bims-liverm 2023-03-12 papers

bims-liverm

Biomed News

on Liver Metabolism

Issue of 2023–03–12
eight papers selected by

In vitro models to measure effects on intestinal deconjugation and transport of mixtures of bile acids.
Bile Acids and Biliary Fibrosis.
Activation of the bile acid receptors TGR5 and FXR in the spinal dorsal horn alleviates neuropathic pain.
A Dual Coverage Monitoring of the Bile Acids Profile in the Liver-Gut Axis throughout the Whole Inflammation-Cancer Transformation Progressive: Reveal Hepatocellular Carcinoma Pathogenesis.
Molecular Determinants for Differential Activation of the Bile Acid Receptor from the Pathogen Vibrio parahaemolyticus.
The role of bile acid in intestinal metaplasia.
Targeting mTOR/YY1 signaling pathway by quercetin through CYP7A1-mediated cholesterol-to-bile acids conversion alleviated type 2 diabetes mellitus induced hepatic lipid accumulation.
Mitotic CDK1 and 4E-BP1 II: A single phosphomimetic mutation in 4E-BP1 induces glucose intolerance in mice.

Chem Biol Interact. 2023 Mar 06. pii: S0009-2797(23)00112-6. [Epub ahead of print] 110445

In vitro models to measure effects on intestinal deconjugation and transport of mixtures of bile acids.

Nina Zhang, Weijia Zheng, Wouter Bakker, Bennard van Ravenzwaay, Ivonne M C M Rietjens.

  Bile acid metabolism and transport are critical to maintain bile acid homeostasis and host health. In this study, it was investigated if effects on intestinal bile acid deconjugation and transport can be quantified in in vitro model systems using mixtures of bile acids instead of studying individual bile acids. To this end deconjugation of mixtures of selected bile acids in anaerobic rat or human fecal incubations and the effect of the antibiotic tobramycin on these reactions was studied. In addition, the effect of tobramycin on the transport of the bile acids in isolation or in a mixture across Caco-2 cell layers was characterized. The results demonstrate that both the reduction of bile acid deconjugation and transport by tobramycin can be adequately detected in in vitro systems using a mixture of bile acids, thus eliminating the need to characterize the effects for each bile acid in separate experiments. Subtle differences between the experiments with single or combined bile acids point at mutual competitive interactions and indicate that the use of bile acid mixtures is preferred over use of single bile acid given that also in vivo bile acids occurs in mixtures.

Keywords:  Bile acid transport; Caco-2 cells; Conjugated bile acids; Fecal incubation; Tobramycin

DOI:  https://doi.org/10.1016/j.cbi.2023.110445
Cells. 2023 Mar 02. pii: 792. [Epub ahead of print]12(5):

Bile Acids and Biliary Fibrosis.

Sayed Obaidullah Aseem, Phillip B Hylemon, Huiping Zhou.

  Biliary fibrosis is the driving pathological process in cholangiopathies such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Cholangiopathies are also associated with cholestasis, which is the retention of biliary components, including bile acids, in the liver and blood. Cholestasis may worsen with biliary fibrosis. Furthermore, bile acid levels, composition and homeostasis are dysregulated in PBC and PSC. In fact, mounting data from animal models and human cholangiopathies suggest that bile acids play a crucial role in the pathogenesis and progression of biliary fibrosis. The identification of bile acid receptors has advanced our understanding of various signaling pathways involved in regulating cholangiocyte functions and the potential impact on biliary fibrosis. We will also briefly review recent findings linking these receptors with epigenetic regulatory mechanisms. Further detailed understanding of bile acid signaling in the pathogenesis of biliary fibrosis will uncover additional therapeutic avenues for cholangiopathies.

Keywords:  bile acid receptors; bile acids; biliary fibrosis; cholangiocytes; cholangiopathies

DOI:  https://doi.org/10.3390/cells12050792
CNS Neurosci Ther. 2023 Mar 07.

Activation of the bile acid receptors TGR5 and FXR in the spinal dorsal horn alleviates neuropathic pain.

Yuning Wu, Yuxin Qiu, Minzhi Su, Linjie Wang, Qingjuan Gong, Xuhong Wei.

   AIMS: Beyond digestion, bile acids have been recognized as signaling molecules with broad paracrine and endocrine functions by activating plasma membrane receptor (Takeda G protein-coupled receptor 5, TGR5) and the nuclear farnesoid X receptor (FXR). The present study investigated the role of bile acids in alleviating neuropathic pain by activating TGR5 and FXR.
METHOD: Neuropathic pain was induced by spared nerve injury (SNI) of the sciatic nerve. TGR5 or FXR agonist was injected intrathecally. Pain hypersensitivity was measured with Von Frey test. The amount of bile acids was detected using a bile acid assay kit. Western blotting and immunohistochemistry were used to assess molecular changes.
RESULTS: We found that bile acids were downregulated, whereas the expression of cytochrome P450 cholesterol 7ahydroxylase (CYP7A1), a rate-limiting enzyme for bile acid synthesis, was upregulated exclusively in microglia in the spinal dorsal horn after SNI. Furthermore, the expression of the bile acid receptors TGR5 and FXR was increased in glial cells and GABAergic neurons in the spinal dorsal horn on day 7 after SNI. Intrathecal injection of either TGR5 or FXR agonist on day 7 after SNI alleviated the established mechanical allodynia in mice, and the effects were blocked by TGR5 or FXR antagonist. Bile acid receptor agonists inhibited the activation of glial cells and ERK pathway in the spinal dorsal horn. All of the above effects of TGR5 or FXR agonists on mechanical allodynia, on the activation of glial cells, and on ERK pathway were abolished by intrathecal injection of the GABAA receptor antagonist bicuculline.
CONCLUSION: These results suggest that activation of TGR5 or FXR counteracts mechanical allodynia. The effect was mediated by potentiating function of GABAA receptors, which then inhibited the activation of glial cells and neuronal sensitization in the spinal dorsal horn.

Keywords:  Takeda G protein-coupled receptor 5; astrocyte; bile acid; mechanical allodynia; nuclear farnesoid X receptor; spinal cord

DOI:  https://doi.org/10.1111/cns.14154
Int J Mol Sci. 2023 Feb 21. pii: 4258. [Epub ahead of print]24(5):

A Dual Coverage Monitoring of the Bile Acids Profile in the Liver-Gut Axis throughout the Whole Inflammation-Cancer Transformation Progressive: Reveal Hepatocellular Carcinoma Pathogenesis.

Luwen Xing, Yiwen Zhang, Saiyu Li, Minghui Tong, Kaishun Bi, Qian Zhang, Qing Li.

  Hepatocellular carcinoma (HCC) is the terminal phase of multiple chronic liver diseases, and evidence supports chronic uncontrollable inflammation being one of the potential mechanisms leading to HCC formation. The dysregulation of bile acid homeostasis in the enterohepatic circulation has become a hot research issue concerning revealing the pathogenesis of the inflammatory-cancerous transformation process. We reproduced the development of HCC through an N-nitrosodiethylamine (DEN)-induced rat model in 20 weeks. We achieved the monitoring of the bile acid profile in the plasma, liver, and intestine during the evolution of "hepatitis-cirrhosis-HCC" by using an ultra-performance liquid chromatography-tandem mass spectrometer for absolute quantification of bile acids. We observed differences in the level of primary and secondary bile acids both in plasma, liver, and intestine when compared to controls, particularly a sustained reduction of intestine taurine-conjugated bile acid level. Moreover, we identified chenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, and glycolithocholic acid in plasma as biomarkers for early diagnosis of HCC. We also identified bile acid-CoA:amino acid N-acyltransferase (BAAT) by gene set enrichment analysis, which dominates the final step in the synthesis of conjugated bile acids associated with the inflammatory-cancer transformation process. In conclusion, our study provided comprehensive bile acid metabolic fingerprinting in the liver-gut axis during the inflammation-cancer transformation process, laying the foundation for providing a new perspective for the diagnosis, prevention, and treatment of HCC.

Keywords:  BAAT; bile acids; enterohepatic circulation; hepatocellular carcinoma; inflammation-cancer transformation process; liver–gut axis

DOI:  https://doi.org/10.3390/ijms24054258
J Biol Chem. 2023 Mar 07. pii: S0021-9258(23)00233-8. [Epub ahead of print] 104591

Molecular Determinants for Differential Activation of the Bile Acid Receptor from the Pathogen Vibrio parahaemolyticus.

AngelaJ Zou, Lisa Kinch, Suneeta Chimalapati, Nalleli Garcia, DianaR Tomchick, Kim Orth.

  Bile acids are important for digestion of food and for antimicrobial activity. Pathogenic Vibrio parahaemolyticus senses bile acids and induce pathogenesis. The bile acid taurodeoxycholate (TDC) was shown to activate the master regulator, VtrB, of this system, while other bile acids such as chenodeoxycholate (CDC) do not. Previously, VtrA/VtrC was discovered to be the co-component signal transduction system that binds bile acids and induces pathogenesis. TDC binds to the periplasmic domain of the VtrA/VtrC complex, activating a DNA-binding domain in VtrA that then activates VtrB. Here, we find that CDC and TDC compete for binding to the VtrA/VtrC periplasmic heterodimer. Our crystal structure of the VtrA/VtrC heterodimer bound to CDC revealed CDC binds in the same hydrophobic pocket as TDC, but differently. Using isothermal titration calorimetry (ITC), we observe most mutants in the binding pocket of VtrA/VtrC caused a decrease in bile acid binding affinity. Notably, two mutants in VtrC bound bile acids with a similar affinity as the wild-type protein but were attenuated for TDC-induced Type III Secretion System 2 (T3SS2) activation. Collectively, these studies provide a molecular explanation for the selective pathogenic signaling by Vibrio parahaemolyticus and reveal insight into a host's susceptibility to disease.

Keywords:  bacterial pathogenesis; bile acid; host-pathogen interaction; receptor structure-function; type III secretion system (T3SS)

DOI:  https://doi.org/10.1016/j.jbc.2023.104591
Front Physiol. 2023 ;14 1115250

The role of bile acid in intestinal metaplasia.

Menglei Wang, Enzhe Lou, Zengfu Xue.

  A precancerous lesion of gastric cancer (GC), intestinal metaplasia (IM) is a pathological transformation of non-intestinal epithelium into an intestinal-like mucosa. It greatly raises the risk of developing the intestinal type of GC, which is frequently observed in the stomach and esophagus. It is understood that esophageal adenocarcinoma's precursor lesion, chronic gastroesophageal reflux disease (GERD), is what causes Barrett's esophagus (BE), an acquired condition. Recently, Bile acids (BAs), which are one of the compositions of gastric and duodenal contents, have been confirmed that it led to the occurrence and development of BE and gastric intestinal metaplasia (GIM). The objective of the current review is to discuss the mechanism of IM induced by bile acids. This review serves as a foundation for further research aimed at improving the way BE and GIM are currently managed.

Keywords:  Barrett’s esophagus (BE); bile acid; gastroesophageal reflux; intestinal metaplasia; molecular mechanism

DOI:  https://doi.org/10.3389/fphys.2023.1115250
Phytomedicine. 2023 Feb 05. pii: S0944-7113(23)00063-6. [Epub ahead of print]113 154703

Targeting mTOR/YY1 signaling pathway by quercetin through CYP7A1-mediated cholesterol-to-bile acids conversion alleviated type 2 diabetes mellitus induced hepatic lipid accumulation.

Tingting Yang, Yiying Wang, Xinyun Cao, Yuting Peng, Jiawan Huang, Li Chen, Jiale Pang, Zhenzhou Jiang, Sitong Qian, Ying Liu, Changjiang Ying, Tao Wang, Fan Zhang, Qian Lu, Xiaoxing Yin.

   BACKGROUND: Hepatic lipid accumulation was a major promoter for the further development of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2DM). mTOR/YY1 signaling pathway regulated many metabolic processes in different organs, and played an important role in hepatic lipid metabolism. Thus, targeting mTOR/YY1 signaling pathway might be a novel therapeutic strategy of T2DM-associated NALFD.
PURPOSE: To investigate the effects and the mechanism of quercetin against T2DM-associated NAFLD.
STUDY DESIGN AND METHODS: The combine abilities of 24 flavonoid compounds with mTOR were detected by computer virtual screening (VS) and molecular modeling. mTOR/YY1 signaling pathway was examined in the liver of db/db mice, and high glucose (HG) and free fatty acid (FFA) co-cultured HepG2 cells. YY1 overexpression lentivirus vector and mTOR specific inhibitor rapamycin were used to further identify the indispensable role of mTOR/YY1 signaling pathway in quercetin's amelioration effect of hepatic lipid accumulation in vitro. Clinical studies, luciferase assay and chromatin immunoprecipitation (ChIP) assay were all carried out to investigate the potential mechanisms by which quercetin exerted its amelioration effect of hepatic lipid accumulation.
RESULTS: Quercetin had the strongest ability to combine with mTOR and could competitively occupy its binding pocked. Along with the alleviated hepatic injury by quercetin, mTOR/YY1 signaling pathway was down-regulated in vivo and in vitro. However, the alleviation effect of quercetin against hepatic lipid accumulation was inhibited by YY1 overexpression in vitro. Mechanistically, the down-regulated nuclear YY1 induced by quercetin directly bound to CYP7A1 promoter and activated its transcription, resulting in the restoration of cholesterol homeostasis via the conversion of cholesterol-to-bile acids (BAs).
CONCLUSION: The hepatoprotective effect of quercetin on T2DM-associated NAFLD was linked to the restoration of cholesterol homeostasis by the conversion of cholesterol-to-BAs via down-regulating mTOR/YY1 signaling pathway, leading to the increased CYP7A1 activity.

Keywords:  Bile acids; CYP7A1; Cholesterol homeostasis; Quercetin; T2DM-associated fatty liver disease; mTOR/YY1 signaling pathway

DOI:  https://doi.org/10.1016/j.phymed.2023.154703
PLoS One. 2023 ;18(3): e0282914

Mitotic CDK1 and 4E-BP1 II: A single phosphomimetic mutation in 4E-BP1 induces glucose intolerance in mice.

Simon Cao, Michael J Jurczak, Yoko Shuda, Rui Sun, Masahiro Shuda, Yuan Chang, Patrick S Moore.

OBJECTIVE: Cyclin-dependent kinase 1 (CDK1)/cyclin B1 phosphorylates many of the same substrates as mTORC1 (a key regulator of glucose metabolism), including the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Only mitotic CDK1 phosphorylates 4E-BP1 at residue S82 in mice (S83 in humans), in addition to the common 4E-BP1 phospho-acceptor sites phosphorylated by both CDK1 and mTORC1. We examined glucose metabolism in mice having a single aspartate phosphomimetic amino acid knock in substitution at the 4E-BP1 serine 82 (4E-BP1S82D) mimicking constitutive CDK1 phosphorylation.
METHODS: Knock-in homozygous 4E-BP1S82D and 4E-BP1S82A C57Bl/6N mice were assessed for glucose tolerance testing (GTT) and metabolic cage analysis on regular and on high-fat chow diets. Gastrocnemius tissues from 4E-BP1S82D and WT mice were subject to Reverse Phase Protein Array analysis. Since the bone marrow is one of the few tissues typically having cycling cells that transit mitosis, reciprocal bone-marrow transplants were performed between male 4E-BP1S82D and WT mice, followed by metabolic assessment, to determine the role of actively cycling cells on glucose homeostasis.
RESULTS: Homozygous knock-in 4E-BP1S82D mice showed glucose intolerance that was markedly accentuated with a diabetogenic high-fat diet (p = 0.004). In contrast, homozygous mice with the unphosphorylatable alanine substitution (4E-BP1S82A) had normal glucose tolerance. Protein profiling of lean muscle tissues, largely arrested in G0, did not show protein expression or signaling changes that could account for these results. Reciprocal bone-marrow transplantation between 4E-BP1S82D and wild-type littermates revealed a trend for wild-type mice with 4E-BP1S82D marrow engraftment on high-fat diets to become hyperglycemic after glucose challenge.
CONCLUSIONS: 4E-BP1S82D is a single amino acid substitution that induces glucose intolerance in mice. These findings indicate that glucose metabolism may be regulated by CDK1 4E-BP1 phosphorylation independent from mTOR and point towards an unexpected role for cycling cells that transit mitosis in diabetic glucose control.

DOI: https://doi.org/10.1371/journal.pone.0282914