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Docosahexaenoic acid (DHA) is a substrate for acyl‐CoA:cholesterol acyltransferase 1 (ACAT1) and inhibits cholesterol ester (CE) formation from oleic acid in MCF‐10A cells

Omega‐3 fatty acids (FA) have beneficial effects in cardiovascular disease and cancer, and excess CE formation is implicated in both diseases. It is thought that oleic acid (OA) is the preferred substrate for ACAT1, while polyunsaturated FAs are substrates for ACAT2. We investigated the kinetics of CE formation from DHA, OA, and the combination in MCF‐10A breast epithelial cells. We previously showed a high expression of ACAT1 in these cells, while ACAT2 expression was very low (ACAT1/ACAT2 mRNA¡Ö2400). We equilibrated the cell cholesterol (C) pool with 3H‐C in serum‐free defined media supplemented with water‐soluble C, and then added the FAs. At the specified time, the cells were collected and washed and the lipids extracted. After separation by TLC, the bands corresponding to free C (FC) and CE were scraped and counted. The percentage of counts in CE/(FC+CE) was analyzed. The rate of CE formation from OA was 4‐fold higher than from DHA. Formation of OA‐CE increased dose‐responsively to added OA from 10 to 100 μM, while DHA‐CE formation peaked at 25 μM. DHA dose‐dependently decreased CE formation when given in combination with OA. Quantitative FA analysis of CEs from cells treated with either or both FAs confirmed that DHA was incorporated into CE, that DHA competitively decreased OA incorporation into CE, and that DHA decreased total CE. These data suggest that DHA is both a substrate and a partial inhibitor of ACAT1.