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1
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Zhang X, Shi L, Lu X, Zheng W, Shi J, Yu S, Feng H, Yu Z. Bile Acids and Liver Cancer: Molecular Mechanism and Therapeutic Prospects. Pharmaceuticals (Basel) 2024; 17:1142. [PMID: 39338306 PMCID: PMC11435149 DOI: 10.3390/ph17091142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/08/2024] [Accepted: 08/27/2024] [Indexed: 09/30/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive liver malignancy and one of the most lethal cancers globally, with limited effective therapeutic options. Bile acids (BAs), as primary metabolites of hepatic cholesterol, undergo enterohepatic circulation involving secretion into the intestine and reabsorption into the liver, and their composition is modulated in this process. Recent clinical observations have revealed a correlation between alteration in the BAs profile and HCC incidence, and the effect of various species of BAs on HCC development has been investigated. The regulatory effect of different BA species on cell proliferation, migration, and apoptosis in tumor cells, as well as their interaction with gut microbiota, inflammation, and immunity have been identified to be involved in HCC progression. In this review, we summarize the current understanding of the diverse functions of BAs in HCC pathogenesis and therapy, from elucidating the fundamental mechanisms underlying both tumor-promoting and tumor-suppressive consequences of various BA species to exploring potential strategies for leveraging BAs for HCC therapy. We also discuss ongoing efforts to target specific BA species in HCC treatment while highlighting new frontiers in BA biology that may inspire further exploration regarding their connection to HCC.
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Affiliation(s)
- Xuemei Zhang
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.Z.); (X.L.); (W.Z.); (J.S.); (S.Y.)
| | - Lei Shi
- Department of Clinical Laboratory, Shuguang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai 201203, China;
| | - Xiaona Lu
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.Z.); (X.L.); (W.Z.); (J.S.); (S.Y.)
| | - Wenlan Zheng
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.Z.); (X.L.); (W.Z.); (J.S.); (S.Y.)
| | - Jia Shi
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.Z.); (X.L.); (W.Z.); (J.S.); (S.Y.)
| | - Shihan Yu
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.Z.); (X.L.); (W.Z.); (J.S.); (S.Y.)
| | - Hai Feng
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhuo Yu
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.Z.); (X.L.); (W.Z.); (J.S.); (S.Y.)
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2
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Fleishman JS, Kumar S. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:97. [PMID: 38664391 PMCID: PMC11045871 DOI: 10.1038/s41392-024-01811-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/06/2024] [Accepted: 03/17/2024] [Indexed: 04/28/2024] Open
Abstract
Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.
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Affiliation(s)
- Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
| | - Sunil Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA.
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3
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He J, Li H, Jia J, Liu Y, Zhang N, Wang R, Qu W, Liu Y, Jia L. Mechanisms by which the intestinal microbiota affects gastrointestinal tumours and therapeutic effects. MOLECULAR BIOMEDICINE 2023; 4:45. [PMID: 38032415 PMCID: PMC10689341 DOI: 10.1186/s43556-023-00157-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/08/2023] [Indexed: 12/01/2023] Open
Abstract
The intestinal microbiota is considered to be a forgotten organ in human health and disease. It maintains intestinal homeostasis through various complex mechanisms. A significant body of research has demonstrated notable differences in the gut microbiota of patients with gastrointestinal tumours compared to healthy individuals. Furthermore, the dysregulation of gut microbiota, metabolites produced by gut bacteria, and related signal pathways can partially explain the mechanisms underlying the occurrence and development of gastrointestinal tumours. Therefore, this article summarizes the latest research progress on the gut microbiota and gastrointestinal tumours. Firstly, we provide an overview of the composition and function of the intestinal microbiota and discuss the mechanisms by which the intestinal flora directly or indirectly affects the occurrence and development of gastrointestinal tumours by regulating the immune system, producing bacterial toxins, secreting metabolites. Secondly, we present a detailed analysis of the differences of intestinal microbiota and its pathogenic mechanisms in colorectal cancer, gastric cancer, hepatocellular carcinoma, etc. Lastly, in terms of treatment strategies, we discuss the effects of the intestinal microbiota on the efficacy and toxic side effects of chemotherapy and immunotherapy and address the role of probiotics, prebiotics, FMT and antibiotic in the treatment of gastrointestinal tumours. In summary, this article provides a comprehensive review of the pathogenic mechanisms of and treatment strategies pertaining to the intestinal microbiota in patients with gastrointestinal tumours. And provide a more comprehensive and precise scientific basis for the development of microbiota-based treatments for gastrointestinal tumours and the prevention of such tumours.
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Affiliation(s)
- Jikai He
- Central Laboratory, Bayannur Hospital, Bayannur, 015000, Inner Mongolia, China
| | - Haijun Li
- Department of Gastrointestinal Surgery, Inner Mongolia Autonomous Region People's Hospital, Hohhot, 010017, Inner Mongolia, China
| | - Jiaqi Jia
- Graduate School of Youjiang Medical University for Nationalities, No. 98 Chengcheng Road, Youjiang District, Baise City, 533000, China
| | - Yang Liu
- Central Laboratory, Bayannur Hospital, Bayannur, 015000, Inner Mongolia, China
| | - Ning Zhang
- Central Laboratory, Bayannur Hospital, Bayannur, 015000, Inner Mongolia, China
| | - Rumeng Wang
- Central Laboratory, Bayannur Hospital, Bayannur, 015000, Inner Mongolia, China
| | - Wenhao Qu
- Graduate School of Youjiang Medical University for Nationalities, No. 98 Chengcheng Road, Youjiang District, Baise City, 533000, China
| | - Yanqi Liu
- Department of Gastroenterology, Affiliated Hospital of Inner Mongolia Medical University, Hohhot City, 010050, Inner Mongolia, China.
| | - Lizhou Jia
- Central Laboratory, Bayannur Hospital, Bayannur, 015000, Inner Mongolia, China.
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4
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Guan Z, Luo L, Liu S, Guan Z, Zhang Q, Wu Z, Tao K. The role of TGR5 as an onco-immunological biomarker in tumor staging and prognosis by encompassing the tumor microenvironment. Front Oncol 2022; 12:953091. [PMID: 36338742 PMCID: PMC9630950 DOI: 10.3389/fonc.2022.953091] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/22/2022] [Indexed: 11/29/2022] Open
Abstract
The relationship between G protein–coupled bile acid receptor 1 (TGR5, GPBAR1) and, specifically, cancer has been studied in in vivo and in vitro experiments, but there is still a lack of pan-cancer analysis to understand the prognostic significance and functioning mechanism of TGR5 in different cancer-driving oncogenic processes. Here, we used Gene Expression Integration, Human Protein Atlas, and The Cancer Genome Atlas (TCGA) to perform a pan-cancer analysis of the role of TGR5 in all 33 tumors. In all TCGA tumors, the TGR5 gene expression has been assessed, and we found that the high TGR5 gene expression in most cancers is associated with poor prognosis of overall survival for cancers such as glioblastoma multiforme (p = 0.0048), kidney renal papillary cell carcinoma (p = 0.033), lower grade glioma (p = 0.0028), thymoma (p = 0.048), and uveal melanoma (p = 0.004), and then the lower expression of TGR5 was linked with poor prognosis in cervical squamous cell carcinoma and endocervical adenocarcinoma (p = 0.014), malignant mesothelioma (MESO) (p = 0.048), sarcoma (p = 0.018), and skin cutaneous melanoma (p = 0.0085). The TGR5 expression was linked with the immune infiltration level of the macrophage M2_TIDE and was also associated with DNA methylation in ovarian and breast cancers. The regulation of hormone secretion, Rap1 pathway, osteoclast differentiation, and bile acid pathway was involved in the functional mechanism of TGR5. Besides, gene expressions were different in different tumors detected by RT-PCR, and cell activity experiments have also found that TGR5 can increase the activity of renal cell carcinoma and reduce the activity of skin cancer and osteosarcoma cells. In this investigation, the aim was to assess the comprehensive overview of the oncogenic roles of TGR5 in all TCGA tumors using pan-analysis.
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Affiliation(s)
- Zhiyuan Guan
- Department of Orthopedics, The Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Liying Luo
- Department of Ophthalmology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shengfu Liu
- Department of Orthopedics, The Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Zhiqiang Guan
- Department of Dermatology, Xuzhou Municipal Hospital Affiliated With Xuzhou Medical University, Xuzhou, China
- *Correspondence: Kun Tao, ; Zhong Wu, ; Qinggang Zhang, ; Zhiqiang Guan,
| | - Qinggang Zhang
- Department of Orthopedics, The Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
- *Correspondence: Kun Tao, ; Zhong Wu, ; Qinggang Zhang, ; Zhiqiang Guan,
| | - Zhong Wu
- Department of Orthopedics, The Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
- *Correspondence: Kun Tao, ; Zhong Wu, ; Qinggang Zhang, ; Zhiqiang Guan,
| | - Kun Tao
- Department of Orthopedics, The Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
- *Correspondence: Kun Tao, ; Zhong Wu, ; Qinggang Zhang, ; Zhiqiang Guan,
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Luo W, Guo S, Zhou Y, Zhu J, Zhao J, Wang M, Sang L, Wang B, Chang B. Hepatocellular carcinoma: Novel understandings and therapeutic strategies based on bile acids (Review). Int J Oncol 2022; 61:117. [PMID: 35929515 PMCID: PMC9450808 DOI: 10.3892/ijo.2022.5407] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 07/26/2022] [Indexed: 11/06/2022] Open
Abstract
Bile acids (BAs) are the major components of bile and products of cholesterol metabolism. Cholesterol is catalyzed by a variety of enzymes in the liver to form primary BAs, which are excreted into the intestine with bile, and secondary BAs are formed under the modification of the gut microbiota. Most of the BAs return to the liver via the portal vein, completing the process of enterohepatic circulation. BAs have an important role in the development of hepatocellular carcinoma (HCC), which may participate in the progression of HCC by recognizing receptors such as farnesoid X receptor (FXR) and mediating multiple downstream pathways. Certain BAs, such as ursodeoxycholic acid and obeticholic acid, were indicated to be able to delay liver injury and HCC progression. In the present review, the structure and function of BAs were introduced and the metabolism of BAs and the process of enterohepatic circulation were outlined. Furthermore, the mechanisms by which BAs participate in the development of HCC were summarized and possible strategies for targeting BAs and key sites of their metabolic processes to treat HCC were suggested.
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Affiliation(s)
- Wenyu Luo
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Shiqi Guo
- 104K class 87, The Second Clinical College, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Yang Zhou
- 104K class 87, The Second Clinical College, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Junfeng Zhu
- Department of Clinical Laboratory, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, P.R. China
| | - Jingwen Zhao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Mengyao Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Lixuan Sang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Bingyuan Wang
- Department of Geriatric Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Bing Chang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110122, P.R. China
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Režen T, Rozman D, Kovács T, Kovács P, Sipos A, Bai P, Mikó E. The role of bile acids in carcinogenesis. Cell Mol Life Sci 2022; 79:243. [PMID: 35429253 PMCID: PMC9013344 DOI: 10.1007/s00018-022-04278-2] [Citation(s) in RCA: 146] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/03/2022] [Accepted: 03/28/2022] [Indexed: 12/17/2022]
Abstract
AbstractBile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; however, other tissues have also the capacity to generate bile acids (e.g. ovaries). Hepatic bile acids are then transported to bile and are subsequently released into the intestines. In the large intestine, a fraction of primary bile acids is converted to secondary bile acids by gut bacteria. The majority of the intestinal bile acids undergo reuptake and return to the liver. A small fraction of secondary and primary bile acids remains in the circulation and exert receptor-mediated and pure chemical effects (e.g. acidic bile in oesophageal cancer) on cancer cells. In this review, we assess how changes to bile acid biosynthesis, bile acid flux and local bile acid concentration modulate the behavior of different cancers. Here, we present in-depth the involvement of bile acids in oesophageal, gastric, hepatocellular, pancreatic, colorectal, breast, prostate, ovarian cancer. Previous studies often used bile acids in supraphysiological concentration, sometimes in concentrations 1000 times higher than the highest reported tissue or serum concentrations likely eliciting unspecific effects, a practice that we advocate against in this review. Furthermore, we show that, although bile acids were classically considered as pro-carcinogenic agents (e.g. oesophageal cancer), the dogma that switch, as lower concentrations of bile acids that correspond to their serum or tissue reference concentration possess anticancer activity in a subset of cancers. Differences in the response of cancers to bile acids lie in the differential expression of bile acid receptors between cancers (e.g. FXR vs. TGR5). UDCA, a bile acid that is sold as a generic medication against cholestasis or biliary surge, and its conjugates were identified with almost purely anticancer features suggesting a possibility for drug repurposing. Taken together, bile acids were considered as tumor inducers or tumor promoter molecules; nevertheless, in certain cancers, like breast cancer, bile acids in their reference concentrations may act as tumor suppressors suggesting a Janus-faced nature of bile acids in carcinogenesis.
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Affiliation(s)
- Tadeja Režen
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Damjana Rozman
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tünde Kovács
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary
| | - Patrik Kovács
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
| | - Adrienn Sipos
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
| | - Péter Bai
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Edit Mikó
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary.
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary.
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Fu J, Yu M, Xu W, Yu S. Research Progress of Bile Acids in Cancer. Front Oncol 2022; 11:778258. [PMID: 35127481 PMCID: PMC8810494 DOI: 10.3389/fonc.2021.778258] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 12/27/2021] [Indexed: 01/09/2023] Open
Abstract
Bile acids (BAs) were originally known as detergents to facilitate the digestion and absorption of lipids. And our current knowledge of BAs has been extended to potential carcinogenic or cancer suppressor factors due to constant research. In fact, BAs were regarded as a tumor promoters as early as the 1940s. Differential bile acid signals emitted by various bile acid profiles can produce distinct pathophysiological traits, thereby participating in the occurrence and development of tumors. Nevertheless, in recent years, more and more studies have noticed the value of BAs as therapeutic targets. And several studies have applied BAs as a therapeutic agent for various diseases including cancer. Based on the above evidence, we acknowledge that the role of BAs in cancer has yet to be exploited, although considerable efforts have been made to probe the functions of BAs. In this review, we describe the characteristics of BAs as a double-edged sword in cancer, hoping to provide references for future cancer treatments.
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Affiliation(s)
- Junhao Fu
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Min Yu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Wenxia Xu
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Shian Yu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
- *Correspondence: Shian Yu,
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Zhang Q, He Z, Liu Z, Gong L. Integrated plasma and liver gas chromatography mass spectrometry and liquid chromatography mass spectrometry metabolomics to reveal physiological functions of sodium taurocholate cotransporting polypeptide (NTCP) with an Ntcp knockout mouse model. J Chromatogr B Analyt Technol Biomed Life Sci 2021; 1165:122531. [DOI: 10.1016/j.jchromb.2021.122531] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 12/10/2020] [Accepted: 01/05/2021] [Indexed: 12/12/2022]
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Lu X, Liu L, Shan W, Kong L, Chen N, Lou Y, Zeng S. The Role of the Sodium-taurocholate Co-transporting Polypeptide (NTCP) and Bile Salt Export Pump (BSEP) in Related Liver Disease. Curr Drug Metab 2019; 20:377-389. [PMID: 31258056 DOI: 10.2174/1389200220666190426152830] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 03/10/2019] [Accepted: 03/26/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Sodium Taurocholate Co-transporting Polypeptide (NTCP) and Bile Salt Export Pump (BSEP) play significant roles as membrane transporters because of their presence in the enterohepatic circulation of bile salts. They have emerged as promising drug targets in related liver disease. METHODS We reviewed the literature published over the last 20 years with a focus on NTCP and BSEP. RESULTS This review summarizes the current perception about structure, function, genetic variation, and regulation of NTCP and BSEP, highlights the effects of their defects in some hepatic disorders, and discusses the application prospect of new transcriptional activators in liver diseases. CONCLUSION NTCP and BSEP are important proteins for transportation and homeostasis maintenance of bile acids. Further research is needed to develop new models for determining the structure-function relationship of bile acid transporters and screening for substrates and inhibitors, as well as to gain more information about the regulatory genetic mechanisms involved in the processes of liver injury.
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Affiliation(s)
- Xiaoyang Lu
- The First Affiliated Hospital, Zhejiang University, Zhejiang, China
| | - Lin Liu
- The First Affiliated Hospital, Zhejiang University, Zhejiang, China
| | - Wenya Shan
- The First Affiliated Hospital, Zhejiang University, Zhejiang, China
| | - Limin Kong
- The First Affiliated Hospital, Zhejiang University, Zhejiang, China
| | - Na Chen
- The First Affiliated Hospital, Zhejiang University, Zhejiang, China
| | - Yan Lou
- The First Affiliated Hospital, Zhejiang University, Zhejiang, China
| | - Su Zeng
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Zhejiang, China
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Jiang JW, Chen XH, Ren Z, Zheng SS. Gut microbial dysbiosis associates hepatocellular carcinoma via the gut-liver axis. Hepatobiliary Pancreat Dis Int 2019; 18:19-27. [PMID: 30527903 DOI: 10.1016/j.hbpd.2018.11.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 09/28/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. Gut microbiota has been demonstrated to play a critical role in liver inflammation, chronic fibrosis, liver cirrhosis, and HCC development through the gut-liver axis. DATA SOURCES Recently there have been several innovative studies investigating gut microbial dysbiosis-mediated enhancement of HCC through the gut-liver axis. Literatures from January 1998 to January 2018 were searched in the PubMed database using the keywords "gut microbiota" and "hepatocellular carcinoma" or "liver cancer", and the results of experimental and clinical studies were analyzed. RESULTS Gut microbial dysbiosis accompanies the progression of alcoholic liver disease, non-alcoholic fatty liver disease and liver cirrhosis, and promotes HCC progression in an experimental mouse model. The immune system and key factors such as Toll-like receptor 4 are involved in the process. There is evidence for gut microbial dysbiosis in hepatitis virus-related HCC patients. CONCLUSIONS Gut microbial dysbiosis is closely associated with hepatic inflammation disease and HCC through the gut-liver axis. With the enhanced understanding of the interactions between gut microbiota and liver through the gut-liver axis, new treatment strategies for HCC are being developed.
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Affiliation(s)
- Jian-Wen Jiang
- Department of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, #79 Qingchun Road, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China; Health Management Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xin-Hua Chen
- Department of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, #79 Qingchun Road, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China
| | - Zhigang Ren
- Department of Infectious Disease, Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Shu-Sen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, #79 Qingchun Road, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China.
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Cho Y, Yoon JH, Yoo JJ, Lee M, Lee DH, Cho EJ, Lee JH, Yu SJ, Kim YJ, Kim CY. Fucoidan protects hepatocytes from apoptosis and inhibits invasion of hepatocellular carcinoma by up-regulating p42/44 MAPK-dependent NDRG-1/CAP43. Acta Pharm Sin B 2015; 5:544-53. [PMID: 26713269 PMCID: PMC4675821 DOI: 10.1016/j.apsb.2015.09.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 08/21/2015] [Accepted: 09/07/2015] [Indexed: 02/07/2023] Open
Abstract
Fucoidan is a traditional Chinese medicine suggested to possess anti-tumor effects. In this study the anti-metastatic effects of fucoidan were investigated in vitro in human hepatocellular carcinoma (HCC) cells (Huh-7 and SNU-761) under normoxic and hypoxic conditions and in vivo using a distant liver metastasis model involving injection of MH134 cells into spleen via the portal vein. Its ability to protect hepatocytes against bile acid (BA)-induced apoptosis was investigated in primary hepatocytes. Fucoidan was found to suppress the invasion of HCC cells through up-regulation of p42/44 MAPK-dependent NDRG-1/CAP43 and partly, under normoxic conditions, through up-regulation of p42/44 MAPK-dependent VMP-1 expression. It also significantly decreased liver metastasis in vivo. As regards its hepatoprotective effect, fucoidan decreased BA-induced hepatocyte apoptosis as shown by the attenuation of caspase-8, and -7 cleavages and suppression of the mobilization of caspase-8 and Fas associated death domain (FADD) into the death-inducing signaling complex. In summary, fucoidan displays inhibitory effects on proliferation of HCC cells and protective effects on hepatocytes. The results suggest fucoidan is a potent suppressor of tumor invasion with hepatoprotective effects.
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Key Words
- BA, bile acid
- CXCL, chemokine ligand
- Cultured hepatocyte
- DISC, death-inducing signaling complex
- DMEM, Dulbecco׳s modified Eagle׳s medium
- DNA, deoxyribonucleic acid
- ELISA, enzyme-linked immunosorbent assay
- FADD, Fas associated death domain
- FBS, fetal bovine serum
- FCS, fetal calf serum
- Fucoidan
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
- GP, glypican
- HCC, hepatocellular carcinoma
- Hepatocellular carcinoma
- Hepatoprotective
- Hypoxia
- IHC, immunohistochemistry
- Invasion
- JNK, c-Jun NH2-terminal kinase
- MAPK, mitogen-activated protein kinase
- MTS, 3,4-(5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt
- NDRG, N-myc downstream-regulated gene
- NDRG-1/CAP43
- PCR, polymerase chain reaction
- RNA, ribonucleic acid
- SD, standard deviation
- SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis
- VMP, vacuole membrane protein
- VMP-1
- WME, William's medium E
- cDNA, complementary DNA
- siRNA, small interfering RNA
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Affiliation(s)
| | - Jung-Hwan Yoon
- Corresponding author. Tel.: +82 2 2072 2228; fax: +82 2 743 6701.
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Hwang SR, Kim IJ, Park JW. Formulations of deoxycholic for therapy: a patent review (2011 – 2014). Expert Opin Ther Pat 2015; 25:1423-40. [DOI: 10.1517/13543776.2016.1102888] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Yu SJ, Bae S, Kang JS, Yoon JH, Cho EJ, Lee JH, Kim YJ, Lee WJ, Kim CY, Lee HS. Hepatoprotective effect of vitamin C on lithocholic acid-induced cholestatic liver injury in Gulo(−/−) mice. Eur J Pharmacol 2015; 762:247-55. [DOI: 10.1016/j.ejphar.2015.06.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 06/01/2015] [Accepted: 06/02/2015] [Indexed: 12/21/2022]
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