Lifestyle diseases such as cancer, heart disease, cerebrovascular disease, are the three leading causes of death among the Japanese, and the prevention of lifestyle diseases is an important issue in Japan. Daily high energy intake and high fat diet are involved in the onset of lifestyle diseases, and nutritional therapy is important for the prevention of lifestyle diseases. Nutritional therapy for lifestyle diseases is based on scientific data which is important to be established. The authors found that lipid nutrition for insulin resistance and non-alcoholic fatty liver disease （NAFLD） from the association of physical measurement, clinical data, nutrient intake and plasma fatty acid composition. As a result, it was suggested that the low levels of n-3 Polyunsaturated Fatty Acids （n-3 PUFA） in plasma phospholipid may be related to insulin resistance, and the decrease in n-3 PUFA intake was also involved in the rise in n-6/n-3 ratio. It was also suggested that increasing NAFLD Score not only reduces energy intake, but also increases fish and n-3 PUFA intakes. The clarification that n-3 PUFA intakes of eicosapentaenoic acid and docosahexaenoic acid is involved in the prevention and improvement of lifestyle related diseases in elucidating the nutritional therapy of lipids in lifestyle related diseases has revealed the importance of lipid nutrition in lifestyle related diseases. It is thought that it contributes to the establishment of nutritional therapy of lipid.

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Arachidonic acid　（ARA） and docosahexaenoic acid　（DHA） are the principal n-6 and n-3 polyunsaturated fatty acids （PUFAs） in the brain, respectively, and essential for proper brain development. Previous in vitro studies have revealed that ARA induces astrocytic differentiation of neural stem cells （NSCs）， and that DHA induces neuronal differentiation of NSCs. Thus, n-6 and n-3 PUFAs have different roles in brain development. Regarding the evaluation of in vivo roles of these PUFAs, the balance of n-6/n-3 PUFAs is considered to be important because these PUFAs compete each other in their synthesis, metabolism, and transport. Indeed, we have reported neurodevelopmental consequences of maternal consumption of an n-6-rich/n-3-poor diet in mice. We found that epoxy metabolites of ARA and DHA oppositely regulated the neurogenic-to-gliogenic fate transition of NSCs, and consequently they affected brain development. These findings are scientifically and socially important, because intake of seed oils, which are abundant in n-6 PUFAs, and that of fishes, which are abundant in n-3 PUFAs, have recently been increased and decreased, respectively, in many countries. In another study from our collaborators, a mouse model for schizophrenia has been proposed based on phenotypes of offspring derived from pregnant mice fed a PUFA-deficient diet. In the present review, we summarize the functions of dietary n-6 and n-3 PUFAs in brain development.

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The Japan Atherosclerosis Society Guidelines for the Prevention of Atherosclerotic Cardiovascular Diseases （JASGL） were based on “the lower, the better” hypothesis. However, we published Cholesterol Guidelines for Longevity 2010 based on the fact that cholesterol levels are inversely associated with all-cause mortality among general populations aged at 40 years and over. Here, we summarized the mechanisms of atherogenesis caused by statins and some types of vegetable oils with strokestimulating activity in the rat; they inhibit the VK1-VK2- osteocalcin target organs link, leading to artery calcification and lifestyle-related diseases. The mainstay of JASGL 2017 is the Suita study published in 2014, which is much smaller than the previous epidemiological study, NIPPONDATA 80, for JASGL 2012. Besides, the total and cardiovascular mortality of the study has not been published yet. We found some terrible mathematical errors that cannot be simple calculation mistakes. For example, deleting some study subjects actually increased the number of male participants instead. It is likely that no consistent epidemiological studies are available any more to JAS to protect their cholesterol hypothesis. JASGL 2017 calculated risk of coronary artery disease （CAD） in Japan where the incidence is very low. Then the story was fabricated to protect their notion that even the group with a very low risk in the world standard was classified as middle to high risk groups of CAD, which can lead to unnecessary medication. The GLs are disguised as those based on the cholesterol hypothesis; actually it became very clear that they are simply selling tools for statins.

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An open-label, randomized controlled trial in type 2 diabetics with hypertension, dyslipidemia, or both was reported （J-DOIT3 study）．The participants were randomly assigned to receive conventional or intensive therapy with respect to HbA1c, blood pressure and LDL-C （n=1,271 in each group），and were followed for 8.5 years at 81 clinical sites. Both the participants and doctors in charge were aware of the group assigned. The experimental design was essentially as recommended in the [Comprehensive risk management chart for the prevention of cerebro- and cardiovascular diseases 2015] from the Joint Committee consisted of 13 internal medicine-related societies in Japan, and the Japan Atherosclerotic Society Guidelines 2017. Therefore, the conclusion from the J-DOIT3 study is expected in medical field to affect the current and future medications for the prevention of atherosclerotic cerebro- and cardiovascular diseases （ASCVD）．While analyzing the results of this study，we encountered serious problems associated with the methodology, logics and its interpretations, which were summarized in this review. The follow-up study appears to be in progress as described in the Discussion, but we interpret that the intensive therapy used in the J-DOIT3 study is risky in view of currently available evidence. We propose the authors of the study to let the participants know of the results on its objective endpoint, and newly obtain Informed Consents including the potential risks of the intensive intervention based on the progress in this field after the start of this study.

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A nationwide multicenter randomized controlled study （JDCS） was performed in type-2 diabetes patients. The conventional （CON） group received usual care including anti-diabetic, anti-hypertensive and anti-hyperlipidemic agents to maintain their targeted levels, and the intervention （INT） group additionally received intensive education on lifestyle modifications and adherence to treatment by telephone counselling and at each time outpatient clinic visit for 8 years. The JDCS appears to be based on an assumption that usual treatment of diabetes is appropriate for the prevention of diabetes complications, and that the lack of patients’ compliance is the major cause of unsuccessful treatments. No significant differences between the two groups were found in most of the test results （BMI, blood pressure, fasting glucose level, TC, HDL, lipoprotein-a）, use of agents, life style （energy intake, smoking and alcohol intake） at 4 years of intervention. The exercise level was higher at 5 years of intervention, and triglyceride level was lower at 8 years. The incidence of coronary heart disease, retinopathy and neuropathy did not differ significantly between the two groups, but stroke incidence was lower in the INT group. We conducted new analyses on the changes of some explanatory variables in each group. The proportion of participants with pharmacological treatment including insulin significantly increased in both groups except sulfonylureas which about 60% of the participants used at the baseline. On the other hand, those without pharmacological treatment decreased from 19% to 4% in both groups. These indicate that both groups failed in diabetes treatment together. As for the exercise and the smoking cessation, these may prevent stroke, but do not contribute to improvement of diabetes. It is not convincing enough for us to support the validity of publicizing the treatment of diabetes patients used in the JDCS study performed at 59 universities and general hospitals in Japan.

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