Effects of Perfluorinated Fatty Acids with Different Carbon Chain Length on Fatty Acid Profiles of Hepatic Lipids in Mice

Abstract

A growing body of evidence supporting the key role of fatty acid species in maintaining systemic metabolic homeostasis has been accumulated in recent years. Many studies showed that free fatty acids and a particular molecular species of phosphatidylcholine (PC), palmitoyl-oleoyl-PC, extend molecular effects to cellular homeostasis as lipid signaling molecules through nuclear receptors.1-3) Palmitic acid (16 : 0) and stearic acid (18 : 0) are known to cause endoplasmic reticulum stress, leading to inductions of insulin resistance, and apoptosis of liver cells and pancreatic b-cells. 4-8)Moreover, oleic acid (18 : 1) in a large amount was shown to induce hepatic endoplasmic reticulum stress, resulting in inhibition of very low-density-lipoprotein secretion. 9) 18 : 1 is a major component of triacylglycerol (TG), the accumulation of which causes fatty liver, obesity and muscle insulin resistance. [10][11][12] Recently, palmitoleic acid (16 : 1) was demonstrated to strongly stimulate muscle insulin action and suppress hepatosteatosis.13) Thus, the nature of the fatty acid species is now considered crucial for maintaining homeostasis in organs. Accordingly, it is plausible that xenobiotics affect systemic metabolic homeostasis through changing the fatty acid profile of organs, especially the liver, because the changes that occur in the liver extend to the fatty acid composition of extrahepatic tissues.14) In this context, it is clearly important to accumulate information with respect to the effects of xenobiotics on the fatty acid profile for hepatic lipids.Perfluorinated fatty acids (PFCAs) are straight-chain fatty acid analogues of which all aliphatic hydrogens are substituted with fluorine. Because of their surfactant properties and their chemical and thermal stability, PFCAs are primarily used as industrial materials.15) Since perfluorooctanoic acid (PFOA) accumulates in the environment and in the serum of not only occupationally exposed workers, but also the general population, [16][17][18][19] most research has been focused on the study of the toxicological effects of PFOA, so toxicological information pertaining to PFCAs is limited largely to PFOA. However, PFCAs having shorter perfluoroalkyl chains are candidates of substitutes for PFOA, and PFCAs having longer perfluoroalkyl chains exist in the environment as pollutants. Therefore, more information on the toxicological aspects of PFCAs having shorter or longer perfluoroalkyl chains must be accumulated.The primary target organ of PFCAs is considered to be the liver. 19,20) PFOA was shown to be accumulated in the liver of rats and mice and to cause hepatomegaly, 21) induction of enzymes including peroxisomal acyl-CoA oxidase (AOX) in particular [22][23][24] and accumulation of TG. 24) Our previous studies showed that, although a striking difference exists in the effects of PFCAs on the liver when they are estimated by the induction of AOX as a parameter, the induction of AOX by PFCAs depends on only the number of PFCA molecules, but not the difference in their...

Percentages of oleic acid and arachidonic acid are inversely related in phospholipids of human sera

“…Furthermore, in accordance with this suggestion, Kudo et al [21] observed in mice treated with perfluorinated fatty acids, zenobiotics used as surfactants in various industrial products, that oleic acid was inversely related to arachidonic acid in hepatic phospholipids and total lipids.…”

The inverse association between relative abundances of oleic acid and arachidonic acid is related to alpha -linolenic acid

“…The finding of a negative correlation between OA and AA also in mice treated with perfluorinated fatty acids [25], zenobiotics used as surfactants in various industrial products, would seem in support of the contention that the inverse relationship between this couple of fatty acids exists in many species.…”

Regulation of Connexin-Based Channels by Fatty Acids

“…Research has proven that FAs of different lengths have unique chemical properties (Layden et al, 2013). In fact, perfluorinated FAs (PFFAs), which are FA analogs (Kudo et al, 2011), were shown to inhibit GJCs in a concentration-dependent manner in a liver epithelial cell line due to their aliphatic chains ranging from 7 to 10 carbons. PFFAs, on the other hand, with 2–5 or 16–18 carbon chain lengths had no effect on GJCs (Upham et al, 1998, 2009).…”

“…It is thus possible that PFFAs activate membrane receptors, which in turn activate signaling proteins such as protein kinases (Upham et al, 2009). It should also be considered that PFFAs with a carbon chain between 6 and 9 carbons increase the liver FA profile after 5 days of treatment, with specific increases in palmitoleic acid (PO, 16:1), OA (18:1) and eicosatrienoic acid (20:3) content (Kudo et al, 2011). Consequently, treatment under different exposure times may also induce different effects (e.g., acute vs. chronic treatments).…”