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  • Selection of the month br Fibrosis br Liver protection

    2022-08-09

    Selection of the month
    Fibrosis
    Liver protection device
    Non-alcoholic steatohepatitis
    Genetic metabolic liver disease
    Hepatitis C virus (HCV) infection
    Hepatitis B virus (HBV) infection
    Cirrhosis
    Regeneration
    Introduction Upon catalysis by hepatic and bacterial enzymes, cholesterol converts into bile acids (BAs)., In addition, BAs have bacteriostatic effects. Thus, BAs are the intrinsic links that explain how foods, through gut microbiota, affect host metabolism and immunity. Hepatic enzymes generate free primary BAs such as chenodeoxycholic Cladribine (CDCA) and cholic acid (CA). Hepatic conjugation of BAs increases the hydrophilicity of BAs and changes their binding affinity to their receptors. In the gut, bacterial enzyme, i.e., bile salt hydrolase deconjugates BAs. Moreover, bacterial enzyme 7α-dehydroxylase that can be found in Firmicutes converts primary BAs into secondary BAs such as deoxycholic acid (DCA) and lithocholic acid (LCA)., Therefore, host and bacteria jointly produce various BAs, and eubiosis is essential for maintaining BA homeostasis. In contrast, dysregulated BA synthesis accompanied by dysbiosis is implicated in the development of metabolic diseases including obesity, steatosis, steatohepatitis, as well as liver and colon cancer.,5, 6, 7, 8, 9, 10 Free and conjugated primary as well as secondary BAs have differential binding affinities to various receptors including nuclear farnesoid X receptor (FXR) as well as membrane Takeda G protein receptor 5 (TGR5), and sphingosine-1-phosphate receptor 2 (S1PR2). Additionally, pregnane X receptor (PXR), vitamin D receptor (VDR), constitutive androstane receptor (CAR), and cholinergic receptor muscarinic 2 (CHRM2) can be activated by BAs or their precursors and metabolites (Table 1). Thus, BA receptors are essentially endobiotic and xenobiotic sensors. For an organism to adapt to constant environmental change, epigenetic mechanism is used to regulate host response. Epigenetic effects such as acetylation and methylation are ways to switch genes on and off without changing deoxyribonucleic acid (DNA) sequence. Thus, as nutrient and chemical sensors, epigenetic mechanisms should be important for regulating the expression and activity of BA receptors. This review article summarizes epigenetic regulation and post-transcriptional modification of BA receptors. The information is critically important to understand how these receptors are activated or silenced, thereby leading to metabolic or detoxification function or dysfunction. We focus on FXR, TGR5, and S1PR2 since the information available for other receptors in this area is limited. The search was done using combinations of following keywords: FXR, G protein-coupled bile acid receptor, TGR5, S1PR2, acetylation, methylation, glycosylation, epigenetics, and bile acid in the PubMed.
    FXR
    TGR5
    S1PR2 S1PR2 or S1P2 is a G protein-coupled receptor for sphingosine-1-phosphate (S1P). S1PR2 was also found to be the receptor for conjugated BAs such as taurocholic acid (TCA) and taurodeoxycholic acid (TDCA) (Table 1)., S1P is a bioactive lipid mediator that regulates proliferation, immunity, cell trafficking, inflammation, etc., TCA-activated S1PR2 induces the expression and activity of sphingosine kinase (SphK2) to increase the conversion of sphingosine into S1P and leading to increased lipid and sterol metabolism in the liver. Thus, conjugated BAs have a pivotal role Cladribine in S1P singling via SphK2 induction as well as S1PR2. Consistent with these findings, both SphK2 and S1PR2 knockout mice are susceptible to diet-induced fatty liver., It is interesting to note that nuclear S1P, produced by either induction of SphK2 or inhibition of S1Plyase, binds to histone deacetylases (HDAC) 1 and 2, thereby increasing histone acetylation and up-regulating the expression of metabolic genes. Through such HDAC inhibitory mechanism, sphingosine has a role in regulating apoptosis and metabolism. Furthermore, glycochenodeoxycholate (GCDC) via S1PR2 as well as cell entrance have an apoptotic effect in human liver cancer Huh7 cells. These results suggested that S1PR2 activation has a pro-apoptotic effect in GCDC-treated liver cancer cells, but the effect is not simply due to just binding between the GCDC and S1PR2.