Genetic and metabolic determinants of fatty acid chain length and desaturation, their incorporation into lipid classes and their effects on risk of vascular and metabolic disease

Abstract

Chronic fatty acid overload is a major determinant of vascular and metabolic diseases associated with excess western diet and sedentary lifestyle. Beyond the complex traits behind diabetes and obesity (diabesity), a number of rare genetic disorders related to mitochondrial and peroxisomal function and metabolic myopathies directly affect fatty acid metabolism. The detailed molecular analysis of these disorders will provide deeper insight into the genetic and metabolic determinants of lipid metabolism. Fatty acids are either synthesized de novo or taken up as nutrients. The elongation and desaturation of fatty acids follows several distinct pathways regulated by desaturases and elongases. Unsaturated fatty acids are precursors for prostanoid synthesis, which have pro- and anti-inflammatory or -aggregatory and -proliferative effects. Fatty acids are differentially incorporated into acylglycerols, cholesterylesters, glycerophospholipids and sphingolipids, with the latter being major membrane constituents but are also involved in signalling and metabolic regulation. Fatty acid b-oxidation in mitochondria provides energy. Thus, fatty acid metabolism is the result of the complex interaction of synthesis, remodelling and b-oxidation with some minor lipid species being involved in signalling and other regulatory mechanisms.