Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide–dependent deacetylase that modifies gene expression through histone deacetylation. It also deacetylates nonhistone substrates, e.g., tumor suppressor p53, NOS3, HIF1A, NFKB, FOXO3a, PGC-1α, and PPARγ . Consequently, it regulates a wide range of physiological functions including cell cycle control, energy expenditure, oxidative stress response, apoptosis, and aging. SIRT1 is expressed in ovarian granulosa cells (GCs) of various species including humans at different stages of the reproductive cycle. The importance of SIRT1 in female reproduction is supported by the findings that SIRT1-knockout mice exhibit defects in reproductive tissue development. These mice were found to have a thin-walled uterus, small ovaries, with follicles present but no corpora lutea. This review aims to provide state-of-the-art information on SIRT1's mode of action and its roles in human granulosa-lutein cells and GCs from other species where data are available. It also discusses the overlapping actions of SIRT1 and human chorionic gonadotropin on the production of critical GC-borne factors.

Summary Sentence

SIRT1 regulates the expression of a battery of genes known to affect angiogenesis, ovulation, and glucose metabolism in human luteinized GCs as well as their survival, most likely in a cAMP-dependent manner.

Graphical Abstract

Illustrative summary depicting the diverse actions of SIRT1 in luteinized human granulosa cells. SIRT1, activated by SRT2104, was previously shown to elevate cAMP levels [21]. Therefore, SIRT1-induced genes are pivotal for ovulation (EREG and PTGS2), angiogenesis (FGF2 and VEGFA), and glucose metabolism (SLC2A1), most likely in a cAMP-dependent manner. SIRT1 activation and the subsequent elevation of cAMP may also promote the reduction of EDN2 and anti-apoptotic proteins BCL-XL and MCL1. This triggers the cleavage and activation of caspase 3. Cleaved caspase 3 then cleaves PARP, consequently leading to apoptosis. One may therefore suggest that SIRT1-induced cAMP is responsible for the coexistence of luteinization and apoptosis in luteinizing GCs. SIRT1 also activates RIPK1 and MLKL proteins, thereby advancing necroptosis. In addition, activation of RIPK1 can also mediate apoptosis by activating caspase 3. The role of RIPK1 in SIRT1-induced apoptosis and necroptosis is manifested by the attenuation of apoptotic and necroptotic proteins by Nec-1. The patterns of FACS-sorted cells further support the role of SIRT1 as an inducer of apoptosis and necroptosis. Ablation of endogenous SIRT1 with siRNA produces opposing actions, thereby corroborating the effects observed with SIRT1 activation. Adapted from [51].