Retinoic acid enhances ovarian steroidogenesis by regulating granulosa cell proliferation and MESP2/STAR/CYP11A1 pathway

Shuang Cai; Meixia Chen; Bangxin Xue; Zhekun Zhu; Xinyu Wang; Jie Li; Huakai Wang; Xiangzhou Zeng; Shiyan Qiao; Xiangfang Zeng

Journal of Advanced Research (Apr 2024)

Retinoic acid enhances ovarian steroidogenesis by regulating granulosa cell proliferation and MESP2/STAR/CYP11A1 pathway

Shuang Cai,
Meixia Chen,
Bangxin Xue,
Zhekun Zhu,
Xinyu Wang,
Jie Li,
Huakai Wang,
Xiangzhou Zeng,
Shiyan Qiao,
Xiangfang Zeng

Affiliations

Shuang Cai: State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, PR China; Beijing Biofeed Additive Key Laboratory, China Agricultural University, Beijing 100193, PR China
Meixia Chen: State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, PR China; Beijing Biofeed Additive Key Laboratory, China Agricultural University, Beijing 100193, PR China; Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, PR China
Bangxin Xue: State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, PR China; Beijing Biofeed Additive Key Laboratory, China Agricultural University, Beijing 100193, PR China
Zhekun Zhu: State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, PR China; Beijing Biofeed Additive Key Laboratory, China Agricultural University, Beijing 100193, PR China
Xinyu Wang: State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, PR China; Beijing Biofeed Additive Key Laboratory, China Agricultural University, Beijing 100193, PR China
Jie Li: State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, PR China
Huakai Wang: State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, PR China; Beijing Biofeed Additive Key Laboratory, China Agricultural University, Beijing 100193, PR China
Xiangzhou Zeng: State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, PR China; Beijing Biofeed Additive Key Laboratory, China Agricultural University, Beijing 100193, PR China
Shiyan Qiao: State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, PR China; Beijing Biofeed Additive Key Laboratory, China Agricultural University, Beijing 100193, PR China
Xiangfang Zeng: State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, PR China; Beijing Biofeed Additive Key Laboratory, China Agricultural University, Beijing 100193, PR China; Corresponding author.

Journal volume & issue: Vol. 58
pp. 163 – 173

Abstract

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Introduction: Ovarian steroidogenesis not only affects the embryonic development and pregnancy outcome, but also associates with many diseases in mammals and women. Exploring the nutrients and mechanisms influencing ovarian steroidogenesis is critical to maintaining the optimal reproductive performance, as well as guaranteeing body health. Objectives: This research aimed to explore the effect of retinol metabolism on ovarian steroidogenesis and the underlying mechanisms. Methods: Comparative transcriptomic analysis of ovaries from normal and low reproductive performance sows were performed to identify the main causes leading to low fertility. The metabolites regulating steroid hormones synthesis were investigated in ovarian granulosa cells. Gene interference, overexpression, dual-luciferase reporter assays, chromatin immunoprecipitation and transcriptome analysis were further conducted to explore the underlying mechanisms of Aldh1a1 mediating ovarian steroidogenesis. Results: Transcriptome analysis of ovaries from normal and low reproductive performance sows showed the significant differences in both retinol metabolism and steroid hormones synthesis, indicating retinol metabolism probably influenced steroid hormones synthesis. The related metabolite retinoic acid was furtherly proven a highly active and potent substance strengthening estrogen and progesterone synthesis in ovarian granulosa cells. For the first time, we revealed that retinoic acid synthesis in porcine and human ovarian granulosa cells was dominated by Aldh1a1, and required the assistance of Aldh1a2. Importantly, we demonstrated that Aldh1a1 enhanced the proliferation of ovarian granulosa cells by activating PI3K-Akt-hedgehog signaling pathways. In addition, Aldh1a1 regulated the expression of transcription factor MESP2, which targeted the transcription of Star and Cyp11a1 through binding to corresponding promoter regions. Conclusion: Our data identified Aldh1a1 modulates ovarian steroidogenesis through enhancing granulosa cell proliferation and MESP2/STAR/CYP11A1 pathway. These findings provide valuable clues for improving ovarian health in mammals.

Published in Journal of Advanced Research

ISSN: 2090-1232 (Print); 2090-1224 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Science (General)
Website: http://www.journals.elsevier.com/journal-of-advanced-research/

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