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Saturated FFAs, Palmitic Acid and Stearic Acid, Induce Apoptosis in Human Granulosa Cells

Third Department of Internal Medicine (Y.-M.M., T.Y., M.S., C.M., T.O., M.N., K.G., H.N.), Faculty of Medicine, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan; Department of Endocrinology (Y.-M.M.), Chinese PLA General Hospital, Beijing 100853, People’s Republic of China; Division of Internal Medicine (Y.N.), National Kokura Hospital, Kokura-Minami-Ku, Kitakyushu, 802-0803, Japan; Department of Obstetrics and Gynecology (A.T.), Saint Mother Hospital, Kitakyushu City, Fukuoka, 807-0825, Japan; Department of Pediatrics (C.-H.J.), Faculty of Medicine, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan; and Core Research for Evolutional Science and Technology (T.Y., K.G., H.N.), Kawaguchi 332-0012, Japan

Address all correspondence and requests for reprints to: Toshihiko Yanase, M.D., Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: yanase{at}mail.server.med.kyushu-u.ac.jp

Obesity is associated with insulin resistance and some reproductive abnormalities. Circulating FFAs are often elevated in obese subjects and are also closely linked to insulin resistance. In this study, we demonstrated that saturated FFAs, such as palmitic acid and stearic acid, markedly suppressed the granulosa cell survival in a time- and dose-dependent manner. Polyunsaturated FFA, arachidonic acid, had no effect on the cell survival, even at supraphysiological concentrations. The suppressive effect of saturated FFAs on cell survival was caused by apoptosis, as evidenced by DNA ladder formation and annexin V-EGFP/propidium iodide staining of the cells. The apoptotic 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 addition, acylcoenzyme A, pamitoylcoenzyme A, and stearylcoenzyme A markedly suppressed granulosa cell survival, whereas arachidonoylcoenzyme A had no such effect, and this finding was consistent with the effect of the respective FFA form. Surprisingly, arachidonic acid instead showed a protective 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 inhibitor, Bcl-2, and the up-regulation of an apoptosis effector, Bax. These results indicate that saturated FFAs induce apoptosis in human granulosa cells caused by the metabolism of the respective acylcoenzyme A form, and the actual composition of circulating FFAs may thus play a critical role in the apoptotic events of human granulosa cells. These effects of FFAs on granulosa cell survival may be a possible mechanism for reproductive abnormalities, such as amenorrhea, which is frequently observed in obese women.

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