroxidation produces fluorescence, cross-links and borohydride-reducible functions in proteins, but the fluorescence characteristics of the products are not always similar to those in cells and tissues. Other carbonyls that are generated during lipid peroxidation may be responsible for the formation of the damaged proteins in cells and tissues. Modified proteins or the cells that contain the modified proteins may be removed by several mechanisms. These processes of removal may link to certain abnormal disorders so called “free radical disorders”.
The aerobic organisms are protected from oxygen toxicity by an array of defense systems. They are divided into two categories; one is the preventive antioxidants and the other is the chain -breaking antioxidants. Preventive antioxidants reduce the radical formation. Glutathione peroxidase decomposes, without generation of free radicals, lipid hydroperoxides and hydrogen peroxide which are precursors to peroxyl, alkoxyl, hydroperoxyl and hydroxyl radicals. Catalase decomposes hydrogen peroxide. Proteins such as transferrin chelate and deactivate metal ions. On the other hand, the chain-breaking antioxidants such as vitamin E and vitamin C scavenge peroxyl radicals and interrupt the chain oxidation. The antioxidant activity and efficacy are determined not only by its inherent reactivity but also by its local concentration at specific micro-environment where the oxygen toxicity is taking place.
The recent extensive studies have demonstrated that the oxygenated unsaturated fatty acids play the important role in both animal and plant kingdoms. This article reviews the physiological activities of the oxygenated fatty acids, showing that the acids act as defensive substances in the living bodies.
Glycosphingolipids(GSLs), which are amphipathic molecules composed of both hydrophobic and hydrophilic moieties and synthesized by a group of Golgi enzymes, glycosyltransferases, are located almost exclusively on the outer leaflet of plasma membranes of mammalian cells in general, and have become known to show unexpectedly vast molecular heterogeneity due to the recent uncovering of extremely minor constituents by means of remarkable development of analytical methods, which include the immunochemical analyses using monoclonal antibodies highlyprogressed in recent years. Furthermore, GSLs have been considered to be involved in cellular interactions and cell growth regulations, changing characteristically their composition and biosynthesis during cell development, differentiation, and oncogenic transformation although they constitute only a small portion of the cell surface glycoconjugates. In addition, acidic GSLs, gangliosides, have been recently shown to exhibit special receptor-functions for exogenous, bioactive factors such as bacterial toxins, hormones, and interferons. GSLs are classified into three major molecular series, i.e. globo-, lacto-, and ganglio-type, according to their carbohydrate structures, and various cells and tissues have characteristic compositions and structural specificities as to their GSLs. We and other investigators have recently found that human and murine hematopoietic malignant cells show ganglioside profiles characteristic of their cell lineages and differentiation-stages, serving as complemental differentiation-markers for both normal and malignant hematopoietic cells, and further, discovered that particular ganglioside molecules themselves, which specifically increase during differentiation along particular cell lineages induced by a variety of chemical agents, exhibit remarkably potent differentiationinducing and growth-inhibitory activities on human myelog-hous leukemia cells. On the basis of these recent findings, some important biological functions of GSLs, especially sialoglycolipids, will be discussed in special reference to cell differentiation.
Glycolipids are localized on the outer surface of cell membranes, providing recognition sites for various ligands. Glycolipid contents vary according to cell types, and different sugar chain spectra are developed among different cell types. The specific sugar chains are one of phenotypes of differentiated cells, and at the same time they should play some physiological roles. In the first section of this article, possible roles of glycolipids are discussed in relation to membrane functions, such as membrane surface functions, roles in ontogeny and organogenesis, receptor functions, cell growth regulation, and regulation of membrane-bound enzymes. Description about gangliosides is placed in the second section in special relation to neural functions. Since gangliosides are specifically distributed among each membrane and are supposed to play different roles, myelin and synaptic plasma membrane which are two representative membrane systems in the central nervous system are dealt for discussion. Finally, a new trend in the ganglioside researches is briefly mentioned, suggesting possible participation of gangliosides in neuronal membrane plasticity.
It has been widely recognized by in uivo studies that the vitamin A has many physiolosical roles such as on the visual cycle, growth, reproduction, normal development, and the maintenance of some epithelial tissues. However, the mechanisms of those functions at the molecular level are still remained obscure, except on the vision which has been elucidated in some detail. In the past ten years, a variety of vitamin A binding proteins were found in several tissues, and their functions particularly on the roles of transportation system of the vitamin have been studied in animal. Furthermore, the recent topics of great interest were isolations of specific nuclear receptors for retinoic acid from some animal tissues. In this review, the author briefly described the recent advancement of vitamin A researchs.
Vitamin D is metabolized to 25-hydroxyvitamin D (25-OH-D) in the liver and subsequently to 1α, 25-dihydrovitamin D [1, 25-(OH)2D] or 24 R, 25- dihydroxyvitamin D [24, 25-(OH)2D] in the kidney when plasma calcium concentrations are lower or higher than normal (10 mg/ 100 mL). 1, 25-(OH)2D, which is known as an active form of vitamin D, is transported to the target organs, i.e., intestine, bone and others, to show the physiological activity. The most important role of 1, 25-(OH)2D is to keep the calcium homeostasis by accerelating the intestinal calcium absorption and bone remodeling. Recently, it has been clarified that the metabolite has the activity to differentiate myeloid leukemia cells to macrophages. The results suggested that 1, 25-(OH)2D and its modified compounds are available for the differentiation therapy for curing and preventing some kinds of cancer, i.e., myeloid leukemia, skin cancer, colon cancer and others. The metabolite has been also confirmed to be effective for curing the psoriasis.
Vitamin E has been established from the experimental results that unknown substance contained in lettuce prevented fetal reabsorption in rats who fed synthetic diets including the vitamins previously found. Then, the multiplicity of severe pathological reactions that could be obtained in animals when vitamin E was removed from their diets, presents a confusing picture that is difficult to relate to human disorders. Recently, careful clinical studies of individuals with low plasma tocopherol levels together with trials of therapy have clarified the clinical situations and physical features which can be attributed to vitamin E deficiency. There have been three categories in the human vitamin E deficiency : (1) premature infants, (2) fat-malabsorption syndrome, and (3) isolated vitmain E deficient neuropathy. Free radical reactions, ubiquitous in living systems, which are of both enzymatic and non-enzymatic origin, may chemically explain the clinical changes relating to diseases. Biological scavenge systems and substances for protecting the progressive radical chain reactions exist in living systems. Vitamin E as a nutrients for scavenging the chain, may play an important role in maintaining health. In this paper, the scavenging action of vitamin E contained in erythrocyte membranes has been shown as a model, that radical reactants are introduced in biological system. Introduced radicals in erythrocyte membranes were used a xanthine oxidase reaction and an azo compound, AAPH, which are known to produce superoxide anions and hydroperoxides, respectively. In addition, erythrocyte tocopherol levels are shown to be clinically available for the assessment of nutritional status of vitamin E.
Studies on Coenzyme Q (Co Q) have been developed as an intrinsic factor in the mitochondrial respiratory chain. Among electron transfer members in the chain, Co Q is the sole lipid soluble substance and occupies a pivotal position. A mobile quinone model involving Q binding protiens is proposed to explain the topology of Co Q in mitochondrial membranes. HMG Co A reductase inhibitors were used to clarify the role of Co Q in cell biology. When Co Q is administered at pharmacological doses, additional roles as a non-specific antioxidant and membrane stabilizer are considered. The incorporation of Co Q into tissues has been investigated in detail. Clinical applications, particularly in cardiac disorders, have been perfomed successfully.