Alpha/Beta Hydrolase Domain-Containing Protein 2 Regulates the Rhythm of Follicular Maturation and Estrous Stages of the Female Reproductive Cycle

Abstract

Mammalian female fertility is defined by a successful and strictly periodic ovarian cycle, which is under the control of gonadotropins and steroid hormones, particularly progesterone and estrogen. The latter two are produced by the ovaries that are engaged in controlled follicular growth, maturation, and release of the eggs, i.e., ovulation. The steroid hormones regulate ovarian cycles via genomic signaling, by altering gene transcription and protein synthesis. However, despite this well-studied mechanism, steroid hormones can also signal via direct, non-genomic action, by binding to their membrane receptors. Here we show, that the recently discovered membrane progesterone receptor α/β hydrolase domain-containing protein 2 (ABHD2) is highly expressed in mammalian ovaries where the protein plays a novel regulatory role in follicle maturation and the sexual cycle of females. Ablation of Abhd2 caused a dysregulation of the estrous cycle rhythm with females showing shortened luteal stages while remaining in the estrus stage for a longer time. Interestingly, the ovaries of Abhd2 knockout (KO) females resemble polycystic ovary morphology (PCOM) with a high number of atretic antral follicles that could be rescued with injection of gonadotropins. Such a procedure also allowed Abhd2 KO females to ovulate a significantly increased number of mature and fertile eggs in comparison with their wild-type littermates. These results suggest a novel regulatory role of ABHD2 as an important factor in non-genomic steroid regulation of the female reproductive cycle.

Lipidomic QTL in Diversity Outbred mice identifies a novel function for α/β hydrolase domain 2 (Abhd2) as an enzyme that metabolizes phosphatidylcholine and cardiolipin

“…To determine if Abhd2 is a key driver of liver phospholipids, we obtained a whole-body knockout of Abhd2 from Dr. Polina Lishko at UC Berkeley [ 23 , 24 ]. Wildtype (WT) and Abhd2 knockout ( Abhd2 KO ) mice were maintained on the same Western diet (WD), high in fat and sucrose, that was provided to DO mice used for the lipidomic genetic screen [ 14 ].…”

“…Abhd2 has been previously characterized as a monoacylglycerol lipase with potent effects on male fertility [ 24 ] and ovulation in female mice [ 23 ]. In sperm, ABHD2 is activated by progesterone and cleaves monoacylglycerols (1-arachadonoylglycerol and 2-arachadonoylglycerol) to remove the inhibition of the CatSper calcium channel, thereby allowing for sperm activation.…”

Lipidomic QTL in Diversity Outbred mice identifies a novel function for α/β hydrolase domain 2 (Abhd2) as an enzyme that metabolizes phosphatidylcholine and cardiolipin

“…Abhd2 has been previously characterized as a monoacylglycerol lipase with potent effects on male fertility[24] and ovulation in female mice[23]. In sperm, Abhd2 is activated by progesterone, cleaves monoacylglycerols (1-arachadonoylglycerol and 2-arachadonoylglycerol) to remove the inhibition of the CatSper calcium channel thereby allowing for sperm activation.…”

Ginsenosides improve reproductive capability of aged female Drosophila through mechanism dependent on ecdysteroid receptor (ECR) and steroid signaling pathway

“…Ovarian function deteriorates as women age, resulting in a lack of steroid hormones and infertility ( 40 , 41 ). Ginsenosides can promote the release of steroid hormones to play an estrogen-like role ( 42 ).…”