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H4K12 Lactylation-activated c-JUN signaling aggravates bile acid dysfunction in intrahepatic cholestasis during pregnancy

ABSTRACT: The occurrence of hepatic cholestasis during pregnancy is accompanied by the disorders of glucose and lipid metabolism, especially the acceleration of glycolysis. Here, we reported a novel mechanism that the glycolysis metabolic intermediate lactate-induced histone 4 at K12 (H4K12) hyperlactylation aggravates bile acid (BA) dysfunction in intrahepatic cholestasis during pregnancy by activating c-JUN and in turn facilitating RXRɑ cytoplasmic relocalization. Lactylome analysis in livers of late pregnant sows with high levels of BA revealed induction of H4K12 hyperlactylation. Target correction of aberrant histone lactylation prevented the hepatic BA disorders in both sows and mice models. Mechanistically, H4K12la was enriched in promoter regions of c-JUN and activated its expression Moreover, activated c-JUN facilitated the RXRɑ phosphorylation and cytoplasmic relocalization, which resulted in the activation of whole BA synthesis pathway and inhibition of BA transport pathway. Inhibitor of the glycolysis pathway and lactate inhibitor as nutritional intervention ameliorated BA metabolic disorder in pregnant sows and cholestasis in mice. Our findings demonstrate the catalytic role of lactate on hepatic BA disorders in late pregnancy, we also provided a novel pattern of nutritional intervention to precisely target and regulate bile acid metabolism, and may open the new direction of nutritional epigenetic regulation of metabolic diseases.

ORGANISM(S): Sus scrofa

PROVIDER: GSE214238 | GEO | 2023/09/21

REPOSITORIES: GEO

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Project description:Background and Aims - Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for human diseases, but differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70-deficiency in mice. Methods - BA-related parameters, hepatic and intestinal gene expression patterns, liver morphology and intestinal barrier function were assessed in male and female Cyp2c70-/- mice and WT controls at different ages. Effects of ursodeoxycholic acid (UDCA) treatment were evaluated in young adult female mice. Results – Cyp2c70-/- mice were completely devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. BA pool size was unaffected in young-adult male but reduced by 40% in female Cyp2c70-/- mice. Interestingly, plasma BAs and transaminases were highest in Cyp2c70-/- mice at weaning and spontaneously decreased with age. Although bile flow and biliary BA secretion were unchanged in young-adult Cyp2c70-/- mice, indicating absence of cholestasis, plasma BA and transaminase levels were still elevated. These young-adult Cyp2c70-/- mice displayed cholangiocyte proliferation, mild portal fibrosis, altered microbiome composition and increased gut permeability. Only the female Cyp2c70-/- mice developed bridging fibrosis with age (7-8 months). UDCA treatment normalized hepatic and intestinal functions and fully restored liver morphology in female Cyp2c70-/- mice. Conclusion – Cyp2c70-/- mice show transient neonatal cholestasis and develop cholangiopathic features which progress to bridging fibrosis in female mice only. These consequences of Cyp2c70-deficiency are fully restored by treatment with UDCA.

Project description:[Background] DNA methylation plays a crucial role in regulating cell proliferation, differentiation, gene expression, and embryonic development. However, the comprehensive changes in genome-wide DNA methylation during early pregnancy in sows remain unknown. This study aimed to investigate the DNA methylation profiles and to construct an early gene pool of sows during early gestation.[Results] In this investigation, we utilized blood samples from 20 healthy sows and applied Reduced Representation Bisulfite Sequencing (RBSS) technology to systematically examine alterations in DNA methylation in sow blood during early pregnancy. Screening and validating the Methylation differential genes by using bisulfite sequencing PCR (BSP) and Quantitative Real-time PCR (RT-qPCR). Our findings indicated a significant increase in methylation levels on day 28 of pregnancy (pre28) compared to non-pregnancy (ctrl) across various gene elements, including CGI, promoter, and genebody. A total of 64,908 differentially methylated sites (DMCs) and 12,119 differentially methylated regions (DMRs) were identified, predominantly exhibiting methylation upregulation. Randomly selected five differentially methylated genes—VBP1, UPRT (upregulated methylation), RPL10, RAB33A, and CD93 (downregulated methylation)—were validated. Between the pregnant (pre28) and non-pregnant (ctrl) groups the BSP results showed highly significant methylation differences (P<0.01) in VBP1, UPRT, RPL10, and RAB33A. DMC gene ontology (GO) analysis revealed significant enrichment in nuclear receptor activity, negative regulation of cysteine-type endopeptidase activity during apoptosis, heme binding, and hormonal activity. DMRs GO analysis highlighted significant enrichment in 1-acylglycerol-3-phosphate O-acyltransferase activity, regulation of transforming growth factor β receptor signaling pathway, mitochondrial outer membrane and myotubular cell development, and cellular calcium homeostasis. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated significant enrichment in the MAPK signaling pathway and the PI3K-Akt signaling pathway.[Conclusion] During sow early gestation, DNA methylation is significant changes and is mainly upregulated. The observed upregulation of DNA methylation during early gestation in sows may regulate the MAPK and PI3K-Akt signaling pathways, potentially influencing embryonic development. Methylated differential genes VBP1 and RPL10 can be used as potential markers for early sow pregnancy diagnosis. These findings offer novel insights into the epigenetic changes occurring in sows during early gestation.

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H4K12 Lactylation-activated c-JUN signaling aggravates bile acid dysfunction in intrahepatic cholestasis during pregnancy

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