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Chen W, Zhang Q, Ding M, Yao J, Guo Y, Yan W, Yu S, Shen Q, Huang M, Zheng Y, Lin Y, Wang Y, Liu Z, Lu L. Alcohol triggered bile acid disequilibrium by suppressing BSEP to sustain hepatocellular carcinoma progression. Chem Biol Interact 2022; 356:109847. [PMID: 35149083 DOI: 10.1016/j.cbi.2022.109847] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 01/20/2022] [Accepted: 02/07/2022] [Indexed: 12/12/2022]
Abstract
Bile acids (BAs), the most important components of bile, attribute predominately to maintain metabolic homeostasis. In hepatocellular carcinoma (HCC) patients, the BAs homeostasis was seriously disturbed, especially in those patients with alcohol-intake history. However, whether alcohol consumption could promote HCC progression via influencing BAs homeostasis and the precise mechanism underlying are still unclear. In our study, by collecting HCC specimens from both alcohol-drinkers (n = 15) and non-alcohol drinkers (n = 22), we found that compared to non-alcohol intake HCC patients, BAs homeostasis was disturbed in HCC patients who drank alcohol. Furthermore, ethanol treatment was also found to promote HCC progression by markedly activating oncogenes (RAS, MYC, MET, and HER2), while remarkably suppressing tumor suppressor genes (BRCA2 and APC). We evaluated 14 key functional genes that maintain the homeostasis of BAs and found that either in alcohol-intake HCC patients (n = 15), or in ethanol-treated mice, BSEP, rate-limiting transporter governing excreting BAs from liver into bile duct, was remarkably decreased when exposed to alcohol. Moreover, by screening for changes in the epigenetic landscape of liver cancer cells exposed to alcohol, we strikingly found that histone methyltransferases (RBBP-5, Suv39h1, ASH2L, and SET7/9) were increased, and KMT3B, KMT4, and KMT7 gene expression was also elevated, while histone demethyltransferases (JARID1a, JARID1b, JARID1c) were decreased. In summary, we found that alcohol could trigger BAs disequilibrium to initiate and promote HCC progression. Our study provided a novel and supplementary mechanism to determine the important role of alcohol-intake in HCC development regarding from the perspective of BAs homeostasis.
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Affiliation(s)
- Wenbo Chen
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
| | - Qisong Zhang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China; Medical College of Guangxi University, Guangxi University, Nanning, Guangxi, 530004, PR China
| | - Ming Ding
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
| | - Jingjing Yao
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
| | - Yajuan Guo
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
| | - Wenxin Yan
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
| | - Shaofang Yu
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
| | - Qinghong Shen
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
| | - Min Huang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
| | - Yaqiu Zheng
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
| | - Yuefang Lin
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
| | - Ying Wang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
| | - Zhongqiu Liu
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR, China.
| | - Linlin Lu
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, SAR, China.
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Khalil A, Elfert A, Ghanem S, Helal M, Abdelsattar S, Elgedawy G, Obada M, Abdel-Samiee M, El-Said H. The role of metabolomics in hepatocellular carcinoma. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00085-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Abstract
Background
Hepatocellular carcinoma is the most common primary liver malignancy, with the highest incidence in the developing world, including Egypt. Hepatocellular carcinoma is usually diagnosed in the terminal stage of the disease because of the low sensitivity of the available screening tests. During the process of carcinogenesis, the cellular metabolism is altered to allow cancer cells to adapt to the hypoxic environment and therefore increase anabolic synthesis and survival and avoid the apoptotic death signals. These changes in metabolic status can be tracked by metabolomics analysis.
Main body
Metabolomics is a comprehensive approach for identifying metabolic signatures towards the screening, prediction, and earlier diagnosis of hepatocellular carcinoma with greater efficiency than the conventional diagnostic biomarker. The identification of metabolic changes associated with hepatocellular carcinoma is essential to the understanding of disease pathophysiology and enables better monitoring of high-risk individuals. However, due to the complexity of the metabolic pathways associated with hepatocellular carcinoma, the details of these perturbations are still not adequately characterized. The current status of biomarkers for hepatocellular carcinoma and their insufficiencies and metabolic pathways linked to hepatocellular carcinogenesis are briefly addressed in this mini-review. The review focused on the significantly changed metabolites and pathways associated with hepatocellular carcinoma such as phospholipids, bile acids, amino acids, reactive oxygen species metabolism, and the metabolic changes related to energy production in a cancer cell. The review briefly discusses the sensitivity of metabolomics in the prediction and prognosis of hepatocellular carcinoma and the effect of coexisting multiple etiologies of the disease.
Conclusions
Metabolomics profiling is a potentially promising tool for better predicting, diagnosis, and prognosis of hepatocellular carcinoma.
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Glycochenodeoxycholate promotes hepatocellular carcinoma invasion and migration by AMPK/mTOR dependent autophagy activation. Cancer Lett 2019; 454:215-223. [PMID: 30980867 DOI: 10.1016/j.canlet.2019.04.009] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 04/05/2019] [Accepted: 04/05/2019] [Indexed: 01/07/2023]
Abstract
Metastasis and recurrence severely impact the treatment effect of hepatocellular carcinoma (HCC). HCC complicated with cholestasis is more prone to recurrence and metastasis. Previous studies have implicated pathogenesis of HCC by bile acid; however, the underlying mechanism is unknown yet. Glycochenodeoxycholate (GCDC) is one of most important component of bile acid (BA). In the present study, the role of GCDC in HCC cells invasion was detected by in vitro and in vivo assays. GCDC was found to significantly enhance the invasive potential of HCC cells; Further studies showed that GCDC could induce autophagy activation and higher invasive capability in HCC cells. Interestingly, inhibition of autophagy by chloroquine (CQ) reversed this phenomenon. Subsequently, the correlation between TBA expression level and clinicopathological characteristics was analyzed in HCC patients. Clinically, high TBA level in HCC tissue was found to be associated with more invasive and poor survival in HCC patients. Mechanistic study showed that bile acid induced autophagy by targeting the AMPK/mTOR pathway in HCC cells. Therefore, our results suggest that bile acid may promote HCC invasion via activation of autophagy and the level of bile acid may serve as a potential useful indicator for prognosis of HCC patients.
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Shiffka SJ, Kane MA, Swaan PW. Planar bile acids in health and disease. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2017; 1859:2269-2276. [PMID: 28887043 DOI: 10.1016/j.bbamem.2017.08.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 08/24/2017] [Accepted: 08/29/2017] [Indexed: 12/26/2022]
Abstract
Bile acids are the amphipathic primary end-products of cholesterol metabolism that aid in digestion as well as participate in signal transduction in several hepatic and enteric pathways. Despite the reputation of bile acids as signaling molecules implicated in disease states such as cancer and diabetes, there remain numerous bile acid species that are weakly characterized in either physiological or pathological conditions. This review presents one such group: the flat or planar bile acids, a set of bile acids found in humans during infancy and occurring again during certain diseases. As their name implies, these molecules are structurally distinct from the typical human bile acids, retaining the planar structure of their cholesterol predecessor instead of bending or twisting at the A ring. This review defines these species of bile acids in detail and describes their presence in infancy, gestation, and in disease. The large gaps in research regarding the flat bile acids are highlighted and all available experimental knowledge collected as far as 60years ago is summarized. Further, the potential for these molecules as endogenous biomarkers of liver disease and injury is discussed. Finally, the flat bile salts found in humans are compared to the ancestral and evolutionary older bile salts, which similarly have a flat steroidal structure, as mechanisms of flat bile acid biosynthesis are explored.
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Affiliation(s)
- Stephanie J Shiffka
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201, USA
| | - Maureen A Kane
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201, USA
| | - Peter W Swaan
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201, USA.
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Fitian AI, Cabrera R. Disease monitoring of hepatocellular carcinoma through metabolomics. World J Hepatol 2017; 9:1-17. [PMID: 28105254 PMCID: PMC5220267 DOI: 10.4254/wjh.v9.i1.1] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 09/20/2016] [Accepted: 10/24/2016] [Indexed: 02/06/2023] Open
Abstract
We elucidate major pathways of hepatocarcinogenesis and accurate diagnostic metabolomic biomarkers of hepatocellular carcinoma (HCC) identified by contemporary HCC metabolomics studies, and delineate a model HCC metabolomics study design. A literature search was carried out on Pubmed for HCC metabolomics articles published in English. All relevant articles were accessed in full text. Major search terms included “HCC”, “metabolomics”, “metabolomics”, “metabonomic” and “biomarkers”. We extracted clinical and demographic data on all patients and consolidated the lead candidate biomarkers, pathways, and diagnostic performance of metabolomic expression patterns reported by all studies in tables. Where reported, we also extracted and summarized the metabolites and pathways most highly associated with the development of cirrhosis in table format. Pathways of lysophospholipid, sphingolipid, bile acid, amino acid, and reactive oxygen species metabolism were most consistently associated with HCC in the cited works. Several studies also elucidate metabolic alterations strongly associated with cirrhosis, with γ-glutamyl peptides, bile acids, and dicarboxylic acids exhibiting the highest capacity for stratifying cirrhosis patients from appropriately matched controls. Collectively, global metabolomic profiles of the referenced works exhibit a promising diagnostic capacity for HCC at a capacity greater than that of conventional diagnostic biomarker alpha-fetoprotein. Metabolomics is a powerful strategy for identifying global metabolic signatures that exhibit potential to be leveraged toward the screening, diagnosis, and management of HCC. A streamlined study design and patient matching methodology may improve concordance among metabolomic datasets in future works.
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Wahlström A, Sayin SI, Marschall HU, Bäckhed F. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab 2016; 24:41-50. [PMID: 27320064 DOI: 10.1016/j.cmet.2016.05.005] [Citation(s) in RCA: 1771] [Impact Index Per Article: 196.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The gut microbiota is considered a metabolic "organ" that not only facilitates harvesting of nutrients and energy from the ingested food but also produces numerous metabolites that signal through their cognate receptors to regulate host metabolism. One such class of metabolites, bile acids, is produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. These bioconversions modulate the signaling properties of bile acids via the nuclear farnesoid X receptor and the G protein-coupled membrane receptor 5, which regulate numerous metabolic pathways in the host. Conversely, bile acids can modulate gut microbial composition both directly and indirectly through activation of innate immune genes in the small intestine. Thus, host metabolism can be affected through microbial modifications of bile acids, which lead to altered signaling via bile acid receptors, but also by altered microbiota composition.
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Affiliation(s)
- Annika Wahlström
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, 413 45 Gothenburg, Sweden
| | - Sama I Sayin
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, 413 45 Gothenburg, Sweden
| | - Hanns-Ulrich Marschall
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, 413 45 Gothenburg, Sweden
| | - Fredrik Bäckhed
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, 413 45 Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research and Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
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Cho JG, Lee JH, Hong SH, Lee HN, Kim CM, Kim SY, Yoon KJ, Oh BJ, Kim JH, Jung SY, Asahara T, Kwon SM, Park SG. Tauroursodeoxycholic acid, a bile acid, promotes blood vessel repair by recruiting vasculogenic progenitor cells. Stem Cells 2015; 33:792-805. [PMID: 25407160 DOI: 10.1002/stem.1901] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/22/2014] [Accepted: 10/26/2014] [Indexed: 01/19/2023]
Abstract
Although serum bile acid concentrations are approximately 10 µM in healthy subjects, the crosstalk between the biliary system and vascular repair has never been investigated. In this study, tauroursodeoxycholic acid (TUDCA) induced dissociation of CD34(+) hematopoietic stem cells (HSCs) from stromal cells by reducing adhesion molecule expression. TUDCA increased CD34(+) /Sca1(+) progenitors in mice peripheral blood (PB), and CD34(+) , CD31(+) , and c-kit(+) progenitors in human PB. In addition, TUDCA increased differentiation of CD34(+) HSCs into EPC lineage cells via Akt activation. EPC invasion was increased by TUDCA, which was mediated by fibroblast activating protein via Akt activation. Interestingly, TUDCA induced integration of EPCs into human aortic endothelial cells (HAECs) by increasing adhesion molecule expression. In the mouse hind limb ischemia model, TUDCA promoted blood perfusion by enhancing angiogenesis through recruitment of Flk-1(+) /CD34(+) and Sca-1(+) /c-kit(+) progenitors into damaged tissue. In GFP(+) bone marrow-transplanted hind limb ischemia, TUDCA induced recruitment of GFP(+) /c-kit(+) progenitors to the ischemic area, resulting in an increased blood perfusion ratio. Histological analysis suggested that GFP(+) progenitors mobilized from bone marrow, integrated into blood vessels, and differentiated into VEGFR(+) cells. In addition, TUDCA decreased cellular senescence by reducing levels of p53, p21, and reactive oxygen species and increased nitric oxide. Transplantation of TUDCA-primed senescent EPCs in hind limb ischemia significantly improved blood vessel regeneration, as compared with senescent EPCs. Our results suggested that TUDCA promoted neovascularization by enhancing the mobilization of stem/progenitor cells from bone marrow, their differentiation into EPCs, and their integration with preexisting endothelial cells.
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Affiliation(s)
- Jin Gu Cho
- Department of Biomedical Science, CHA University, Sungnamsi, Gyunggido, Korea
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Li T, Apte U. Bile Acid Metabolism and Signaling in Cholestasis, Inflammation, and Cancer. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2015; 74:263-302. [PMID: 26233910 DOI: 10.1016/bs.apha.2015.04.003] [Citation(s) in RCA: 213] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Bile acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in bile acid synthesis. Bile acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid-soluble vitamins. Bile acid synthesis, transport, and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired bile flow leads to accumulation of bile acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis, and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that bile acids act as signaling molecules that regulate various cellular processes. The bile acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of bile acid, drug, and xenobiotic metabolism. In cholestasis, these bile acid-activated receptors regulate a network of genes involved in bile acid synthesis, conjugation, transport, and metabolism to alleviate bile acid-induced inflammation and injury. Additionally, bile acids are known to regulate cell growth and proliferation, and altered bile acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate bile acid homeostasis and detoxification during cholestasis, and the roles of bile acids in the initiation and regulation of hepatic inflammation, regeneration, and carcinogenesis.
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Affiliation(s)
- Tiangang Li
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, USA.
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, USA
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Han J, Liu Y, Wang R, Yang J, Ling V, Borchers CH. Metabolic profiling of bile acids in human and mouse blood by LC-MS/MS in combination with phospholipid-depletion solid-phase extraction. Anal Chem 2015; 87:1127-36. [PMID: 25496250 DOI: 10.1021/ac503816u] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
To obtain a more comprehensive profile of bile acids (BAs) in blood, we developed an ultrahigh performance liquid chromatography/multiple-reaction monitoring-mass spectrometry (UPLC-MRM-MS) method for the separation and detection of 50 known BAs. This method utilizes phospholipid-depletion solid-phase extraction as a new high-efficiency sample preparation procedure for BA assay. UPLC/scheduled MRM-MS with negative ion electrospray ionization enabled targeted quantitation of 43 and 44 BAs, respectively, in serum samples from seven individuals with and without fasting, as well as in plasma samples from six cholestatic gene knockout mice and six age- and gender-matched wild-type (FVB/NJ) animals. Many minor BAs were identified and quantitated in the blood for the first time. Method validation indicated good quantitation precision with intraday and interday relative standard deviations of ≤9.3% and ≤10.8%, respectively. Using a pooled human serum sample and a pooled mouse plasma sample as the two representative test samples, the quantitation accuracy was measured to be 80% to 120% for most of the BAs, using two standard-substance spiking approaches. To profile other potential BAs not included in the 50 known targets from the knockout versus wild-type mouse plasma, class-specific precursor/fragment ion transitions were used to perform UPLC-MRM-MS for untargeted detection of the structural isomers of glycine- and taurine-conjugated BAs and unconjugated tetra-hydroxy BAs. As a result, as many as 36 such compounds were detected. In summary, this UPLC-MRM-MS method has enabled the quantitation of the largest number of BAs in the blood thus far, and the results presented have revealed an unexpectedly complex BA profile in mouse plasma.
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Affiliation(s)
- Jun Han
- University of Victoria-Genome BC Proteomics Centre, University of Victoria , Vancouver Island Technology Park, 3101-4464 Markham Street, Victoria, British Columbia V8Z 7X8, Canada
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Yin P, Xu G. Metabolomics for tumor marker discovery and identification based on chromatography–mass spectrometry. Expert Rev Mol Diagn 2014; 13:339-48. [DOI: 10.1586/erm.13.23] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Differential activation of the human farnesoid X receptor depends on the pattern of expressed isoforms and the bile acid pool composition. Biochem Pharmacol 2013; 86:926-39. [PMID: 23928191 DOI: 10.1016/j.bcp.2013.07.022] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2013] [Revised: 07/23/2013] [Accepted: 07/23/2013] [Indexed: 12/15/2022]
Abstract
The farnesoid X receptor (FXR) is a key sensor in bile acid homeostasis. Although four human FXR isoforms have been identified, the physiological role of this diversity is poorly understood. Here we investigated their subcellular localization, agonist sensitivity and response of target genes. Measurement of mRNA revealed that liver predominantly expressed FXRα1(+/-), whereas FXRα2(+/-) were the most abundant isoforms in kidney and intestine. In all cases, the proportion of FXRα(1/2)(+) and FXRα(1/2)(-) isoforms, i.e., with and without a 12bp insert, respectively, was approximately 50%. When FXR was expressed in liver and intestinal cells the magnitude of the response to GW4064 and bile acids differs among FXR isoforms. In both cell types the strongest response was that of FXRα1(-). Different efficacy of bile acids species to activate FXR was found. The four FXR isoforms shared the order of sensitivity to bile acids species. When in FXR-deficient cells FXR was transfected, unconjugated, but not taurine- and glycine-amidated bile acids, were able to activate FXR. In contrast, human hepatocytes and cell lines showing an endogenous expression of FXR were sensitive to both unconjugated and conjugated bile acids. This suggests that to activate FXR conjugated, but not unconjugated, bile acids require additional component(s) of the intracellular machinery not related with uptake processes, which are missing in some tumor cells. In conclusion, cell-specific pattern of FXR isoforms determine the overall tissue sensitivity to FXR agonists and may be involved in the differential response of FXR target genes to FXR activation.
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Hoekstra LT, Rietkerk M, van Lienden KP, van den Esschert JW, Schaap FG, van Gulik TM. Bile salts predict liver regeneration in rabbit model of portal vein embolization. J Surg Res 2012; 178:773-8. [PMID: 22763217 DOI: 10.1016/j.jss.2012.06.038] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Revised: 06/14/2012] [Accepted: 06/15/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Portal vein embolization (PVE) is employed to increase future remnant liver (FRL) volume through induction of hepatocellular regeneration in the nonembolized liver lobe. The regenerative response is commonly determined by CT volumetry after PVE. The aim of the study was to examine plasma bile salts and triglycerides in the prediction of the regenerative response following PVE. METHODS PVE of the cranial liver lobe was performed in 15 rabbits, divided into three groups: NaCl (control), gelatin sponge (short-term occlusion), and polyvinyl alcohol particles with coils (PVAc, long-term occlusion). In all rabbits CT volumetry and blood sampling were performed prior to PVE and on days 3 and 7. Plasma bile salts and triglycerides were correlated with volume increase of the nonembolized liver lobe. RESULTS After 3 and 7 d, respectively, FRL volume was increased in both embolized groups, with the largest hypertrophy response observed in the PVAc group. Plasma bile salt levels were increased after PVE, especially in the PVAc group at day 3 (P < 0.01 compared to gelatin sponge). Plasma bile salts at day 3 predicted FRL volume increase at day 7 showing a positive correlation of 0.811 (P < 0.001). Levels of triglycerides were not significantly altered in either of the PVE procedures. CONCLUSIONS Plasma bile salt levels early after PVE strongly correlated with the regenerative response in a rabbit model of PVE, showing more pronounced elevation with larger volume increase of the nonembolized lobe. Therefore, plasma bile salts, but not triglycerides, can be used in the prediction of the regenerative response after PVE.
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Affiliation(s)
- Lisette T Hoekstra
- Department of Surgery (Surgical Laboratory), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Kurogi K, Krasowski MD, Injeti E, Liu MY, Williams FE, Sakakibara Y, Suiko M, Liu MC. A comparative study of the sulfation of bile acids and a bile alcohol by the Zebra danio (Danio rerio) and human cytosolic sulfotransferases (SULTs). J Steroid Biochem Mol Biol 2011; 127:307-14. [PMID: 21839837 PMCID: PMC3515676 DOI: 10.1016/j.jsbmb.2011.07.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Revised: 07/26/2011] [Accepted: 07/29/2011] [Indexed: 01/15/2023]
Abstract
The current study was designed to examine the sulfation of bile acids and bile alcohols by the Zebra danio (Danio rerio) SULTs in comparison with human SULTs. A systematic analysis using the fifteen Zebra danio SULTs revealed that SULT3 ST2 and SULT3 ST3 were the major bile acid/alcohol-sulfating SULTs. Among the eleven human SULTs, only SULT2A1 was found to be capable of sulfating bile acids and bile alcohols. To further investigate the sulfation of bile acids and bile alcohols by the two Zebra danio SULT3 STs and the human SULT2A1, pH-dependence and kinetics of the sulfation of bile acids/alcohols were analyzed. pH-dependence experiments showed that the mechanisms underlying substrate recognition for the sulfation of lithocholic acid (a bile acid) and 5α-petromyzonol (a bile alcohol) differed between the human SULT2A1 and the Zebra danio SULT3 ST2 and ST3. Kinetic analysis indicated that both the two Zebra danio SULT3 STs preferred petromyzonol as substrate compared to bile acids. In contrast, the human SULT2A1 was more catalytically efficient toward lithocholic acid than petromyzonol. Collectively, the results imply that the Zebra danio and human SULTs have evolved to serve for the sulfation of, respectively, bile alcohols and bile acids, matching the cholanoid profile in these two vertebrate species.
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Affiliation(s)
- Katsuhisa Kurogi
- Department of Pharmacology, College of Pharmacy, The University of Toledo, Toledo, OH 43614, USA
| | - Matthew D. Krasowski
- Department of Pathology, University of Iowa Hospitals and Clinics, RCP 6233, 200 Hawkins Drive, Iowa City, IA 52242, USA
| | - Elisha Injeti
- Department of Pharmacology, College of Pharmacy, The University of Toledo, Toledo, OH 43614, USA
| | - Ming-Yih Liu
- National Synchrotron Radiation Research Center, Hsinchu, Taiwan, ROC
| | - Frederick E. Williams
- Department of Pharmacology, College of Pharmacy, The University of Toledo, Toledo, OH 43614, USA
| | - Yoichi Sakakibara
- Biochemistry and Applied Biosciences, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Masahito Suiko
- Biochemistry and Applied Biosciences, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Ming-Cheh Liu
- Department of Pharmacology, College of Pharmacy, The University of Toledo, Toledo, OH 43614, USA
- Corresponding author at: Department of Pharmacology, College of Pharmacy, The University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614, USA. Tel.: +1 419 383 1918; fax: +1 419 383 1909. , (M.-C. Liu)
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Patterson AD, Maurhofer O, Beyoglu D, Lanz C, Krausz KW, Pabst T, Gonzalez FJ, Dufour JF, Idle JR. Aberrant lipid metabolism in hepatocellular carcinoma revealed by plasma metabolomics and lipid profiling. Cancer Res 2011; 71:6590-600. [PMID: 21900402 DOI: 10.1158/0008-5472.can-11-0885] [Citation(s) in RCA: 216] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
There has been limited analysis of the effects of hepatocellular carcinoma (HCC) on liver metabolism and circulating endogenous metabolites. Here, we report the findings of a plasma metabolomic investigation of HCC patients by ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS), random forests machine learning algorithm, and multivariate data analysis. Control subjects included healthy individuals as well as patients with liver cirrhosis or acute myeloid leukemia. We found that HCC was associated with increased plasma levels of glycodeoxycholate, deoxycholate 3-sulfate, and bilirubin. Accurate mass measurement also indicated upregulation of biliverdin and the fetal bile acids 7α-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxochol-4,6-dien-24-oic acid in HCC patients. A quantitative lipid profiling of patient plasma was also conducted by ultraperformance liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (UPLC-ESI-TQMS). By this method, we found that HCC was also associated with reduced levels of lysophosphocholines and in 4 of 20 patients with increased levels of lysophosphatidic acid [LPA(16:0)], where it correlated with plasma α-fetoprotein levels. Interestingly, when fatty acids were quantitatively profiled by gas chromatography-mass spectrometry (GC-MS), we found that lignoceric acid (24:0) and nervonic acid (24:1) were virtually absent from HCC plasma. Overall, this investigation illustrates the power of the new discovery technologies represented in the UPLC-ESI-QTOFMS platform combined with the targeted, quantitative platforms of UPLC-ESI-TQMS and GC-MS for conducting metabolomic investigations that can engender new insights into cancer pathobiology.
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Affiliation(s)
- Andrew D Patterson
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
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Monte MJ, Marin JJG, Antelo A, Vazquez-Tato J. Bile acids: Chemistry, physiology, and pathophysiology. World J Gastroenterol 2009; 15:804-16. [PMID: 19230041 PMCID: PMC2653380 DOI: 10.3748/wjg.15.804] [Citation(s) in RCA: 392] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The family of bile acids includes a group of molecular species of acidic steroids with very peculiar physical-chemical and biological characteristics. They are synthesized by the liver from cholesterol through several complementary pathways that are controlled by mechanisms involving fine-tuning by the levels of certain bile acid species. Although their best-known role is their participation in the digestion and absorption of fat, they also play an important role in several other physiological processes. Thus, genetic abnormalities accounting for alterations in their synthesis, biotransformation and/or transport may result in severe alterations, even leading to lethal situations for which the sole therapeutic option may be liver transplantation. Moreover, the increased levels of bile acids reached during cholestatic liver diseases are known to induce oxidative stress and apoptosis, resulting in damage to the liver parenchyma and, eventually, extrahepatic tissues. When this occurs during pregnancy, the outcome of gestation may be challenged. In contrast, the physical-chemical and biological properties of these compounds have been used as the bases for the development of drugs and as pharmaceutical tools for the delivery of active agents.
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Stärkel P, Shindano T, Horsmans Y, Gigot JF, Fernandez-Tagarro M, Marin JJG, Monte MJ. Foetal 'flat' bile acids reappear during human liver regeneration after surgery. Eur J Clin Invest 2009; 39:58-64. [PMID: 19087130 DOI: 10.1111/j.1365-2362.2008.02059.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Changes in bile acid (BA) pool, such as the reappearance of typically foetal-type molecular species with a 'flat' structure at the steroid ring, occur during hepatocarcinogenesis, both in humans and rodents. Moreover flat-BAs also appear during rat liver regeneration. These changes can be detected in urine. The aim of the present study was to investigate whether flat-BAs also reappear during human liver regeneration, and whether this change correlates with the magnitude of liver resection. MATERIALS AND METHODS Patients undergoing partial hepatectomy were divided in two groups: major hepatectomy group (> 50% of hepatic tissue resection, n = 17) and minor hepatectomy group (< 50%, n = 13). BAs were extracted from serum and urine (collected over 24 h) and analysed by gas chromatography-mass spectrometry. Samples were obtained before surgery (day 0) and on the third and seventh days after hepatectomy. RESULTS In serum, total BAs significantly increased on day seven after hepatectomy, but only a moderate increase in flat-BA concentrations was observed. By contrast, urinary excretion of total as well as flat-BAs significantly increased at day three and day seven after hepatectomy. Moreover, the amount of flat-BAs excreted in urine during the first week after partial hepatectomy correlated with the magnitude of the resection. CONCLUSIONS Urinary BA output increases and flat-BAs reappear in urine during human liver regeneration. These results suggest that determination of BAs in urine may be an interesting parameter obtained by non-invasive techniques whose actual clinical value during human liver regeneration warrants further evaluation.
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Affiliation(s)
- P Stärkel
- Department of Gastroenterology, St. Luc University Hospital, Brussels, Belgium.
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17
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Cuesta de Juan S, Monte MJ, Macias RIR, Wauthier V, Calderon PB, Marin JJG. Ontogenic development-associated changes in the expression of genes involved in rat bile acid homeostasis. J Lipid Res 2007; 48:1362-70. [PMID: 17332599 DOI: 10.1194/jlr.m700034-jlr200] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Ontogenic changes in the rat bile acid (BA) pool, measured enzymatically and by GC-MS, and expression of enzymes (5alpha-reductase, 5beta-reductase, and cytochrome P450 enzymes Cyp7a1, Cyp8b1, Cyp27 and Cyp3a11), transporters [bile salt export pump, sodium taurocholate-cotransporting polypeptide, apical sodium-dependent bile acid transporter, and organic solute transporter alpha/beta (Ostalpha/Ostbeta)], and nuclear receptors [fetoprotein transcription factor (Ftf), farnesoid X receptor (Fxr), small heterodimer partner (Shp), and hepatic nuclear factor 4alpha (HNF-4alpha)], determined by quantitative PCR, were investigated. The absolute size of the BA pool increased progressively up to adulthood, whereas the complexity of its composition was high in fetuses, decreased after birth, increased again progressively up to adulthood, and decreased in aged animals. Allo-cholic acid only appeared early in development, in spite of low 5alpha-reductase expression. The relative size of the BA pool, corrected by liver weight, was maintained from 1 week after birth, except at weaning, when a transient peak accompanied by Shp downregulation and Cyp7a1 upregulation was observed. An imposed weaning delay of 1 week had no effect on the time course of the BA pool size but decreased the proportion of chenodeoxycholic and alpha-muricholic acids, whereas the proportion of cholic acid was increased, probably as a result of Cyp8b1 upregulation. In conclusion, changes in the expression of genes involved in BA homeostasis may play a role in physiological adaptations to digestive functions during the rat life span.
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Affiliation(s)
- Susana Cuesta de Juan
- Laboratory of Experimental Hepatology and Drug Targeting, Centro de Investigación Biomédica en Red for Hepatology and Gastroenterology Research (CIBERehd), University of Salamanca, Salamanca, Spain
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18
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Vallejo M, Briz O, Serrano MA, Monte MJ, Marin JJG. Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy. J Hepatol 2006; 44:1150-7. [PMID: 16458994 DOI: 10.1016/j.jhep.2005.09.017] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2005] [Revised: 09/20/2005] [Accepted: 09/22/2005] [Indexed: 12/27/2022]
Abstract
BACKGROUND/AIMS Progesterone metabolites such as 5alpha-pregnan-3alpha-ol-20-one (PM4) are elevated in serum of women with intrahepatic cholestasis of pregnancy (ICP). METHODS/RESULTS When assayed in isolated perfused rat liver, PM4 did not induce cholestasis, whereas sulfated PM4 (PM4-S), which unlike PM4 is secreted into bile, reduced bile flow and bile acid (BA) output. Whether PM4-S inhibited the bile salt export pump (BSEP) was investigated. Radiolabeled methylesters (ME) of cholic acid and chenodeoxycholic acid were taken up by Xenopus laevis oocytes co-expressing rat BSEP and human carboxylesterase-1 (CES1), efficiently hydrolyzed to free BAs by CES1 and subsequently exported by BSEP. Rifampicin or cyclosporin A in the extracellular medium had no effect on BA efflux. In contrast, estradiol 17beta-D-glucuronide and several progesterone metabolites, including PM4-S, induced a marked non-competitive trans-inhibition of BSEP-mediated BA efflux (Ki=20-60 microM). Mitochondrial activity was markedly impaired in oocytes incubated with BA-MEs, but not with free BAs. Co-expression of CES1 and BSEP partly protected oocytes from this toxic effect. Trans-inhibition of BSEP abolished this protection. CONCLUSIONS Several estrogens and progesterone metabolites are able to induce trans-inhibition of BSEP and the subsequent toxicity induced by the accumulation of BAs, which may play a role in the etiopathogenesis of ICP.
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Affiliation(s)
- Marta Vallejo
- Laboratory of Experimental Hepatology and Drug Targeting, University of Salamanca, Salamanca, Spain
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19
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Monte MJ, Fernandez-Tagarro M, Macias RIR, Jimenez F, Gonzalez-San Martin F, Marin JJG. Changes in the expression of genes related to bile acid synthesis and transport by the rat liver during hepatocarcinogenesis. Clin Sci (Lond) 2005; 109:199-207. [PMID: 15853769 DOI: 10.1042/cs20050035] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The relationship between BA (bile acid) secretion (measured by GC–MS) and the expression of genes (measured by reverse transcription real-time PCR) involved in liver BA transport and metabolism was investigated at 20 and 32 weeks during rat hepatocarcinogenesis. A progressive loss of mRNA for transporters (more marked for Ntcp, Bsep and Mrp2 than for Oatp1/Oatp1a1, Oatp2/Oatp1a4 and Oatp4/Oatp1b2) was found. The mRNA levels of Cyp7a1 and the nuclear receptors FXR (farnesoid X receptor), SHP (small heterodimer partner) and FTF (α-fetoprotein transcription factor) were not modified, whereas those of Cyp8b1 were enhanced and those of Cyp27 were reduced. Biliary secretion of CA (cholic acid) remained unchanged, whereas that of CDCA (chenodeoxycholic acid) and other non-C12-hydroxylated BAs was diminished. The re-appearance of ‘flat-BAs’ (mainly allo-BAs at 20 weeks and Δ4-unsaturated-BAs at 32 weeks) probably reflects the progressive decrease observed in the expression of 3-oxo-Δ4-steroid 5β-reductase, together with the maintenance of steroid 5α-reductase type I. A significant correlation between the 5α-reductase/5β-reductase ratio and bile output of ‘flat-BAs’ was found. In conclusion, during rat hepatocarcinogenesis, the expression of transporters/enzymes responsible for BA homoeostasis is changed due to mechanisms other than those controlled by FXR/SHP/FTF. These modifications result in the re-appearance of ‘flat-BAs’, together with an increased CA/CDCA ratio in bile.
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Affiliation(s)
- Maria J Monte
- Laboratory of Experimental Hepatology and Drug Targeting, Department of Physiology and Pharmacology, University of Salamanca, Spain
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20
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Monte MJ, Fernandez-Tagarro M, Marin JJG. Transient changes in the expression pattern of key enzymes for bile acid synthesis during rat liver regeneration. Biochim Biophys Acta Mol Cell Biol Lipids 2005; 1734:127-35. [PMID: 15904869 DOI: 10.1016/j.bbalip.2005.02.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2004] [Revised: 02/17/2005] [Accepted: 02/18/2005] [Indexed: 12/23/2022]
Abstract
Changes in the expression patterns of genes involved in bile acid (BA) synthesis were investigated during rat liver regeneration that follows two-thirds partial hepatectomy. BAs in bile were measured by GC-MS and the absolute and relative abundance of specific mRNAs in the liver by RT-real-time quantitative PCR. Cyclin E mRNA, used as an indicator of liver cell proliferation, peaked at day 1. The levels of mRNA of alpha-fetoprotein transcription factor (FTF) and small heterodimer partner (SHP) were first reduced (day 1) and then (days 2-3) increased, when those of farnesoid X receptor (FXR) were also transiently enhanced. The early (day 1) up-regulation of Cyp7a1, and Cyp8b1, together with the down-regulation of Cyp27, was consistent with an increased proportion of cholic acid versus chenodeoxycholic acid and a progressive recovery in total BAs secretion. The transient appearance of flat BAs (allo-BAs plus Delta4-unsaturated-BAs) during rat liver regeneration was probably due to the changes in the expression ratio of steroid 5alpha- versus 5beta-reductase. Both were first (day 1) down-regulated and then up-regulated (5alpha-reductase more than 5beta-reductase). In conclusion, changes in the expression patterns of nuclear receptors and enzymes involved in BA synthesis are consistent with the transient modifications that occur in BA pool during rat liver regeneration.
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Affiliation(s)
- Maria J Monte
- Department of Physiology and Pharmacology, Campus Miguel de Unamuno E.I.D. S-09, University of Salamanca, 37007 Salamanca, Spain
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21
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Jorquera F, Monte MJ, Guerra J, Sanchez-Campos S, Merayo JA, Olcóz JL, González-Gallego J, Marin JJG. Usefulness of combined measurement of serum bile acids and ferritin as additional prognostic markers to predict failure to reach sustained response to antiviral treatment in chronic hepatitis C. J Gastroenterol Hepatol 2005; 20:547-54. [PMID: 15836702 DOI: 10.1111/j.1440-1746.2005.03725.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIM To investigate the relationship between serum levels of ferritin and bile acids (BA) and the response to antiviral treatment in chronic hepatitis C (HCV). METHODS A retrospective study was carried out on 35 control volunteers and 50 patients receiving interferon alpha-2b alone or plus ribavirin for 48 weeks. These were classified as sustained responders (SR) for >6 months after therapy (n = 17), non-responders (NR) (n = 27) and relapsers (RL) (n = 6). Before treatment, serum ferritin levels were determined by immunoturbidometry, 3alpha-hydroxyl-BA levels (S-3alpha-OH-BA) were assayed enzymatically and total (desulfated, deglucuronidated and deamidated) BA concentrations (STBA) by gas chromatography-mass spectrometry. RESULTS STBA were lower in controls than in patients (SR < NR + RL). The highest levels of cholic acid and chenodeoxycholic acid families were found in NR + RL. Levels of cholic acid family were similar in controls and SR, whereas those of chenodeoxycholic acid family were higher in SR than in controls. A significant correlation between STBA (but not S-3alpha-OH-BA) and ferritin was found. Apparent value to predict the absence of a sustained response was calculated by combining elevated ferritin (>300 microg/mL) and STBA or individual BA species at different cut-off values. The best degree of certainty (100% specificity) was obtained using STBA >15 microM. CONCLUSION These results recommend that larger prospective trials should be performed in chronic HCV patients to evaluate the usefulness of combined measuring of STBA and ferritin as additional prognostic markers to predict the existence of a very low probability of a sustained response to the current standard treatment, i.e. pegylated interferon in combination with ribavirin.
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Affiliation(s)
- Francisco Jorquera
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
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22
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Abstract
In the adult, several endogenous compounds, such as bile acids and biliary pigments, as well as many xenobiotics are mainly biotransformed and eliminated by the hepatobiliary system. However, because this function is immature in the foetus, this role is carried out by the placenta during the intrauterine life. This review describes current knowledge of the trophoblastic machinery responsible for this function, which includes transport and metabolic processes, similar in part to those existing in the mature liver. Because many of the studies reviewed here were conducted on human or rat near-term placentae, two aspects should be borne in mind: (i) although both types of placenta are haemochorial, profound species-specific differences at the structural, molecular and functional levels do exist, and (ii) the placenta is an organ undergoing continuous developmental changes, including its hepatobiliary-like excretory function.
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Affiliation(s)
- J J G Marin
- Department of Physiology, University of Salamanca, Spain.
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Mendoza ME, Monte MJ, Serrano MA, Pastor-Anglada M, Stieger B, Meier PJ, Medarde M, Marin JJG. Physiological characteristics of allo-cholic acid. J Lipid Res 2003; 44:84-92. [PMID: 12518026 DOI: 10.1194/jlr.m200220-jlr200] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The physiological characterstics of allo-cholic acid (ACA), a typically fetal bile acid that reappears during liver regeneration and carcinogenesis were investigated. [(14)C] Tauro-ACA (TACA) uptake by Chinese hamster ovary cells expressing rat organic anion transporter polypeptide (Oatp)1 or sodium-taurocholate cotransporter polypeptide (Ntcp) was lower than that of [(14)C]taurocholic acid (TCA). Although TACA inhibited ATP-dependent TCA transport across plasma membrane vesicles from Sf9 cells expressing rat or mouse bile salt export pump (Bsep), no ATP-dependent TACA transport was found. In rats, TACA was secreted into bile with no major biotransformation and it had lower clearance and longer half-life than TCA. In mice, TACA bile output was lower (-50%) than that of TCA, whereas TACA induced 9-fold higher bile flow than TCA. Even though the intracellular levels were lower for TACA, translocation into the hepatocyte nucleus was higher for TACA than for TCA; however, rate of DNA synthesis, expression levels of alpha-fetoprotein, albumin, Ntcp, and Bsep, cell viability, and apoptosis in rat hepatocytes were similarly affected by both isomers. In conclusion, TACA partly shares hepatocellular uptake system(s) for TCA. Furthermore, in contrast to other "flat" bile acids, TACA is efficiently secreted into bile via transport system(s) other than Bsep and is highly choleretic, hence its appearance during certain situations may prevent accumulation of cholestatic precursors.
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Affiliation(s)
- Maria E Mendoza
- Department of Physiology and Pharmacology, University of Salamanca, Spain
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Monte MJ, Martinez-Diez MC, El-Mir MY, Mendoza ME, Bravo P, Bachs O, Marin JJG. Changes in the pool of bile acids in hepatocyte nuclei during rat liver regeneration. J Hepatol 2002; 36:534-42. [PMID: 11943426 DOI: 10.1016/s0168-8278(01)00296-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND/AIMS To investigate changes in nuclear bile acids (BAs) during rat liver regeneration. METHODS Nuclei were isolated from control rat livers and after two-thirds partial hepatectomy (PH). BAs in bile, liver homogenate and nuclei were measured by gas chromatography-mass spectrometry. Nuclear translocation of radiolabeled BAs was determined using fresh isolated hepatocytes from control donors. RESULTS Liver BA concentrations were transiently reduced after PH. Relative increases in: -MCA at 1 day, deoxycholic acid at 7 days and cholic acid (CA) at 3 and 14 days were found. Nuclear BAs accounted for <0.5% of liver BAs. Contamination with cytosolic BAs during nuclei isolation was <4%. Unconjugated- and conjugated-CA were able to reach the nucleus with similar efficiency. The pattern of nuclear BAs--CA (80%) and ursodeoxycholic acid (UDCA) (8.5%) being the most abundant--did not match that found in liver or bile. A transient decrease in CA/UDCA ratio, in absence of significant change in total BA content, was observed in nuclei after PH. "Flat" BA species were only detected in homogenate, but not in nuclei, at 1 day after PH. CONCLUSIONS BA pool in nuclei of rat hepatocytes, whose composition is different to that of total liver BA pool, undergoes important changes during liver regeneration.
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Affiliation(s)
- Maria J Monte
- Department of Physiology and Pharmacology, University of Salamanca, Campus Miguel de Unamuno, E.I.D. S-09 37007, Salamanca, Spain
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Monte MJ, Badia MD, Serrano MA, Sacristan MP, Cassio D, Marin JJ. Predominance of human versus rat phenotype in the metabolic pathways for bile acid synthesis by hybrid WIF-B9 cells. BIOCHIMICA ET BIOPHYSICA ACTA 2001; 1534:45-55. [PMID: 11750886 DOI: 10.1016/s1388-1981(01)00175-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The rat hepatoma-human fibroblast hybrid cell line WIF-B9 stably exhibits the structural and functional characteristics of normal differentiated hepatocytes. The abilities of these cells to synthesize bile acids and amidate them with glycine and taurine were investigated. The release of bile acids into the culture media over 72 h was assessed by gas chromatography-mass spectrometry. WIF-B9 cells were able to synthesize bile acids (1.10+/-0.17 nmol/mg protein) but less efficiently than rat hepatocytes in primary culture (2.19+/-0.19 nmol/mg protein; P<0.01). The patterns of major bile acid species produced by both types of cells were also different. Cholic acid (CA; 72%) and beta-muricholic acid (19%) were the major bile acids produced by rat hepatocytes, while chenodeoxycholic acid (CDCA) accounted for only 4.5% of total bile acids. In contrast, muricholic acids were absent, while CA (62%) and CDCA (34%) were the most abundant bile acids synthesized by WIF-B9 cells. Using reverse transcription-polymerase chain reaction and gene- and species-specific primers for key enzymes involved in bile acid synthesis, the expression of human, but not rat, orthologues of CYP7A1, CYP27, CYP8B and CYP7B1 was found in WIF-B9 cells. Induction of cell stress by serum deprivation did not change the amount of total bile acids synthesized by these cells, but an inversion of the CA-to-CDCA ratio from 1.8 to 0.3 together with a marked increase in the proportion of intermediate metabolites related to the acidic pathway was found. Using 500 microM radiolabeled CA and 2 mM of taurine or glycine, the ability to amidate CA over 48 h was determined by high performance liquid chromatography. Rat hepatocytes conjugated more than 90% CA with either amino acid, whereas this ability was very poor (< 2%) in WIF-B9 cells. Regarding the expression of enzymes and the products of bile acid synthesis, it may be concluded that the human phenotype predominates over that of the rat in WIF-B9 cells. Moreover, these cells are almost completely unable to further conjugate primary bile acids, which facilitates the manipulation of these steroids in analytical procedures. These characteristics make WIF-B9 cells a suitable in vitro model to carry out studies on bile acid synthesis by 'human-like' metabolic pathways.
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