Curcumin protects against palmitic acid-induced apoptosis via the inhibition of endoplasmic reticulum stress in testicular Leydig cells.

Publisher: BioMed Central Country of Publication: England NLM ID: 101153627 Publication Model: Electronic Cited Medium: Internet ISSN: 1477-7827 (Electronic) Linking ISSN: 14777827 NLM ISO Abbreviation: Reprod Biol Endocrinol Subsets: MEDLINE

Original Publication: London : BioMed Central, 2003-

Apoptosis/*drug effects ; Curcumin/*pharmacology ; Endoplasmic Reticulum Stress/*drug effects ; Leydig Cells/*drug effects ; Palmitic Acid/*pharmacology; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Apoptosis Regulatory Proteins/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Endoplasmic Reticulum Chaperone BiP ; Leydig Cells/cytology ; Leydig Cells/metabolism ; Male ; Mice ; Phenylbutyrates/pharmacology ; Protective Agents/pharmacology ; Rats, Sprague-Dawley ; Testis/cytology

Background: Palmitic acid (PA) is a common saturated fatty acid that induces apoptosis in various types of cells, including testicular Leydig cells. There is evidence suggesting that PA is increased in patients with obesity and that PA-induced cell apoptosis may play an important role in obesity-related male infertility. Curcumin, a natural polyphenol, has been reported to exert cytoprotective effects in various cell types. However, the cytoprotective effect of curcumin against PA-induced apoptosis in Leydig cells remains unknown. Therefore, the current study was performed to investigate the protective effects of curcumin in response to PA-induced toxicity and apoptosis in murine Leydig tumor cell line 1 (MLTC-1) cells and explore the mechanism underlying its anti-apoptotic action.
Methods: MLTC-1 cells were cultured in Roswell Park Institute-1640 medium and divided into five groups. First four groups were treated with 50-400 μM PA, 400 μM PA + 5-40 μM curcumin, 400 μM PA + 500 nM 4-phenylbutyric acid (4-PBA, an endoplasmic reticulum (ER) stress inhibitor), and 500 nM thapsigargin (TG, an ER stress inducer) + 20 μM curcumin, respectively, followed by incubation for 24 h. Effects of PA and/or curcumin on viability, apoptosis, and ER stress in MLTC-1 cells were then determined by cell proliferation assay, flow cytometry, and western blot analysis. The fifth group of MLTC-1 cells was exposed to 400 μM of PA and 5 IU/mL of human chorionic gonadotropin (hCG) for 24 h in the absence and presence of curcumin, followed by measurement of testosterone levels in cell-culture supernatants by enzyme-linked immunosorbent assay (ELISA). Rats fed a high-fat diet (HFD) were treated with or without curcumin for 4 weeks, and the testosterone levels were detected by ELISA.
Results: Exposure to 100-400 μM PA reduced cell viability, activated caspase 3, and enhanced the expression levels of the apoptosis-related protein BCL-2-associated X protein (BAX) and ER stress markers glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP) in MLTC-1 cells. Treating cells with 500 nM 4-PBA significantly attenuated PA-induced cytotoxicity through inhibition of ER stress. Curcumin (20 μM) significantly suppressed PA- or TG-induced decrease in cell viability, caspase 3 activity, and the expression levels of BAX, CHOP, and GRP78. In addition, treating MLTC-1 cells with 20 μM curcumin effectively restored testosterone levels, which were reduced in response to PA exposure. Similarly, curcumin treatment ameliorated the HFD-induced decrease in serum testosterone level in vivo.
Conclusions: The present study suggests that PA induces apoptosis via ER stress and curcumin ameliorates PA-induced apoptosis by inhibiting ER stress in MLTC-1 cells. This study suggests the application of curcumin as a potential therapeutic agent for the treatment of obesity-related male infertility.

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QJH-KY-Z [2018]419 Natural Science Research Project of Education Department of Guizhou Province of China; QJH-KY-Z [2018]420 Natural Science Research Project of Education Department of Guizhou Province of China; qnsyrc201610 Scientific Research Project of Qiannan Normal University for Nationalities; QNSY2018BS018 Scientific Research Project of Qiannan Normal University for Nationalities; qnsyzw1805 Scientific Research Project of Qiannan Normal University for Nationalities; QNKHNZ[2017]21 Qiannan Agricultural Science and Technology Program of Qiannan Science and Technology Bureau; 201568 Research and Innovation Team Foundation of Guizhou Province Education Department; qnsy Key Support Project for Biology in Qiannan Normal University for Nationalities; 31660056 National Natural Science Foundation of China

Keywords: Apoptosis; Curcumin; Endoplasmic reticulum stress; Leydig cell; Palmitic acid

0 (Anti-Inflammatory Agents, Non-Steroidal)
0 (Apoptosis Regulatory Proteins)
0 (Endoplasmic Reticulum Chaperone BiP)
0 (HSPA5 protein, human)
0 (Hspa5 protein, mouse)
0 (Phenylbutyrates)
0 (Protective Agents)
2V16EO95H1 (Palmitic Acid)
7WY7YBI87E (4-phenylbutyric acid)
IT942ZTH98 (Curcumin)

Date Created: 20190902 Date Completed: 20200203 Latest Revision: 20211204

20240104

PMC6717632

10.1186/s12958-019-0517-4

31472681