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

Abstract 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 su...

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Published inEndocrinology (Philadelphia) Vol. 142; no. 8; pp. 3590 - 3597
Main Authors Mu, Yi-Ming, Yanase, Toshihiko, Nishi, Yoshihiro, Tanaka, Atsushi, Saito, Masayuki, Jin, Cheng-Hao, Mukasa, Chizu, Okabe, Taijiro, Nomura, Masatoshi, Goto, Kiminobu, Nawata, Hajime
Format Journal Article
LanguageEnglish
Published United States Oxford University Press 01.08.2001
Subjects
Online AccessGet full text
ISSN0013-7227
1945-7170
DOI10.1210/endo.142.8.8293

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Abstract Abstract 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.
AbstractList 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.
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.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.
Abstract 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.
Author Saito, Masayuki
Okabe, Taijiro
Nawata, Hajime
Jin, Cheng-Hao
Yanase, Toshihiko
Nomura, Masatoshi
Mukasa, Chizu
Mu, Yi-Ming
Nishi, Yoshihiro
Tanaka, Atsushi
Goto, Kiminobu
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  givenname: Yi-Ming
  surname: Mu
  fullname: Mu, Yi-Ming
  organization: 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
– sequence: 2
  givenname: Toshihiko
  surname: Yanase
  fullname: Yanase, Toshihiko
  email: yanase@mail.server.med.kyushu-u.ac.jp.
  organization: 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
– sequence: 3
  givenname: Yoshihiro
  surname: Nishi
  fullname: Nishi, Yoshihiro
  organization: Division of Internal Medicine (Y.N.), National Kokura Hospital, Kokura-Minami-Ku, Kitakyushu, 802-0803, Japan
– sequence: 4
  givenname: Atsushi
  surname: Tanaka
  fullname: Tanaka, Atsushi
  organization: Department of Obstetrics and Gynecology (A.T.), Saint Mother Hospital, Kitakyushu City, Fukuoka, 807-0825, Japan
– sequence: 5
  givenname: Masayuki
  surname: Saito
  fullname: Saito, Masayuki
  organization: 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
– sequence: 6
  givenname: Cheng-Hao
  surname: Jin
  fullname: Jin, Cheng-Hao
  organization: Department of Pediatrics (C.-H.J.), Faculty of Medicine, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
– sequence: 7
  givenname: Chizu
  surname: Mukasa
  fullname: Mukasa, Chizu
  organization: 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
– sequence: 8
  givenname: Taijiro
  surname: Okabe
  fullname: Okabe, Taijiro
  organization: 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
– sequence: 9
  givenname: Masatoshi
  surname: Nomura
  fullname: Nomura, Masatoshi
  organization: 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
– sequence: 10
  givenname: Kiminobu
  surname: Goto
  fullname: Goto, Kiminobu
  organization: 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
– sequence: 11
  givenname: Hajime
  surname: Nawata
  fullname: Nawata, Hajime
  organization: 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
BackLink https://www.ncbi.nlm.nih.gov/pubmed/11459807$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright Copyright © 2001 by The Endocrine Society 2001
Copyright © 2001 by The Endocrine Society
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Snippet Abstract Obesity is associated with insulin resistance and some reproductive abnormalities. Circulating FFAs are often elevated in obese subjects and are also...
Obesity is associated with insulin resistance and some reproductive abnormalities. Circulating FFAs are often elevated in obese subjects and are also closely...
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SubjectTerms Abnormalities
Acid resistance
Acids
Acyl Coenzyme A - antagonists & inhibitors
Amenorrhea
Annexin V
Apoptosis
Apoptosis - drug effects
Apoptosis - physiology
Arachidonic acid
Arachidonic Acid - pharmacology
BAX protein
Bcl-2 protein
bcl-2-Associated X Protein
Cell survival
Cell Survival - drug effects
Cells, Cultured
Ceramides - biosynthesis
Composition effects
DNA Fragmentation - drug effects
DNA Fragmentation - physiology
Dose-Response Relationship, Drug
Effector cells
Enzyme Inhibitors - pharmacology
Female
Granulosa cells
Granulosa Cells - drug effects
Granulosa Cells - physiology
Humans
Insulin
Insulin resistance
Iodides
Nitric oxide
Nitric Oxide - biosynthesis
Obesity
Palmitic acid
Palmitic Acid - pharmacology
Propidium iodide
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors
Stearic acid
Stearic Acids - pharmacology
Survival
Title Saturated FFAs, Palmitic Acid and Stearic Acid, Induce Apoptosis in Human Granulosa Cells
URI https://www.ncbi.nlm.nih.gov/pubmed/11459807
https://www.proquest.com/docview/3130554138
https://www.proquest.com/docview/71030624
Volume 142
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