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OBJECTIVE: Fish oil supplementation may represent a potential chemopreventive agent for reducing colorectal cancer risk. Fish oil’s mechanism of action is unknown but presumed to be related to eicosanoid modification. The purpose of this study was to evaluate the effects of fish oil supplementation on levels of urinary and rectal eicosanoids. METHODS: We conducted a randomized, double-blind, controlled trial of 2.5 grams of fish oil per day compared to olive oil supplementation over a six month period. Study participants had a history of colorectal adenomas. Randomization was stratified based on the gene variant rs174535 in the fatty acid desaturase 1 enzyme (FADS1), which affects tissue levels of arachidonic acid. RESULTS: A total of 141 subjects were randomized. Urinary prostaglandin E(2) metabolite (PGE-M) was measured at baseline, 3 months, and 6 months and rectal prostaglandin E(2) (PGE(2)) at baseline and 6 months. Repeated measures linear regression was used to determine the effect of the intervention on each outcome measure. Overall, fish oil supplementation was found to reduce urinary PGE-M production compared to olive oil (P = 0.03). Fish oil did not reduce rectal PGE(2) overall, however it did significantly reduce PGE(2) in the subgroup of participants not using aspirin or NSAIDs (P=0.04). FADS1 genotype did not seem to modify fish oils effects on PGE(2) production. CONCLUSIONS: We conclude that fish oil supplementation has a modest but beneficial effect on eicosanoids associated with colorectal carcinogenesis, particularly in those not taking aspirin or NSAIDs.

Objective— Acyl-coenzyme A: cholesterol acyltransferase (ACAT) converts intracellular free cholesterol (FC) into cholesteryl esters (CE) for storage in lipid droplets. Recent studies in our laboratory have shown that the deletion of the macrophage ACAT1 gene results in apoptosis and increased atherosclerotic lesion area in the aortas of hyperlipidemic mice. The objective of the current study was to elucidate the mechanism of the increased atherosclerosis. Methods and Results— CE storage and FC efflux were studied in ACAT1 (−/−) peritoneal macrophages that were treated with acetylated low-density lipoprotein (acLDL). Our results show that efflux of cellular cholesterol was reduced by 25% in ACAT1-deficient cells compared with wild-type controls. This decrease occurred despite the upregulated expression of ABCA1, an important mediator of cholesterol efflux. In contrast, ACAT1 deficiency increased efflux of the cholesterol derived from acLDL by 32%. ACAT1-deficient macrophages also showed a 26% increase in the accumulation of FC derived from acLDL, which was associated with a 75% increase in the number of intracellular vesicles. Conclusions— Together, these data show that macrophage ACAT1 influences the efflux of both cellular and lipoprotein-derived cholesterol and propose a pathway for the pro-atherogenic transformation of ACAT1 (−/−) macrophages.