Butyrate drives the acetylation of histone H3K9 to activate steroidogenesis through PPARγ and PGC1α pathways in ovarian granulosa cells

Abstract

Maintaining ovarian steroidogenesis is of critical importance, considering that steroid hormones are required for successful establishment and maintenance of pregnancy and proper development of embryos and fetuses. Investigating the mechanism that butyrate modulates the ovarian steroidogenesis is beneficial for understanding the impact of lipid nutrition on steroidogenesis. Herein, we identified that butyrate improved estradiol and progesterone synthesis in rat primary ovarian granulosa cells and human granulosa KGN cells and discovered the related mechanism. Our data indicated that butyrate was sensed by GPR41 and GPR43 in ovarian granulosa cells. Butyrate primarily upregulated the acetylation of histone H3K9 (H3K9ac). Chromatin immune‐precipitation and sequencing (ChIP‐seq) data of H3K9ac revealed the influenced pathways involving in the mitochondrial function (including cellular metabolism and steroidogenesis) and cellular antioxidant capacity. Additionally, increasing H3K9ac by butyrate further stimulated the PPARγ/CD36/StAR pathways to increase ovarian steroidogenesis and activated PGC1α to enhance mitochondrial dynamics and alleviate oxidative damage. The improvement in antioxidant capacity and mitochondrial dynamics by butyrate enhanced ovarian steroidogenesis. Collectively, butyrate triggers histone H3K9ac to activate steroidogenesis through PPARγ and PGC1α pathways in ovarian granulosa cells.

The Combined Use of Medium- and Short-Chain Fatty Acids Improves the Pregnancy Outcomes of Sows by Enhancing Ovarian Steroidogenesis and Endometrial Receptivity

“…These beneficial effects of the combined use of short- and medium-chain fatty acids were confirmed to effectively improve the embryo adhesion efficiency in vitro, and these beneficial effects were not due to differences in fat content but due to the specific types of fatty acid. Our previous data demonstrated that butyrate supplementation in the pregnant diet could not enhance the citrate cycle, and maintained the ATP levels and AMPK signaling, indicating that this level of butyrate supplementation could not influence the energy metabolism [ 56 ]. Our previous data also indicated that dietary butyrate supplementation during pregnancy primarily acted to promote the ovary function [ 25 ].…”

GPR43 regulation of mitochondrial damage to alleviate inflammatory reaction in sepsis

“…Notably, this study showed that GPR43 induced PAK4 and PPARγ protein expressions and suppressed Nox1 protein expression in macrophage by LPS+ATP or mice model of sepsis. Ye et al reported that Butyrate induced GPR43 expression to activate steroidogenesis through PPARγ in ovarian granulosa cells [ 44 ]. Thus, these results suggest that GPR43 is involved in the inactivation of NLRP3 inflammasome in sepsis model by the inhibition of ROS-induced mitochondrial damage via the induction of PPARγ function.…”

Role of functional fatty acids in modulation of reproductive potential in livestock

“…Butyric acid is found to stimulate the synthesis of progesterone and estradiol in porcine ovarian granulosa cells via the cAMP signaling pathway [ 59 ]. Also, our previous research showed that butyrate triggers histone acetylation of histone H3K9 (H3K9ac) to activate steroidogenesis through peroxisome proliferator-activated receptor gamma (PPARγ) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha-like (PGC1α) pathways in ovarian granulosa cells [ 60 ] (Fig. 3 ).…”