The physical and biochemical properties of trans fatty acids are intermediate between those of saturated fatty acids and cis-unsaturated fatty acids (6,17). The double bond in trans fatty acids is less reactive compared to the double bond in cis-unsaturated fatty acids of comparable chain length (6). Although theoretically trans fats are considered less prone to peroxidation, in a clinical trial in obese men, cis-9,trans-11 conjugated linoleic acid (CLA) has been shown to cause lipid peroxidation, insulin resistance, and production of inflammatory prostanglins (e.g., 8-iso-prostaglandin F_2α and 15-keto-dihydro-prostaglandin F_2α, which reduce noradrenaline release in the stomach and contribute to airway inflammation among other physiologic and pathologic effects) (18). Similar effects have been observed for trans-9, cis-10 CLA (18). Other trans fatty acids have also been associated with an increase in inflammation (2). For instance, several trans fatty acid isomers in the 18:1 and 18:2 configuration occur in high amounts in the human diets and are associated with an increase in circulating concentrations of lipoprotein a (Lp(a)), soluble tumor necrosis factor alpha receptors, high-sensitivity C-reactive protein (hsCRP), and markers of endothelial function such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin (1,2,19). An increase in inflammation due to trans fats could in part explain the observed dyslipidemia associated with consumption of trans fats. Although specific studies linking inflammation to regulation of plasma lipids are lacking, there are a few studies that suggest elevation of inflammation may lead to downregulation of lipoprotein lipase activity (20). This inhibition together with the well-known increase in cholesteryl ester transfer protein (CETP) activity (21), elevated catabolism of apolipoprotein A-I (22), and the known increase in endogenous cholesterol synthesis (23,24) following intake of trans fatty acids may explain the observed increase in fasting lipid concentrations particularly triglycerides (TG), LDL-C, and very low density lipoprotein cholesterol (VLDL-C) and decrease in HDL-C.

Trans fatty acids are very similar to cis-unsaturated fatty acids with regard to enzymes and other metabolic pathways that regulate fat synthesis and conversion to various biochemical by-products. Limited experimental data suggest that trans fats may interfere with de novo synthesis of long-chain polyunsaturated fatty acids (PUFAs) from essential PUFAs such as linoleic acid (25). It has been shown from studies in rats that trans fats reduce the activity of delta-5 and delta-6 desaturases, important enzymes for elongation of essential fatty acids (26). This competition between trans and cis fatty acids for the elongation enzymes and the inhibition of desaturase enzymes by trans fats could in part be a potential mechanism for the elevation of LDL-C and TG and the increased CVD risk attributed to consumption of trans fats. Trans fats, through their effect on desaturase enzymes, may decrease in vivo synthesis of very long chain fatty acids (VCFAs). This could decrease the expected benefit of VCFAs on platelet aggregation and other cardioprotective roles.

Trans fatty acids are rapidly absorbed by the human and animal gastrointestinal tracts and assimilated in membranes of red blood cells, adipocytes, and cells in other tissues where they affect cell membrane fluidity and functioning of membrane receptors (1,17). Whether trans fats also accumulate in lipid droplets of adipocytes is not clear. Because of the long half-life in these tissues, the concentrations of trans fats in red blood cell membranes or adipose tissue are often used as biomarkers for trans fat intake (9,27). In pregnant women, trans fatty acids cross the placenta and enter the fetal circulatory system. Whether the amount of trans fat entering the fetal circulation is proportional to the trans fat content in the maternal adipose tissue is unknown. In animal studies where good data are available, absorption rates for trans fatty acids (93%) are higher than those for saturated fats (86%) of comparable chain length (28). However, trans fat-rich diets seem to be less efficient with regard to energy utilization (28). Whether this implies trans fats are less likely to result in obesity is not known but increase in obesity due to trans fat is unexpected given the low contribution to total energy intake (about 2.6% of energy in the United States).

Mozaffarian et al. (1) and Fernandez and West (23) summarize other less well-known mechanisms of how trans fat may cause dyslipidemia and CVD. These include interaction of trans fats with cell membrane receptors (e.g., toll-like receptor) or nuclear receptors (e.g., nuclear factor kappa beta [NF-κβ], peroxisome proliferator activator receptor gamma [PPAR-γ], sterol regulator element-binding protein-1 [SREBP-1], and liver X-receptor) and cell signaling molecules to adversely affect plasma lipids, inflammation, and probably insulin resistance (29). In summary, the known effects of trans fats on dyslipidemia and CVD cannot be fully explained by the few known mechanisms (e.g., alteration of cell membrane fluidity, reduction of reverse cholesterol transport, and elevation of inflammation), suggesting that there are other unknown mechanisms through which trans fats exert their effects.