1. SIRT6 deficiency causes ovarian hypoplasia by affecting Plod1‐related collagen formation.
- Author
-
Li, Liyuan, Hua, Rui, Hu, Kaiqiang, Chen, Huiling, Yin, Yuemiao, Shi, Xiaojin, Peng, Kezheng, Huang, Qing, Qiu, Ying, Li, Xue, Liu, Qingfei, Liu, Shangfeng, and Wang, Zhao
- Subjects
OVARIAN follicle ,SIRTUINS ,OVARIAN reserve ,COLLAGEN ,GRANULOSA cells ,GENE expression ,BIOSYNTHESIS - Abstract
SIRT6 is a key member of the mammalian sirtuin family of conserved nicotinamide adenine dinucleotide (NAD+)‐dependent deacetylases. Previous studies have shown that SIRT6 can regulate metabolism, DNA damage repair and aging. Ovarian aging process usually share similar mechanisms with general aging, which is characterized by decreases in both numbers of ovarian follicles and the quality of oocytes. It is reported that the expression level of SIRT6 was significantly decreased in the ovaries of aged mice, and the level of SIRT6 was positively correlated with ovarian reserve, indicating that SIRT6 may be potential markers of ovarian aging. However, its biological roles in follicular development are still unclear. Here, we explored the effect of SIRT6 on follicular development and found that ovarian development was interrupted in SIRT6 knockout (KO) mice, leading to disruptions of puberty and the estrus cycle, significant decreases in numbers of secondary and antral follicles, and decreased collagen in the ovarian stroma. Plod1, a lysyl hydroxylase that is vital for collagen crosslinking and deposition, was decreased at both the mRNA and protein levels in SIRT6‐deficient ovaries and granulosa cells (GCs). Additionally, we found abnormal estrogen levels in both SIRT6 KO mice and SIRT6 KD GCs, accompanied by decreases in the levels of the estrogen biosynthesis genes Cyp11a1, Cyp19a1, Mgarp, and increases in the levels of TNF‐α and NF‐κB. These results confirmed the effect of SIRT6 on follicular development and revealed a possible molecular mechanism for SIRT6 involvement in follicular development via effects on estrogen biosynthesis and collagen formation. Our study confirmed that SIRT6 was involved in follicular development in mice in a way that SIRT6 deficiency downregulated the expression level of estrogen biosynthesis related genes Cyp11a1, Cyp19a1, Mgarp, and the expression level of collagen formation gene Plod1. And this molecular mechanism caused ovarian hypoplasia, which is characterized by disruptions of puberty and the estrus cycle, significant decreases in numbers of secondary and antral follicles, as well as decreased collagen in the ovarian stroma. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF