The Origin of Follicular Bile Acids in the Human Ovary

Nagy, Roland; Hollema, Harry; Andrei, Daniela; Jurdzinski, Angelika; Kuipers, Folkert; Hoek, Annemieke; Tietge, Uwe J. F.

doi:10.1016/j.ajpath.2019.06.011

Cited by 13 publications

(9 citation statements)

References 30 publications

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“…In addition, the activation of FXR induces apoptosis of germ cells by decreasing testosterone synthesis [ 16 ] or suppresses sperm production by maintaining an undifferentiated germ cell pool in an androgen-independent manner [ 17 ]. In females, the roles of BAs on oocyte maturation are still unknown, however effects are suspected [ 18 ]. Though, the deactivation of TGR5 and FXR by UDCA treatment did not improve the low pregnancy rate of the DKO mice.…”

Section: Discussionmentioning

confidence: 99%

Sex-, age-, and organ-dependent improvement of bile acid hydrophobicity by ursodeoxycholic acid treatment: A study using a mouse model with human-like bile acid composition

et al. 2022

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Cyp2a12-/-Cyp2c70-/- double knockout (DKO) mice have a human-like hydrophobic bile acid (BA) composition and show reduced fertility and liver injury. Ursodeoxycholic acid (UDCA) is a hydrophilic and cytoprotective BA used to treat various liver injuries in humans. This study investigated the effects of orally administered UDCA on fertility and liver injury in DKO mice. UDCA treatment prevented abnormal delivery (miscarriage and preterm birth) in pregnant DKO mice, presumably by increasing the hydrophilicity of serum BAs. UDCA also prevented liver damage in six-week-old DKO mice, however liver injury emerged in UDCA-treated 20-week-old female, but not male, DKO mice. In 20-week-old male UDCA-treated DKO mice, conjugated plus unconjugated UDCA proportions in serum, liver, and bile were 71, 64, and 71% of the total BAs, respectively. In contrast, conjugated plus unconjugated UDCA proportions in serum, liver, and bile of females were 56, 34, and 58% of the total BAs, respectively. The UDCA proportion was considerably low in female liver only and was compensated by highly hydrophobic lithocholic acid (LCA). Therefore, UDCA treatment markedly reduced the BA hydrophobicity index in the male liver but not in females. This appears to be why UDCA treatment causes liver injury in 20-week-old female mice. To explore the cause of LCA accumulation in the female liver, we evaluated the hepatic activity of CYP3A11 and SULT2A1, which metabolize LCAs to more hydrophilic BAs. However, there was no evidence to suggest that either enzyme activity was lower in females than in males. As female mice have a larger BA pool than males, excessive loading of LCAs on the hepatic bile salt export pump (BSEP) may be the reason for the hepatic accumulation of LCAs in female DKO mice with prolonged UDCA treatment. Our results suggest that the improvement of BA hydrophobicity in DKO mice by UDCA administration is sex-, age-, and organ-dependent.

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Section: Discussionmentioning

confidence: 99%

Sex-, age-, and organ-dependent improvement of bile acid hydrophobicity by ursodeoxycholic acid treatment: A study using a mouse model with human-like bile acid composition

et al. 2022

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“…It has also been demonstrated that FXR is also expressed in mouse ovarian granulosa cells and that FXR can regulate the function of granulosa cells by acting on target genes such as SHP and FABP6 ( 23 ). Another study discovered that the bile acids can be transported from the blood to the follicular fluid and have an impact on the reproductive system ( 24 ). Schuermann et al ( 25 ) used metabolomics to show that metabolites like bile acids are present in the follicular fluid of cows and suggested that these metabolites may be involved in regulating reproductive performance at different physiological stages in cows.…”

Section: Discussionmentioning

confidence: 99%

Analysis of reproduction-related transcriptomes on pineal-hypothalamic-pituitary-ovarian tissues during estrus and anestrus in Tan sheep

et al. 2022

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Seasonal estrus is an important factor limiting the fertility of some animals such as sheep. Promoting estrus in the anestrus season is one of the major ways in improving the fecundity of seasonally breeding animals. The pineal-hypothalamus-pituitary-ovary (PHPO) axis plays a decisive role in regulating animal reproduction. However, the molecular mechanisms by which the PHPO axis regulates seasonal reproduction in animals are not well understood, especially in Tan sheep. To this end, we collected pineal, hypothalamus, pituitary and ovary tissues from Tan sheep during estrus and anestrus for RNA-Sequencing, and performed bioinformatics analysis on the entire regulatory axis of the pineal-hypothalamic-pituitary-ovary (PHPO). The results showed that 940, 1,638, 750, and 971 DEGs (differentially expressed genes, DEGs) were identified in pineal, hypothalamus, pituitary and ovary, respectively. GO analysis showed that DEGs from PHPO axis-related tissues were mainly enriched in “biological processes” such as transmembrane transport, peptide and amide biosynthesis and DNA synthesis. Meanwhile, KEGG enrichment analysis showed that the bile acid secretion pathway and the neuroactive ligand-receptor interaction pathway were significantly enriched. Additionally, four potential candidate genes related to seasonal reproduction (VEGFA, CDC20, ASPM, and PLCG2) were identified by gene expression profiling and protein-protein interaction (PPI) analysis. These findings will contribute to be better understanding of seasonal reproduction regulation in Tan sheep and will serve as a useful reference for molecular breeding of high fertility Tan sheep.

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“…Moreover, DNA methylation mediates cell responses to physiological endocrine signals, so epigenetic changes produced during development might affect persistently endocrine function (García-Carpizo et al, 2011 ). In addition, BAs also have hormonal actions throughout the body, particularly through the farnesoid X receptor and GPBAR1 (also known as TGR5), playing an important role in the regulation of intrafollicular steroid production (Nagy et al, 2019 ), so the different composition of BAs observed in F1-RES might be partially responsible for the low-progesterone concentration. In any case, two functional categories of genes related to reproduction (e.g., mating and response to estrogens) were significantly enriched in F1-RES lambs.…”

Section: Discussionmentioning

confidence: 99%

The Role of Feed Restriction on DNA Methylation, Feed Efficiency, Metabolome, Biochemical Profile, and Progesterone Patterns in the Female Filial Generation (F1) Obtained From Early Feed Restricted Ewes (F0)

et al. 2021

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Deficient management of replacement animals in the farm during early developmental windows may promote adverse programming effects on reproductive traits and subsequent transmission to the next generation. In this sense, DNA methylation profiles allow researchers to decode epigenetic regulation mechanisms in mammals and identify novel candidate genes correlated with phenotype differences in both dams and offspring. Therefore, improving knowledge in the field of epigenetics and intergenerational effects caused by prenatal and postnatal early nutritional events (e.g., feed restriction) is crucial for refining strategies dedicated to animal breeding. In this study, we determined differences in the global blood methylation patterns, biochemical profile, and metabolome of ewe lambs (F1) born from either early feed restricted dams (F0-RES) or fed ad libitum (F0-ADL). Our data show that functional categories such as those related to cellular processes, phosphorylation, nervous system, immunity response, or reproductive function were enriched significantly in the F1-RES lambs due to differences in the methylation of genes in these categories. These F1-RES lambs did not show differences in feed efficiency during the replacement period but presented higher levels of insulin and triglycerides and reduced concentration of progesterone, whereas the metabolome profile demonstrated variations in the bile acid composition when compared with the F1-ADL lambs. Taken together, all these results suggest that intergenerational effects caused by early feed restriction of dams (F0) may persist in the F1 female lambs with negative consequences on genes involved in cellular processes and reproductive traits.

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The Origin of Follicular Bile Acids in the Human Ovary

Abstract: Number of figures: 6 Number of tables: 1 Short running head: Origin of ovarian follicular bile acids

Cited by 13 publications

References 30 publications

Sex-, age-, and organ-dependent improvement of bile acid hydrophobicity by ursodeoxycholic acid treatment: A study using a mouse model with human-like bile acid composition

Sex-, age-, and organ-dependent improvement of bile acid hydrophobicity by ursodeoxycholic acid treatment: A study using a mouse model with human-like bile acid composition

Analysis of reproduction-related transcriptomes on pineal-hypothalamic-pituitary-ovarian tissues during estrus and anestrus in Tan sheep

The Role of Feed Restriction on DNA Methylation, Feed Efficiency, Metabolome, Biochemical Profile, and Progesterone Patterns in the Female Filial Generation (F1) Obtained From Early Feed Restricted Ewes (F0)

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