Pathophysiology and Evolutionary Aspects of Dietary Fats and Long-Chain Polyunsaturated Fatty Acids across the Life Cycle

Dietary fat is our second most important energy-producing macronutrient. It also contains fatty acids and vitamins essential for growth, development, and maintenance of good health. Dietary fat quantity and quality have been subject to tremendous change over the past 10,000 years. This has, together with other man-made changes in our environment, caused a conflict with our slowly adapting genome that is implicated in “typically Western” diseases. Rather than reducing our life expectancy, these diseases notably diminish our number of years in health. Important changes in dietary fat quality are the increased intakes of certain saturated fatty acids (SAFA) and linoleic acid (LA), introduction of industrially produced fatty acids, and reduced intakes of ω3 fatty acids, notably alpha-linolenic acid (ALA) from vegetable sources and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish. The pathophysiological effects of these changes are diverse, but are increasingly ascribed to induction of a proinflammatory state that progresses easily to chronic low-grade inflammation. The latter might affect virtually all organs and systems, possibly beginning at conception, and possibly even prior to gametogenesis through epigenetic alterations. Low-grade inflammation might be a common denominator of the metabolic syndrome and its sequelae (e.g., coronary artery disease (CAD), diabetes mellitus type 2, some types of cancer, and pregnancy complications), some psychiatric diseases (e.g., major and postpartum depression, schizophrenia, and autism), and neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease). The long-chain polyunsaturated fatty acids (LCPUFA) arachidonic acid (AA), EPA, and DHA are intimately related to the initiation and resolution of inflammatory responses. The current balance between AA and EPA + DHA is however disturbed by the dominance of AA, which originates from the diet or synthesis from LA. LCPUFA are together with their highly potent metabolites (prostaglandins, thromboxanes, leukotrienes, resolvins, and (neuro)protectins) involved in the functioning of membrane-bound receptors, transporters, ion channels, and enzymes, and also in signal transduction and gene expression. Among their many targets are nuclear receptors which, upon ligation with LCPUFA and their metabolites, function as transcription factors of a variety of genes functioning in many pathways. For instance, the targeted peroxisome proliferators-activated receptors (PPARs) are strategic intermediates in the coordinated expression of proteins with functions in, for example, lipid and glucose homeostasis and inflammatory reactions. Many interventions have been conducted with LCPUFA, especially EPA and DHA, aiming at primary and secondary CAD preventions, improvement of fetal and newborn (brain) development by supplementation during pregnancy or early postnatal life, and in psychiatric diseases. Consensus has been reached that those in CAD and depression are positive, although more large-scale trials are needed. Many recommendations for the intakes of saturated fat, fat and EPA + DHA have been issued, notably for CAD prevention, and also for EPA + DHA intakes by pregnant women and for AA, EPA, and DHA intakes by newborns. The ultimate goal might, however, be to return to the fat quality of our ancient diet on which our genes have evolved during the past million years of evolution, while this actually applies for our entire dietary composition and lifestyle, as translated to the culture of the current society.