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Familial adenomatous polyposis (FAP) provides a model for sporadic colorectal cancer development. Cyclooxygenase (COX) inhibition may ameliorate polyp development, but rofecoxib was withdrawn due to cardiovascular side effects. Although this selective COX-2 inhibitor, like diet, may alter the fatty acid and eicosanoid pattern, data on the potential alteration in tissues after use, are scarce. The aims were to study if rofecoxib might influence the fatty acid distribution in serum phospholipids and duodenal lesions, mRNA for COX-1 and COX-2 in leucocytes and duodenal lesions, and finally plasma levels of PGE(2) in a randomized, double-blind, placebo controlled study (n = 38). Significant reductions were found for essential fatty acid index both in serum phospholipids (P = 0.01, 95% CI = -0.9; -0.1), and in duodenal lesions (P = 0.04, 95 CI % = -0.9; -0.1) after treatment. No treatment effects were found on the COX mRNA expression, or in the plasma PGE(2) levels. Dietary AA/EPA ratio was inversely associated with all the indicators of EFA status (all P < 0.01). These findings suggest that the effects of COX chemoprevention should be further investigated in FAP and that dietary needs should be included in the treatment of FAP.

Conjugated linoleic acids (CLAs), tetradecylthioacetic acid (TTA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are all shown to differently affect lipid homeostasis. Additionally, previous studies have shown that introducing a methyl group in the molecule potentiates the hypolipidemic effect of EPA. The objective of this study was to determine how cis9,trans11 CLA, trans10,cis12 CLA, TTA, EPA and DHA affect lipid accumulation in 3T3-L1 adipocytes and in cultured primary rat hepatocytes, and to what extent changes in cis/trans configuration or introducing a methyl group in the molecules influence their way of affecting lipid accumulation in these cells. Our results show that trans10,cis12 CLA is highly specific in preventing lipid accumulation in adipocytes, and that small structural changes in the molecule (changing to trans/trans or introducing an alpha-methyl group) totally abolish this effect and up-regulate the expression levels of adipogenic marker genes towards control levels. Furthermore, all the fatty acids increased hepatic lipid accumulation, whereas the lipid content was normalized after adding an alpha-methyl group into the molecules. Taken together, our data demonstrate that the various fatty acids are highly specialized molecules, and that small structural changes markedly alter their way of affecting lipid accumulation in adipocytes and hepatocytes.

FA with varying chain lengths and an alpha-methyl group and/or a sulfur in the beta-position were tested as peroxisome proliferator-activated receptor (PPAR)alpha, -delta(beta), and -gamma ligands by transient transfection in COS-1 cells using chimeric receptor expression plasmids, containing cDNAs encoding the ligand-binding domain of PPARalpha, -delta, and -gamma. For PPARalpha, an increasing activation was found with increasing chain length of the sulfur-substituted FA up to C14-S acetic acid (tetradecylthioacetic acid = TTA). The derivatives were poor, and nonsignificant, activators of PPARdelta. For PPARgamma, activation increased with increasing chain length up to C16-S acetic acid. A methyl group was introduced in the alpha-position of palmitic acid, TTA, EPA, DHA, cis9,trans11 CLA, and trans10,cis12 CLA. An increased activation of PPARalpha was obtained for the alpha-methyl derivatives compared with the unmethylated FA. This increase also resulted in increased expression of the two PPARalpha target genes acyl-CoA oxidase and liver FA-binding protein for alpha-methyl TTA, alpha-methyl EPA, and alpha-methyl DHA. Decreased or altered metabolism of these derivatives in the cells cannot be excluded. In conclusion, saturated FA with sulfur in the beta-position and increasing carbon chain length from C9-S acetic acid to C14-S acetic acid have increasing effects as activators of PPARalpha and -gamma in transfection assays. Furthermore, alpha-methyl FA derivatives of a saturated natural FA (palmitic acid), a sulfur-substituted FA (TTA), and PUFA (EPA, DHA, c9,t11 CLA, and t10,c12 CLA) are stronger PPARalpha activators than the unmethylated compounds.

Partially hydrogenated fish oil (PHFO) contains a high amount of trans fatty acids (TFA). Total hydrogenation results in a minimal amount of TFA, but a high content of very-long-chain saturated fatty acids (VLCSFA). Absorption and metabolism of VLCSFA from totally hydrogenated fish oil (THFO) were studied in rats. Groups of eight rats were fed one of four diets containing 40 g soyabean oil (SBO)/kg (low-fat diet), 150 g SBO/kg (SBO diet), 40 g PHFO/kg (PHFO diet) or 40 g THFO/kg (THFO diet) for 4 weeks. A lower absorption coefficient of the fat content was found in the THFO group (61 %) compared with the other groups (PHFO 95 %, SBO 99 %, low fat 98 %; which was mainly due to reduced absorption of VLCSFA. A reduced weight gain was found for the THFO group compared with the other groups, but this was only significant when compared with the SBO group Faecal fat excretion (dry weight) was markedly increased in the THFO group (47 %), which was 2.4, 4.8 and 8.3 times higher compared with the groups fed PHFO, SBO and low-fat diets respectively. Serum total cholesterol was reduced for the PHFO and THFO groups whereas serum triacylglycerol was increased for the PHFO group compared with the other groups Animals fed THFO diet had an increased content of 20:0 and 22:0 in the serum triacylglycerol fraction whereas only 20:0 was increased in the serum phospholipid fraction The low absorption coefficient of THFO must be considered if this fat is to be used for consumption by animals or man.

(1) The chemical properties of thia fatty acids are similar to normal fatty acids, but their metabolism (see below: points 2-6) and metabolic effects (see below: points 7-15) differ greatly from these and are dependent upon the position of the sulfur atom. (2) Long-chain thia fatty acids and alkylthioacrylic acids are activated to their CoA esters in endoplasmatic reticulum. (3) 3-Thia fatty acids cannot be beta-oxidized. They are metabolized by extramitochondrial omega-oxidation and sulfur oxidation in the endoplasmatic reticulum followed by peroxisomal beta-oxidation to short sulfoxy dicarboxylic acids. (4) 4-Thia fatty acids are beta-oxidized mainly in mitochondria to alkylthioacryloyl-CoA esters which accumulate and are slowly converted to 2-hydroxy-4-thia acyl-CoA which splits spontaneously to an alkylthiol and malonic acid semialdehyde-CoA ester. The latter presumably is hydrolyzed and metabolized to acetyl-CoA and CO2. (5) Both 3- and 4-thiastearic acid are desaturated to the corresponding thia oleic acids. (6) Long-chain 3- and 4-thia fatty acids are incorporated into phospholipids in vivo, particularly in heart, and in hepatocytes and other cells in culture. (7) Long-chain 3-thia fatty acids change the fatty acid composition of the phospholipids: in heart, the content of n-3 fatty acids increases and n-6 fatty acids decreases. (8) 3-Thia fatty acids increase fatty acid oxidation in liver through inhibition of malonyl-CoA synthesis, activation of CPT I, and induction of CPT-II and enzymes of peroxisomal beta-oxidation. Activation of fatty acid oxidation is the key to the hypolipidemic effect of 3-thia fatty acids. Also other lipid metabolizing enzymes are induced. (9) Fatty acid- and cholesterol synthesis is inhibited in hepatocytes. (10) The nuclear receptors PPAR alpha and RXR alpha are induced by 3-thia fatty acids. (11) The induction of enzymes and of PPAR alpha and RXR alpha are increased by dexamethasone and counteracted by insulin. (12) 4-Thia fatty acids inhibit fatty acid oxidation and induce fatty liver in vivo. The inhibition presumably is explained by accumulation of alkylthioacryloyl-CoA in the mitochondria. This metabolite is a strong inhibitor of CPT-II. (13) Alkylthioacrylic acids inhibits both fatty acid oxidation and esterification. Inhibition of esterification presumably follows accumulation of extramitochondrial alkylthioacryloyl-CoA, an inhibitor of microsomal glycerophosphate acyltransferase. (14) 9-Thia stearate is a strong inhibitor of the delta 9-desaturase in liver and 10-thia stearate of dihydrosterculic acid synthesis in trypanosomes. (15) Some attempts to develop thia fatty acids as drugs are also reviewed.