Roles of polyunsaturated fatty acids, from mediators to membranes

The importance of PUFAs in health and disease gained general attention, as exemplified by the belief that eating more -3 PUFAs is good for health. PUFAs are fatty acids that have two or more double bonds, which can be illustrated as XX:Y-Z (XX, Y, and Z are carbon number, double bond number, and the position of the first double bond from the methyl end, respectively). They cannot be synthesized endogenously in mammals, except for mead acid (20:3-9), which is produced under PUFA deficiency (1). Therefore, PUFAs are essential nutrients that have to be obtained from the diet. While important PUFAs, such as AA (20:4-6) and DHA (22:6-3), can be directly taken up from the diet, they can also be converted from other PUFAs endogenously. The liver has a major contribution in this process, where dietary linoleic acid (LA; 18:2-6) and -linolenic acid (18:3-3) are metabolized into other PUFAs by desaturases, elongases, and peroxisomal -oxidation (2) (Fig. Peroxisomes are critical for the final step of DHA synthesis, and their dysfunction leads to the accumulation of the otherwise minor intermediate PUFA, tetracosahexaenoic acid (24:6-3) (3). Analysis of mice lacking elongases or desaturases revealed PUFA functions in brain, metabolic tissues, reproductive organs, and blood cells (4-13). While some of the phenotypes of these mice were seen only when fed PUFA-deficient diets, others, such as the lean phenotype of Fads1-deficient mice (14), were observed even when the diets were PUFA sufficient (7). This supports the importance of obtaining sufficient levels of Abstract PUFAs, such as AA and DHA, are recognized as important biomolecules, but understanding their precise roles and modes of action remains challenging. PUFAs are precursors for a plethora of signaling lipids, for which knowledge about synthetic pathways and receptors has accumulated. However, due to their extreme diversity and the ambiguity concerning the identity of their cognate receptors, the roles of PUFA-derived signaling lipids require more investigation. In addition, PUFA functions cannot be explained just as lipid mediator precursors because they are also critical for the regulation of membrane biophysical properties. The presence of PUFAs in membrane lipids also affects the functions of transmembrane proteins and peripheral membrane proteins. Although the roles of PUFAs as membrane lipid building blocks were difficult to analyze, the discovery of lysophospholipid acyltransferases (LPLATs), which are critical for their incorporation, advanced our understanding. Recent studies unveiled how LPLATs affect PUFA levels in membrane lipids, and their genetic manipulation became an excellent strategy to study the roles of PUFA-containing lipids. In this review, we will provide an overview of metabolic pathways regulating PUFAs as lipid mediator precursors and membrane components and update recent progress about their functions. Some issues to be solved for future research will also be discussed.-Harayama, T., and