Saturated FFAs, palmitic acid and stearic acid, induce apoptosis in human granulosa cells

Obesity is associated with insulin resistance and some reproductive abnorma lities. Circulating FFAs are often elevated in obese subjects and are also closely linked to insulin resistance. In this study, we demonstrated that s aturated FFAs, such as palmitic acid and stearic acid, markedly suppressed the granulosa cell survival in a time- and dose-dependent manner. Polyunsat urated FTA, arachidonic acid, had no effect on the cell survival, even at s upraphysiological concentrations. The suppressive effect of saturated FFAs on cell survival was caused by apoptosis, as evidenced by DNA ladder format ion and annexin V-EGFP/propidium iodide staining of the cells. The apoptoti c effects of palmitic acid and stearic acid were unrelated to the increase of ceramide generation or nitric oxide production and were also completely blocked by Triacsin C, an inhibitor of acylcoenzyme A synthetase. In additi on, acyleoenzyme A, pamitoyleoenzyme A, and stearylcoenzyme A markedly supp ressed granulosa cell survival, finding was consistent with the effect of t he respective FFA form. Surprisingly, arachidonic acid instead showed a pro tective effect on palmitic acid- and stearic acid-induced cell apoptosis. A Western blot analysis showed the apoptosis of the granulosa cells induced by palmitic acid to be accompanied by the down-regulation of an apoptosis i nhibitor, Bcl-2, and the up-regulation of an apoptosis effector, Bax. These results indicate that saturated FFAs induce apoptosis in human granulosa c ells caused by the metabolism of the respective acyl-coenzyme A form, and t he actual composition of circulating FFAs may thus play a critical role in the apoptotic events of human granulosa cells. These effects of FFAs on gra nulosa cell survival may be a possible mechanism for reproductive abnormali ties, such as amenorrhea, which is frequently observed in obese women.