bims-liverm Biomed News
on Liver Metabolism
Issue of 2023–06–18
seven papers selected by
  1. Chronic Arsenic Exposure Perturbs Gut Microbiota and Bile Acid Homeostasis in Mice.
  2. Roles of bile acids signaling in neuromodulation under physiological and pathological conditions.
  3. Bile Acids in Cardiovascular Diseases: Don't Forget Hyocholic Acid.
  4. Saikosaponins regulate bile acid excretion in mice liver and ileum by activating farnesoid X receptor and bile acid transporter.
  5. The Placenta-A New Source of Bile Acids during Healthy Pregnancy? First Results of a Gene Expression Study in Humans and Mice.
  6. Effect of gut flora mediated-bile acid metabolism on intestinal immune microenvironment.
  7. Alternative pathway of bile acid biosynthesis contributes to ameliorate NASH after induction of NAMPT/NAD+/SIRT1 axis.
  1. Chem Res Toxicol. 2023 Jun 09.
    Chronic Arsenic Exposure Perturbs Gut Microbiota and Bile Acid Homeostasis in Mice.
    Yifei Yang, Liang Chi, Chih-Wei Liu, Yun-Chung Hsiao, Kun Lu.
      Arsenic exposure can perturb gut microbiota and their metabolic functions. We exposed C57BL/6 mice to 1 ppm arsenic in drinking water and investigated whether arsenic exposure affects the homeostasis of bile acids, a group of key microbiome-regulated signaling molecules of microbiome-host interactions. We found that arsenic exposure differentially changed major unconjugated primary bile acids and consistently decreased secondary bile acids in the serum and liver. The relative abundance of Bacteroidetes and Firmicutes was associated with the bile acid level in serum. This study demonstrates that arsenic-induced gut microbiota dysbiosis may play a role in arsenic-perturbed bile acid homeostasis.
    DOI:  https://doi.org/10.1021/acs.chemrestox.2c00410
  2. Cell Biosci. 2023 Jun 12. 13(1): 106
    Roles of bile acids signaling in neuromodulation under physiological and pathological conditions.
    Chen Xing, Xin Huang, Dongxue Wang, Dengjun Yu, Shaojun Hou, Haoran Cui, Lung Song.
      Bile acids (BA) are important physiological molecules not only mediating nutrients absorption and metabolism in peripheral tissues, but exerting neuromodulation effect in the central nerve system (CNS). The catabolism of cholesterol to BA occurs predominantly in the liver by the classical and alternative pathways, or in the brain initiated by the neuronal-specific enzyme CYP46A1 mediated pathway. Circulating BA could cross the blood brain barrier (BBB) and reach the CNS through passive diffusion or BA transporters. Brain BA might trigger direct signal through activating membrane and nucleus receptors or affecting activation of neurotransmitter receptors. Peripheral BA may also provide the indirect signal to the CNS via farnesoid X receptor (FXR) dependent fibroblast growth factor 15/19 (FGF15/19) pathway or takeda G protein coupled receptor 5 (TGR5) dependent glucagon-like peptide-1 (GLP-1) pathway. Under pathological conditions, alterations in BA metabolites have been discovered as potential pathogenic contributors in multiple neurological disorders. Attractively, hydrophilic ursodeoxycholic acid (UDCA), especially tauroursodeoxycholic acid (TUDCA) can exert neuroprotective roles by attenuating neuroinflammation, apoptosis, oxidative or endoplasmic reticulum stress, which provides promising therapeutic effects for treatment of neurological diseases. This review summarizes recent findings highlighting the metabolism, crosstalk between brain and periphery, and neurological functions of BA to elucidate the important role of BA signaling in the brain under both physiological and pathological conditions.
    Keywords:  Bile acids; Blood brain barrier; Cholesterol; FXR; Neurodegenerative diseases; TGR5; TUDCA; UDCA
    DOI:  https://doi.org/10.1186/s13578-023-01053-z
  3. Aging Dis. 2023 Jun 07.
    Bile Acids in Cardiovascular Diseases: Don't Forget Hyocholic Acid.
    Piercarlo Minoretti, Enzo Emanuele.
      
    DOI:  https://doi.org/10.14336/AD.2023.0603
  4. Phytother Res. 2023 Jun 15.
    Saikosaponins regulate bile acid excretion in mice liver and ileum by activating farnesoid X receptor and bile acid transporter.
    YuKun Wang, Jing Li, Li Wu, XueMei Qin, Cen Xie, XiaoXia Gao.
      Radix Bupleuri exerts effective hepatoprotective and cholagogic effects through its Saikosaponins (SSs) component. Therefore, we attempted to determine the mechanism of saikosaponins used to promote bile excretion by studying their effects on intrahepatic bile flow, focusing on the synthesis, transport, excretion, and metabolism of bile acids. C57BL/6N mice were continuously gavaged with saikosaponin a (SSa), saikosaponin b2 (SSb2 ), or saikosaponin D (SSd) (200 mg/kg) for 14 days. Liver and serum biochemical indices were determined using Enzyme-linked immunosorbent assay (ELISA) kits. In addition, an ultra-performance liquid chromatography-mass spectrometer (UPLC-MS) was used to measure the levels of the 16 bile acids in the liver, gallbladder, and cecal contents. Furthermore, SSs pharmacokinetics and docking between SSs and farnesoid X receptor (FXR)-related proteins were analyzed to investigate the underlying molecular mechanisms. Administration of SSs and Radix Bupleuri alcohol extract (ESS) did not cause significant changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) levels. Saikosaponin-regulated changes in bile acid (BA) levels in the liver, gallbladder, and cecum were closely related to genes involved in BA synthesis, transport, and excretion in the liver. Pharmacokinetic studies indicated that SSs were characterized by rapid elimination (t1/2 as 0.68-2.47 h), absorption (Tmax as 0.47-0.78 h), and double peaks in the drug-time curves of SSa and SSb2 . A molecular docking study revealed that SSa, SSb2 , and SSd docked well with the 16 protein FXR molecules and target genes (<-5.2 kcal/mol). Collectively, saikosaponins may maintain BA homeostasis in mice by regulating FXR-related genes and transporters in the liver and intestine.
    Keywords:  FXR-related genes; bile acids; enterohepatic circulation; saikosaponins
    DOI:  https://doi.org/10.1002/ptr.7927
  5. Int J Mol Sci. 2023 May 30. pii: 9511. [Epub ahead of print]24(11):
    The Placenta-A New Source of Bile Acids during Healthy Pregnancy? First Results of a Gene Expression Study in Humans and Mice.
    Edgar Ontsouka, Mariana Schroeder, Linda Ok, Cathy Vaillancourt, Deborah Stroka, Christiane Albrecht.
      Bile acids (BAs) are natural ligands for several receptors modulating cell activities. BAs are synthesized via the classic (neutral) and alternative (acidic) pathways. The classic pathway is initiated by CYP7A1/Cyp7a1, converting cholesterol to 7α-hydroxycholesterol, while the alternative pathway starts with hydroxylation of the cholesterol side chain, producing an oxysterol. In addition to originating from the liver, BAs are reported to be synthesized in the brain. We aimed at determining if the placenta potentially represents an extrahepatic source of BAs. Therefore, the mRNAs coding for selected enzymes involved in the hepatic BA synthesis machinery were screened in human term and CD1 mouse late gestation placentas from healthy pregnancies. Additionally, data from murine placenta and brain tissue were compared to determine whether the BA synthetic machinery is comparable in these organs. We found that CYP7A1, CYP46A1, and BAAT mRNAs are lacking in the human placenta, while corresponding homologs were detected in the murine placenta. Conversely, Cyp8b1 and Hsd17b1 mRNAs were undetected in the murine placenta, but these enzymes were found in the human placenta. CYP39A1/Cyp39a1 and cholesterol 25-hydroxylase (CH25H/Ch25h) mRNA expression were detected in the placentas of both species. When comparing murine placentas and brains, Cyp8b1 and Hsd17b1 mRNAs were only detected in the brain. We conclude that BA synthesis-related genes are placentally expressed in a species-specific manner. The potential placentally synthesized BAs could serve as endocrine and autocrine stimuli, which may play a role in fetoplacental growth and adaptation.
    Keywords:  bile acid synthesis; extrahepatic; human; mice; pregnancy
    DOI:  https://doi.org/10.3390/ijms24119511
  6. Immunology. 2023 Jun 15.
    Effect of gut flora mediated-bile acid metabolism on intestinal immune microenvironment.
    Yan Zhang, Xueyan Gao, Shuochen Gao, Yang Liu, Wenkang Wang, Yudi Feng, Liping Pei, Zhenqiang Sun, Lin Liu, Chengzeng Wang.
      According to reports, gut microbiota and metabolites regulate the intestinal immune microenvironment. In recent years, an increasing number of studies reported that bile acids (BAs) of intestinal flora origin affect T helper cells and regulatory T cells (Treg cells). Th17 cells play a pro-inflammatory role and Treg cells usually act in an immunosuppressive role. In this review, we emphatically summarised the influence and corresponding mechanism of different configurations of lithocholic acid (LCA) and deoxycholic acid (DCA) on intestinal Th17 cells, Treg cells and intestinal immune microenvironment. The regulation of BAs receptors G protein-coupled bile acid receptor 1 (GPBAR1/TGR5) and farnesoid X receptor (FXR) on immune cells and intestinal environment are elaborated. Furthermore, the potential clinical applications above were also concluded in three aspects. The above will help researchers better understand the effects of gut flora on the intestinal immune microenvironment via BAs and contribute to the development of new targeted drugs.
    Keywords:  Farnesoid X receptor (FXR); G protein-coupled bile acid receptor 1 (GPBAR1/TGR5); Th17 cells; Treg cells; metabolism
    DOI:  https://doi.org/10.1111/imm.13672
  7. Biomed Pharmacother. 2023 Jun 12. pii: S0753-3322(23)00777-1. [Epub ahead of print]164 114987
    Alternative pathway of bile acid biosynthesis contributes to ameliorate NASH after induction of NAMPT/NAD+/SIRT1 axis.
    Na Yang, Runbin Sun, Xiaoli Zhang, Jing Wang, Lulu Wang, Huaijun Zhu, Man Yuan, Yifan Xu, Chun Ge, Jun He, Min Wang.
      Non-alcoholic steatohepatitis (NASH) is emerging as a serious liver disorder characterized by hepatic steatosis and liver inflammation. Nicotinamide adenine dinucleotide (NAD+) and NAD+-dependent deacetylase, SIRT1, play important roles in lipid metabolism in non-alcoholic fatty liver disease (NAFLD). However, their effects on liver inflammation and homeostasis of bile acids (BAs), the extensively proved pathophysiological actors in NASH, have not been fully understood. NASH animal model was induced by a methionine-choline-deficient (MCD) diet in C57BL/6J mice and intraperitoneally injected with NAD+ precursor, an agonist of upstream rate-limiting enzyme NAMPT or downstream SIRT1, or their vehicle solvents. Free fatty acid (FFA) was applied to HepG2 cells to construct the cell model. Induction of NAMPT/NAD+/SIRT1 axis could remarkably alleviate the aggravated inflammation in the liver of NASH mice, accompanied by decreased levels of total BAs throughout the enterohepatic system and a switch of BA synthesis from the classic pathway to the alternative pathway, resulting in less production of pro-inflammatory 12-OH BAs. The expressions of key enzymes including cyp7a1, cyp8b1, cyp27a1 and cyp7b1 in BA synthesis were significantly modulated after NAMPT/NAD+/SIRT1 axis induction in both animal and cell models. The levels of pro-inflammatory cytokines in liver were significantly negatively correlated with the intermediates in NAD+ metabolism, which may also be related to their regulation on BA homeostasis. Our results indicated that induction of NAMPT/NAD+/SIRT1 axis may be a potential therapeutic strategy for NASH or its complications related with BAs.
    Keywords:  Bile acids; NAD(+); NAMPT; NASH; SIRT1
    DOI:  https://doi.org/10.1016/j.biopha.2023.114987
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