Dietary therapy in Japan, practiced in general, to prevent or inhibit the progression of coronary heart disease, is based on a diet for diabetics. Although the nutrient distribution in the usual diabetic diet is such that carbohydrates, proteins and lipids provide 60%, 15% and 25% of the total calories, respectively, the nutrient group that is considered to have the greatest influence on the development of atherosclerosis is lipids. According to large-scale clinical trials in the U.S., etc., the amount of lipid in the diet should be reduced so that it provides less than 25% of the total calories, especially, no more than 7% from saturated fatty acids. However, there is also the view that the problem is not as much related to the amount of lipid intake as to a high body mass index and/or insulin resistance induced by the intake of excessive calories. Furthermore, although it has been reported that lipids, especially saturated fatty acids, have harmful effects in terms of promoting the progression of coronary heart disease, it has become clear from the results of many large-scale clinical trials and meal intervention trials that the effects of saturated fatty acids are influenced by the amounts of monounsaturated and polyunsaturated fatty acids consumed simultaneously. Moreover, it also remains to be resolved whether the data obtained from studies of western populations, whose daily eating habits differ considerably from those of the Japanese people, are applicable to the Japanese people and whether dietary therapy should be fine-tuned to the needs of individual subjects rather than being prescribed uniformly for groups of individuals. It would seem that further original research from Japan is necessary to clarify these issues.

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It is looking forward to making an appropriate dietary fat instead of trans monounsaturated fats from the aspects of physical and physiological points. Animal and human experiments support the view that stearic acid is different from other saturated fatty acids such as 12 : 0, 14 : 0 and 16 : 0, in term of cholesterol metabolism. Such a difference is affected by an amount of ingested energy from linoleic acid, so that it is critical to evaluate the effect of controlled dietary environment on serum cholesterol and atherosclerosis. A beneficial effect of stearic acid was confirmed by the meta analyses from 60 studies in which a ratio of cholesterol to HDL cholesterol was estimated by regression analyses. Although triacylglycerols containing saturated fatty acid at sn-2 position have been considered to be unfavorable to the risk factor for heart diseases, interesterification of shear butter or cocoa butter which is enriched in saturated fatty acid at sn-1 (3) shows rather beneficial properties against postprandial hyperlipidemia and a coagulation factor level. These studies will contribute to develop better structured triacylglycerols instead of trans monounsaturated fats.

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Cholesterol hypothesis implied that reducing the intake of saturated fats and cholesterol while increasing that of polyunsaturated oils is effective in lowering serum cholesterol, and thereby reducing coronary heart disease (CHD). However, long-term dietary interventions based on the cholesterol hypothesis resulted in no significant decreases in serum cholesterol, but brought about significant increases in CHD and/or all-cause mortality rates. Among general populations over 40-50 years of age, the major risk factor for atherosclerosis-related diseases was not hypercholesterolemia but was high n-6/n-3 ratio of dietary and tissue lipids. Recently, social movements to exclude trans-fatty acids from our food environment have been rapidly in progress. As alternative oils, the supply of palm oil and palm kernel oil is increasing. Currently, they occupy 20% of the total plant oils supplied in Japan. However, the safety of palm oil for human nutrition has not been established as it exhibited unusual cancer-promoting activity and survival-shortening activity in rodents. Minor, unidentified components other than triacylglycerol and phytosterols in palm oil as well as in several other vegetable oils are presumed to cause such effects. Compared with these vegetable oils, animal fats are relatively safe, and their consumption is recommended within a range that does not lead to over-nutrition.

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Do saturated fatty acids (SFAs) do harm? Many people think that ingestion of SFAs increases blood cholesterol levels according to Keys' equation, which in turn induces coronary heart disease (CHD). However, at least, a significant relationship between blood cholesterol (or LDL-cholesterol) levels and CHD incidence/mortality in Japanese women has rarely been published. If familial hypercholesterolemia is excluded, there would be no significant results even in Japanese men, either. In case that all-cause mortality is considered, the meaning of cholesterol is the other way around. In our meta-analysis with five reports, mostly dealing with follow-up studies for 5 years, mortality in men decreased as their total blood cholesterol levels increased; in women, high blood cholesterol levels were not a risk factor of all-cause mortality at all. Now we have to reconsider the sequence of SFAs, high blood cholesterol levels and CHD.

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Since saturated fatty acid is believed to increase blood cholesterol and the risk for cardiovascular disease (CVD), low fat and low saturated fatty acids diet has been recommended. However, we need think about the saturated fat intake again since obesity is related to lifestyle-related diseases. Moreover, high carbohydrate diet increases the plasma TG levels. Therefore, it is necessary to reassess and reevaluate the balance between the fat energy ratio and fat quality vs total energy and carbohydrates. Recent study on the effect of dietary composition analyzed using nutrigenomics showed that the effect of diet was more significant by the decrease in total body fat caused by calories restriction, than the direct effect of fatty acids from on tissue. Dietary saturated fatty acid may result in the increase of HDL cholesterol depends on individual subject and dietary composition, which is a merit other than the increase in LDL cholesterol. It implies that the quantity and quality of lipids intake should consider the amount of carbohydrate intake and individual difference.

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Genome analysis has made great progress in our understanding of a large number of diverse and overlapping enzymes and regulators involved in fatty acid metabolism. Although investigation on the regulation of expression and activities of these enzymes has to await further progress, it is becoming possible to consider the effect of dietary saturated and unsaturated fatty acids on whole-body lipid metabolism at the molecular level. Based on this progress, several mechanisms have been proposed to explain how an excess fat impair the cellular functions (so-called lipotoxicity). In this review, we will present and discuss the regulation of fatty acid remodeling system and lipid-droplet formation and their tissue-specific roles in fatty acid-induced lipotoxicity.

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