According to the Vital Statistics Report published by the Japanese Ministry of Health and Welfare, heat disease and cerebrovascular disease are the main causes of death in Japan in addition to cancer. The main pathological finding in heart and cerebrovascular disease is atherosclerosis and the main risk factors, besides the patient's age and diathesis, include hyperlipidemia, hypertension, diabetes, obesity and smoking. The main pathological findings in atherosclerosis include abnormal reactions of neutrophils, lymphocytes and monocytes/macrophages, vascular smooth muscle cells and vascular endothelial cells, and the accumulation of cholesterol ester in the arterial wall, which are prevent by lowering the serum total cholesterol (TC) levels. An increasing number of large-scale intervention studies have reported beneficial results of drug treatment (clofibrate, fenofibrate, bezafibrate, niacin, cholestiramine, gemfibrozil) on lipoprotein abnormalities. Their findings have also revealed that statins (simvastatin, pravastatin, lovastatin, fluvastatin, atorvastatin and rosuvastatin) are effective in preventing coronary artery disease. However, these results indicate that lowering TC levels by 25-30% prevents only about 30% of cardiovascular events. Thus, 70% of cardiovascular events are still not prevented, and it is important to find out how to treat such patients. In addition, it remains to be determined which risk factors for atherosclerosis other than high TC levels (such as hypertension, diabetes, obesity, smoking, high serum triglyceride (TG) levels and hypo-HDL-cholesterolemia) warrant the highest priority for treatment in Japan. Eventually, these all risk factors for atherosclerosis other than high TC levels are associated with the excessive uptake of fatty acids into liver. Recently, we have shown that the clock gene, CLOCK:BMAL1 regulated the peroxisome proliferator-activated receptor (PPAR) gene. PPAR is a member of the steroid/thyroid-hormone receptor superfamily. Their ligands were fatty acids, the extents of which were greater in polyunsaturated fatty acids. Here, based on recent studies including our own, we describe the relationships between fatty acids, especially clock gene and PPARs in the molecular mechanisms that govern lipid metabolism in the arteries.

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Rats fed n-3 fatty acid deficient diet through two generations exhibit decreased correct response ratios in a brightness-discrimination learning test. This is associated with a decreased docosahexaenoic acid (DHA) to arachidonic acid (AA) ratio in brain lipids. The altered learning behavior associated with a long-term n-3 deficiency was reversed by supplementing DHA after weaning only when the levels of competing n-6 fatty acids in the diet and brain lipids are limited. Endocannabinoid 2-arachidonoylglycerol (2-AG) levels were significantly elevated in the brain of n-3 deficient rats. We evaluated the effect of cannabinoid receptor CB1 antagonist SR141716A (SR) on the learning behavior. SR did not ameliorate the decreased learning performance in the n-3 deficient rats. However, the increased locomotor activity by n-3 deficiency was suppressed by SR. Therefore, the altered behavior is associated with, at least in part, the endocannabinoid signaling. We also found the decreased nerve growth factor (NGF) content and the increased level of the activated form of calmodulin kinase II in the hippocampus of n-3 deficient rats. DHA has an essential role in biomembrane structure and functions, which affect the cellular signaling related to learning behavior.

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Since the enantiomer resolution of synthetic mono- and diacylglycerols as 3,5-dinitrophenylurethanes was achieved by chiral-phase high-performance liquid chromatography (HPLC) in the 1980s, the methodology has been extended to the resolution of various synthetic and naturally occurring chiral glycerolipids. The recent development of polysaccharide-based chiral stationary phases along with optimized chromatographic elution conditions has permitted direct enantiomer resolution of mono-, di-, and triacylglycerols without previous derivatization. However, there are still some compounds for which enantiomer resolution is difficult to achieve, such as phosphatidylcholine and phosphatidylethanolamine. With the development of new derivatization reagents and chromatographic techniques, resolution of these difficult compounds may be possible in the near future. Chiral-phase HPLC will become considerably important in the future as a valuable tool for further expansion of the field of lipidomics and a better understanding of lipid metabolism.

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Dietary carotenoids have attracted much attention because of their antioxidant activities and other biological activities including anti-cancer, anti-allergic, and anti-obese actions. Although no less than forty carotenoids are ingested under usual dietary habits, only six carotenoids and their possible metabolites have been found in human tissues, suggesting selectivity in the intestinal absorption of carotenoids. Recently, facilitated diffusion in addition to simple diffusion has been reported to mediate the intestinal absorption of carotenoids in mammals. The selective absorption of carotenoids may be caused by the uptake to the intestinal epithelia by the facilitated diffusion and an unknown excretion to intestinal lumen. This paper reviews the absorption of carotenoids by introducing recent advances in this field.

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Novel fatty acids originated from the vent bivalves, such as vent clam Calyptogena phaseoliformis and vent mussels Bathymodiolus platifrons and Bathymodiolus japonicus collected from hydrothermal vents in the deep-sea, were determined by using gas chromatography-mass spectrometry analysis of the 4,4-dimethyloxazoline derivatives. The major fatty acids present in the C. phaseoliformis lipids belong to the n-4 family non-methylene interrupted polyunsaturated fatty acids (NMI-PUFA): 20:3n-4,7,15, 20:4n-1,4,7,15, and 21:3n-4,7,16, while two Bathymodiolus mussels contained high levels of methylene interrupted PUFA: 20:3n-4,7,10, 20:4n-1,4,7,10, and 21:3n-4,7,10. The vent bivalves probably have an intrinsic mechanism in vivo so as to maintain the fluidity of the high-melting fatty acids in the membrane lipids by exogenous n-4 family PUFA adaptation as substitutes. Such special kinds of fatty acids are assimilated by the symbiotic chemosynthetic bacteria, which use geothermal energy and minerals from the cold-seep vents. Their unique fatty acid compositions corresponding to the novel n-4 family PUFA markedly differs from those of the reported lipid compositions of other marine animals, which depend on the marine grazing food chain originating from phytoplankton. The present findings confirm a perfect and closed novel food chain in the cold-seep bivalves and in their symbionts, which are independent from the photosynthetic food chain.

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Nutrigenomics is a coined word created from nutrition and genomics. This new research area has been developed to investigate how nutritional components affect all metabolic pathways and homeostasis in organisms, and which genomic types are susceptible to specific nutrients. DNA microarray is a typical nutrigenomics tool for analyzing comprehensive metabolic condition of organism in the level of gene expression. We can obtain huge amount of information suggesting wide functionality of food components from microarray analysis. However, appropriate statistic analyses are required to understand the true meaning of the data. The versatility of DNA microarray analysis may be applicable to measurement of functionality of whole foods as well as food components, although it is difficult to speculate the functionality of the food from the functionalities of the individual food components. Here, we tried to elucidate the functionality of dietary freeze-dried tofu by comparing the functionality of soy protein and isoflavone in rats by DNA microarray analysis. The findings from the experiment suggested that the protein, and not isoflavone, fraction of freeze-dried tofu reduced lipogenesis in liver through gene expression, and that this may result in lower serum lipid levels.

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The eyes are rich in long-chain polyunsaturated fatty acids (LC-PUFAs) such as arachidonic acid (AA; 20:4omega6) and docosahexaenoic acid (DHA; 22:6omega3). Despite their abundance in the eyes, AA and DHA cannot be efficiently synthesized de novo in mammals. During gestation, eye development is exceptionally rapid, and substantial amounts of LC-PUFAs are needed to ensure proper eye development. Here, we studied the influences of dietary LC-PUFAs in dams (C57BL/6 and C3H/He) on the eye morphogenesis and organogenesis of their pups. Intriguingly, fetuses and newborn mice from C57BL/6 dams fed an LC-PUFA (particularly AA)-enriched diet displayed a much higher incidence of eye abnormalities such as microphthalmia (small eye) and corneal opacity than those from dams fed an LC-PUFA-poor diet. The effects of LC-PUFAs on eye anomalies were evident only in the female pups of C57BL/6 inbred mice, not in those of C3H/He mice or male C57BL/6 mice. These results demonstrate a gene-by-environment (GxE) interaction in eye development in mice. Furthermore, our molecular analysis suggested the potential roles of Pitx3 and Pax6 in the above interaction involving AA.

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Almost all Japanese epidemiological studies showed that all-cause mortality was lower in subjects with high serum total or LDL-cholesterol levels. Studies showing the disadvantage of high cholesterol levels included or were likely to include more participants with FH than in the general Japanese population. This also explains why epidemiological studies with elderly people are not able to detect any disadvantage of high cholesterol levels; groups of elderly subjects contain a smaller proportion of vulnerable FH patients who die earlier than those without FH. Meta-analyses of the effects of statins were used to indicate the favorable effects of these drugs, which might be considered as proof that cholesterol has unfavorable effects. However, the absolute effect size of statins on all-cause mortality is rather small, if any. Moreover, studies included in meta-analyses of statins were performed before the new clinical research regulation came into effect in 2005-2006 in the EU, which required clinical trial results to be published even if the data were not favorable for the tested drugs (BJOG 2007; 114: 917, http://www.bjog.org/view/0/index.html). Considering the fact that placebo-controlled clinical trials performed after the new regulation were mostly negative (J Lipid Nutr 2010; 19: 65, http://www.jstage.jst.go.jp/article/jln/19/1/65/_pdf/-char/ja/), the results published before the regulation were questionable and should not be used as the basis for recommendations for treatment with cholesterol-lowering medications. Because the relative risks of high cholesterol for CHD vary from <1 to >5, administering cholesterol-lowering medications to all Japanese individuals equally is not rational; at least women and elderly men need to be carefully re-examined because no or little positive associations between plasma cholesterol and CHD mortality rates have been reported in these groups.

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ファルマシアの2011年６月号に上島弘嗣氏の話題１）が掲載されており、我々の「コレステロールは高いほうが長生きする」の理論の“誤り”について解説している（引用符号は筆者らによる）．小論では、上島氏の指摘に関し、その問題点を取り上げ，反論する．なお、小論は本来2011年に発表すべく努力してきたが、ファルマシアが掲載を認めなかったため、発表が遅れた。

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International epidemiologic data revealed that intake of n-3 polyunsaturated fatty acids (n-3PUFA) from fish is associated with reduced prevalence of depression. Several studies demonstrate that patients with depression have significantly low serum level of n-3PUFA. There are many reports that treatment of depression patients with n-3PUFA is effective. However, there are few studies on the correlation of serum n-3PUFA level and symptoms among Japanese patient with depression. Therefore, in this study, we examined the serum levels and intakes of fatty acids in 89 patients with depression to correlate serum fatty acid and anxiety symptoms of depression, and the difference between depressive disorder and bipolar disorder. In conclusion, saturated fatty acid and n-3PUFA in patients with bipolar disorder were lower than those in patients with major depressive disorder, but monounsaturated fatty acids and n-6/n-3 ratio in the former were higher than those in the latter. We also found a significant correlation between n-6/n-3 ratio and anxiety symptoms only in patients with bipolar disorder.

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