脂質栄養学 Vol. 26(2017) No. 1

Docosahexaenoic acid（C22 :6n-3, DHA）plays a special role in biological membrane dynamics, and especially affects human health and various diseases. I try to review the structural significance of DHA in two points, membrane dynamics and oxidative metabolites, to realize the action mechanisms of DHA on health and diseases. It has been believed that polyunsaturated fatty acids, such asarachidonic acid（C20 :4n-6）and DHA, in bio-membranes may increase fluidity ofthe membrane（ “fluidity hypothesis”）and thus modulate mobility of membrane proteins, however, it is proved recently that the fluidity hypothesis is not always true for DHA. It has been shown that DHA could have quite various conformationsunder physiological conditions for free or ester forms, as determined by simulations and X-ray crystallography of DHA-bound proteins, and this high flexibility of DHA conformation may be a key point to realize the action mechanism of DHA-containing phospholipids on membrane dynamics with high resilience andadaptability（ “flexibility hypothesis”）. With this“flexibility hypothesis”, it could be uniformly recognized how DHA is important for rapid membrane dynamics（fission and fusion）, for lipid-receptors interactions, for modulation of lipid raft size, and for regulation of nuclear receptors and expression of genes. The reason why DHA is enriched in retina, brain, testes, and heart, which tissues are all active in membrane dynamics and oxygen metabolism, may be realized with the flexibility hypothesis. The second point, why DHA is metabolized to quite variousoxidative/oxygenative derivatives（docosanoids）, may be realized under the view of whole oxylipin metabolism including eicosanoids. Oxylipin metabolism is recently summarized as oxygenated polyunsaturated fatty acids, however, it may be more rational to categorize“Oxylipin”as oxidative metabolites of lipids widely including terpenoids, to realize the structural resemblance between DHA and retinoids, and the function of medium chain oxygenated fatty acid metabolites. The view of co-regulation in various oxylipin metabolites including docosanoids and eicosanoids may be needed for realizing the fine regulation mechanism of active tissue metabolism and pathophysiology. The structure-based theory of the effect of DHA and its oxidative metabolites on bio-membrane dynamics and lipid-protein interactions may help largely to realize the action-mechanism of DHA on human health and diseases. Key words: docosahexaenoic acid（DHA）, flexibility hypothesis, fluidity hypothesis, membrane dynamics, oxylipin.

Dietary supplementation of omega-3 polyunsaturated fatty acid（PUFA）includingeicosapentaenoic acid（EPA）and docosahexaenoic acid（DHA）is widely held to be beneficial in human health. Also, elevation in omega-3 PUFA levels in omega-3desaturase（ fat-1）transgenic mice that endogenously biosynthesize omega-3 PUFA from omega-6 PUFA exhibits resistance to inflammatory disease models. To elucidate the molecular mechanisms underlying the beneficial effects of omega-3 PUFAs, we developed a comprehensive LC-MS/MS-based lipidomics method that can detect and quantify more than 500 of PUFA metabolites simultaneously. Using this lipidomics system, and genetically modified animals or nutritional control to manipulate fatty acid balance in the body, we try to understand how different balance of omega-3/omega-6 fatty acids and their unique metabolites function in vivo that could explain the biological significance of omega-3 PUFAs in controlling inflammation and related diseases.

Almost all metabolic activities of nutrients　are　under　control　of　the　endocrine　system, and　among　them　the　 adrenocortical　activity is the most typical example that shows circadian rhythmic changes. We examined relationships between the plasma corticosterone rhythm and feeding schedules in rats. The plasma corticosterone rhythm corresponding to feeding time appears regardless of whether the rats were kept on a light-dark cycle, or in constant light or were blinded. Therefore, it can be concluded that food, more than illumination, is a potent trigger of the circadian adrenocortical rhythm in rats. In addition to the experiments in rats, we also investigated roles of feeding schedulesinformation of the adrenocortical rhythm in human subjects. The corticosterone rhythm disappeared when rats were given a liquid diet intravenously, but not orally, suggesting a necessary role of the oro-gastro-intestinal tract. In addition to the studies in rats, influence to feeding schedules on adrenocortical rhythms was also examined in hospitalized human subjects under a normal light-dark cycle. A clear plasma cortisol rhythm was observed in patients who had been fed on a liquid diet into-duodenum during a restricted time of day, suggest that the circadian cortisol rhythm in man is more closely related to feeding rhythms than cycles of light-dark and sleep-wakefulness. As far as we know, this is the first report demonstrating the important of food in entraining human circadian cortisol rhythm. Next, we measured daily rhythm ofbody temperature in hospitalized patients under continuous and cyclic TEN（totalenteral nutrition）. In the diurnal TEN group, body temperature was low at night and early morning and high in the afternoon early evening. In the continuous TEN group, however, body temperature did not show any significant change with clock-time. In conclusion, the timing of diet intake remarkably modifies the circadian rhythm of body temperature and adrenocortical activity in man. We examined relationship between the feeding time of high salt diet intake and urinary excretion of sodium and chloride. The urinary excretion of sodium and chloride were higher in evening than morning and daytime in woman, is more closely related to the circadian plasma aldosterone rhythm. Furthermore, the clock time difference in endocrine and metabolic responses after physical exercise was assessed according to biorhythm. Physical capacity changed to the time of evaluation, and was greater in the evening than in the morning. Among physiological functions that determine was development of physical strength, plasma growth hormone was higher evening exercise than morning exercise. Further studies are needed on this intriguing idea.

The effectiveness and safety of the conventional diabetes treatment is negative in RCT and RCT meta analysis having high reliability. In other words, take carbohydrate commonly and aiming at blood sugar control by medical treatment strictly, the profit is very few and is degree offset by a hypoglycemia risk. After take carbohydrate, always occurs postprandial hyperglycemia and glucose swing, as a results oxidative stress occurs, and it is with the risk of complications. The hypoglycemia risk occurs if doctor give strict medical treatment. They do notproduce with carbohydrate　restriction diet. It was said that American DiabetesAssociation（ADA）did not recommend a carbohydrate　restriction diet until 2007, but accepted it in“Nutrition Therapy Recommendations for the Management of Adults With Diabetes”formally in October, 2013. The brain cardiovascular event outbreak has nothing to do with a saturated fatty acid intake.“There is no risk of the coronary disease in a low carbohydrate high-fat high-protein meal”and “There is no cardiovascular disease risk improvement effect to low lipid food” articles having high reliability of these three conclusions is reported. The long-term safety of the carbohydrate restriction diet maintained the same and was secured. Furthermore, by carbohydrate restriction diet practice, blood sugar level, HbA1c, acylglycerol level, HDL cholesterol level are improved. The LDL cholesterol level often becomes the standard value in the long term, too. In other words, because all the arteriosclerotic risk factors are improved, and so the long-term prognosis of the carbohydrate restriction diet is very likely good.

Diabetes is a disease with insufficient effects of insulin which acts on more than 100 kinds of genes and essential for metabolism of nutrients including carbohydrates, protein and lipids and for normal function of each cell in the body. Generally believed endpoint“control blood glucose level normal”is misleading. True endpoint is to live long by relieving the deficiency of insulin effects for nutrients to be appropriately utilized to maintain normal function of the body and to reduce complications. The outcome of clinical trials must be all-cause mortality because cause-specific mortality or incidence of diseases may miss the adverse effects especially on cancer incidence leading to shortening of overall survival. Insulin but not insulin analog is the only recommended medicine for diabetes tobe used if appropriate energy of carbohydrate restriction diet, moderate exercise and sufficient sleep without sleeping pills were ineffective. Sulfonyl urea（SU）increases insulin secretion by closing K ATP channels in pancreatic β cells but induces secondary failure without proof of prolongation oflife. Biguanide is an inhibitor of mitochondrial chain complex I（a mitochondrialpoison）and open K ATPchannels leading to reduction of insulin secretion（oppositeto SU）and recover the sensitivity to insulin. It may be beneficial for only thosewith 30 or more of BMI. The incretin-related agents（DPP-4 inhibitor and GLP-1 analogue）show carcinogenicity in both animal toxicity studies and clinical trials. The long term prognosis of incretin-related agents and SGLT-2 inhibitors are not proved because of the serious methodological failures.y

Recently, close correlations of cardiovascular disease（CVD）with diabetes and chronic kidney disease have been emphasized although the causal relationshipsremain to be defined. Current nutritional guidelines for the prevention of these diseases issued from authoritative organizations are consistent with those proposedby a group of Harvard University School of Public Health（Harvard-SPH School） that the intakes of saturated and trans fats should be reduced while increasing that of polyunsaturated linoleic acid in order to lower LDL-C/HDL-C ratio and thereby reduce CVD. The Harvard-SPH School was based on epidemiological studies with unavoidable biases, and more reliable RCT studies reported the opposite conclusions; long-term interventions based on the cholesterol hypothesis resulted in increased CVD and all-cause mortality. Moreover, treatments with statins effectively lowered LDL-C/HDL-C ratios but were essentially ineffective in preventing CVD as shown in RCT trials performed after 2004/5, when new regulations on clinical trials came into effect in the EU and US. Alternatively, we revealed pharmacological mechanisms of statins and warfarin to stimulate atherosclerosis and heart failure. Moreover, some types of vegetable oils were shown to share a mechanism common to statins that they inhibit vitamin K2-dependent processes leading to various lifestyle related diseases. Our nutritional recommendations for the prevention of these diseases are, ①increasing the intake of foods with low ω6/ω3 ratios, ② reducing fats and oils with vitamin K2 inhibitory activities, and ③ evaluating animal fats and cholesterol to be beneficial for the prevention of stroke, but not risky for the development of CVD.

Choline was appointed an essential nutrient in 1998 by the National Academy of Science and The dietary reference intake was evaluated scientifically in Nutrients Food and Nutrition Board Institute of Medicine. Choline is trimethyl aminoethanol of a quaternary ammonium ion constituting choline-phosholipids such as sphingomyelin, phosphatidylcholine or Glycerophosphocholine. Choline is a hydrophilic base moiety of the phosholipids building a cell lipid bilayer. Particularly, choline-phosholipids is the construction materials of lipid monolayer giving lipoprotein and a mother's milk fat globule and therefore is a basic material of the lipid nutrition. Choline functions as a precursor for acetylcholine, choline-phosholipids, and methyl donor betaine. The primary criterion used to estimate the adequate intake for choline is the prevention of liver damage as assessed by measuring serum alanine aminotransferase levels. A nutrient lipid-based in these general remarks in our country: We want to suggest the problem to make Choline widely available.