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Horikoshi K, Sakai N, Oshima M, Yamauchi H, Ikeda M, Hayashi K, Yanagisawa H, Yamamori F, Kajikawa S, Hayashi D, Koshino A, Sako K, Yuasa T, Tamai A, Minami T, Nakagawa S, Kitajima S, Toyama T, Hara A, Shimizu M, Oota S, Ishida Y, Wada T, Iwata Y. Autotaxin concentrations in peritoneal dialysis effluent reflect peritoneal function. Ther Apher Dial 2025; 29:276-284. [PMID: 39326924 DOI: 10.1111/1744-9987.14211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/13/2024] [Accepted: 09/06/2024] [Indexed: 09/28/2024]
Abstract
INTRODUCTION Peritoneal equilibration test (PET) has been used to monitor peritoneal function. A more convenient marker would be useful in clinical situations including home medical care. Autotaxin is known to leak into the interstitium as vascular permeability increases during the progression of tissue fibrosis. Therefore, we hypothesized that autotaxin concentrations in peritoneal dialysis (PD) effluent might reflect peritoneal function. METHODS This study enrolled 45 patients undergoing PD from 2016 to 2021. Autotaxin concentrations measured in PD effluent were evaluated for their associations with markers obtained from PET. RESULTS Mean age was 69 years, and 33 patients were men. Univariate and multivariate analyses revealed that autotaxin concentrations are associated with dialysate/plasma creatinine ratio, end/start dialysate glucose ratio, and the dip in the dialysate sodium concentration, a marker of ultrafiltration capacity, at baseline (all p < 0.05). CONCLUSIONS Autotaxin concentrations in PD effluent might be an adjunct marker that reflects peritoneal function.
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Affiliation(s)
- Keisuke Horikoshi
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Norihiko Sakai
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
- Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan
| | - Megumi Oshima
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hiroyuki Yamauchi
- Department of Nephrology, Seika Town National Health Insurance Hospital, Kyoto, Japan
| | - Megumi Ikeda
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Kaho Hayashi
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hiroyoshi Yanagisawa
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Fumitaka Yamamori
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Sho Kajikawa
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Daiki Hayashi
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akihiko Koshino
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Keisuke Sako
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Takahiro Yuasa
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akira Tamai
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Taichiro Minami
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Shiori Nakagawa
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Shinji Kitajima
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
- Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan
| | - Tadashi Toyama
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akinori Hara
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Miho Shimizu
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Satoshi Oota
- Department of Internal medicine, Toyama City Hospital, Toyama, Japan
| | - Yoichi Ishida
- Department of Internal medicine, Toyama City Hospital, Toyama, Japan
| | - Takashi Wada
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Yasunori Iwata
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
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Hyeong Lee S, Jin Park S, Young Lee M, Young Choi J, Dae Jang W, Jang J, Hyun Lee J, Jo Lim C, Oh KS. Design, synthesis and evaluation of 3-(2-(substituted benzyloxy)benzylidene) pyrrolidine-2,5-dione derivatives for novel ATX inhibitor. Bioorg Med Chem Lett 2024; 114:130006. [PMID: 39477127 DOI: 10.1016/j.bmcl.2024.130006] [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: 09/03/2024] [Revised: 10/16/2024] [Accepted: 10/23/2024] [Indexed: 11/07/2024]
Abstract
Autotaxin (ATX) has emerged as a promising therapeutic target for liver diseases. In this study, we identified potential drug candidates through in silico high-throughput screening. Subsequently, we synthesized a series of small molecules, specifically KR-40795 (2c), a pyrrolidine-2,5-dione-based analogue that binds to the allosteric tunnel and hydrophobic pocket of ATX. This compound was designed to inhibit the enzymatic activity of ATX for the treatment of liver diseases. The inhibitory potency of KR-40795 was evaluated using a biochemical assay that measured the hydrolysis of a specific substrate (FS-3). Notably, KR-40795 demonstrated significant inhibition of both collagen formation and lipid accumulation in liver cells, suggesting its potential as a therapeutic agent for liver diseases, particularly fibrosis and steatosis.
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Affiliation(s)
- Seung Hyeong Lee
- Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Su Jin Park
- Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, KRICT School, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Mi Young Lee
- Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Jun Young Choi
- Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Woo Dae Jang
- Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, KRICT School, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Jidon Jang
- Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Jeong Hyun Lee
- Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Yuseong-gu, Daejeon 34134, Republic of Korea
| | - Chae Jo Lim
- Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Kwang-Seok Oh
- Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, KRICT School, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea.
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Spalding VA, Fellenstein BA, Ahodantin J, Jeyarajan AJ, Wang Y, Khan SK, Xu M, Lin W, Alatrakchi N, Su L, Chung RT, Salloum S. YAP mediates HIV-related liver fibrosis. JHEP Rep 2024; 6:101163. [PMID: 39524207 PMCID: PMC11544392 DOI: 10.1016/j.jhepr.2024.101163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 06/18/2024] [Accepted: 06/26/2024] [Indexed: 11/16/2024] Open
Abstract
Background & Aims HIV accelerates liver fibrosis attributable to multiple etiologies, including HCV, HBV, and steatotic liver disease. Evidence also suggests that HIV infection itself is associated with liver fibrogenesis. Recent studies have implicated Yes-associated protein 1 (YAP1) and the upstream lysophosphatidic acid (LPA)/PI3K/AKT pathway as critical regulators of hepatic fibrogenesis, and suggest a connection to HIV-related liver fibrosis. However, the relationship between YAP/PI3K/AKT pathway activation and HIV-related liver fibrosis remains uncertain. Methods qPCR, western blot, immunofluorescence, and ELISA (replicates n ≥3) were performed in an unbiased humanized mouse model (NRG-hu HSC mice, n = 6), the precision cut liver slice ex vivo model, and both traditional in vitro models as well as a 3D spheroid system. Results YAP target gene mRNA and protein levels (ANKRD, CTGF, CYR61) were upregulated across all models exposed to HIV. Humanized mice infected with HIV had significant increases in the percentage of YAP-positive nuclei (2.2-fold) and the percentage area of Sirius Red collagen staining (3.3-fold) compared to control mice. Serum concentrations of LPA were increased 5.8-fold in people living with HIV compared to healthy controls. Modulation of LPAR1, PI3K, and AKT by either inhibitors or small-interfering RNAs abrogated the fibrotic effects of HIV exposure and downregulated YAP target genes within cultured liver cells. Conclusions The LPAR/PI3K/AKT axis is vital for the activation of YAP and hepatic fibrogenesis due to HIV infection. This novel mechanistic insight suggests new pharmacologic targets for treatment of liver fibrosis in people living with HIV. Impact and implications There are currently no FDA-approved treatments for cirrhosis, while liver disease is the second leading cause of mortality among people living with HIV after AIDS. Increased lysophosphatidic acid concentrations and AKT activation after HIV infection found in recent work suggest that the Hippo pathway may be a key regulator of HIV-related fibrogenesis. By linking lysophosphatidic acid signaling, YAP activation, and HIV-related fibrogenesis, this mechanism presents a target for future research into therapeutic interventions for not only HIV but also other liver diseases, e.g. metabolic dysfunction- or alcohol-associated liver disease.
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Affiliation(s)
- Volney A. Spalding
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Brian A. Fellenstein
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - James Ahodantin
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Andre J. Jeyarajan
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Yongtao Wang
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Sanjoy K. Khan
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Min Xu
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Wenyu Lin
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Nadia Alatrakchi
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Lishan Su
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Raymond T. Chung
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Shadi Salloum
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
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Hiyama Y, Fujino H, Namba M, Fujii Y, Uchikawa S, Ono A, Nakahara T, Murakami E, Kawaoka T, Miki D, Tsuge M, Oka S. Value of autotaxin for hepatocellular carcinoma risk assessment in chronic hepatitis B patients treated with nucleos(t)ide analogs. Hepatol Res 2024; 54:981-992. [PMID: 38539054 DOI: 10.1111/hepr.14042] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 02/23/2024] [Accepted: 03/14/2024] [Indexed: 11/03/2024]
Abstract
AIM Autotaxin (ATX) is a newly identified liver fibrosis biomarker; however, its clinical usefulness remains unclear. Therefore, we analyzed the changes in patients with chronic hepatitis B virus infection treated with nucleos(t)ide analogs (NAs) to evaluate its usefulness. We also investigated the predictors of hepatocellular carcinoma development, including ATX, in patients with chronic hepatitis B based on their clinical characteristics. METHODS This retrospective study included 179 patients with hepatitis B virus infection treated with NAs for >2 years. First, we measured the ATX levels before and up to 10 years after initiating entecavir (therapy for 88 patients whose serial ATX levels could be measured before and during entecavir therapy. Subsequently, for 179 patients whose ATX levels could be measured at the commencement of NAs, we examined the factors involved in developing hepatocellular carcinoma, including ATX. RESULTS The ATX levels showed a gradual and significant decrease during the observation period of up to 10 years. Multivariable analysis showed that a baseline ATX/upper limits of normal ratio ≥1.214, age, and alkaline phosphatase levels were independent risk factors for hepatocellular carcinoma development. The combination of age and ATX/upper limits of normal ratio was used to stratify the high-risk groups for liver carcinogenesis. CONCLUSIONS A decrease in ATX levels up to 10 years after the commencement of therapy suggested that ATX is a helpful biomarker in evaluating fibrosis in patients undergoing long-term NA therapy. Furthermore, this study showed that combining age and the baseline ATX/upper limits of normal ratio may help identify high-risk carcinogenesis groups.
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Affiliation(s)
- Yuichi Hiyama
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Clinical Research Center in Hiroshima, Hiroshima University Hospital, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Maiko Namba
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasutoshi Fujii
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Wiering L, Subramanian P, Hammerich L. Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease. Cell Mol Gastroenterol Hepatol 2023; 15:1277-1292. [PMID: 36828280 PMCID: PMC10148161 DOI: 10.1016/j.jcmgh.2023.02.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 02/15/2023] [Accepted: 02/15/2023] [Indexed: 02/26/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a fast growing, chronic liver disease affecting ∼25% of the global population. Nonalcoholic fatty liver disease severity ranges from the less severe simple hepatic steatosis to the more advanced nonalcoholic steatohepatitis (NASH). The presence of NASH predisposes individuals to liver fibrosis, which can further progress to cirrhosis and hepatocellular carcinoma. This makes hepatic fibrosis an important indicator of clinical outcomes in patients with NASH. Hepatic stellate cell activation dictates fibrosis development during NASH. Here, we discuss recent advances in the analysis of the profibrogenic pathways and mediators of hepatic stellate cell activation and inactivation, which ultimately determine the course of disease in nonalcoholic fatty liver disease/NASH.
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Affiliation(s)
- Leke Wiering
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany
| | - Pallavi Subramanian
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Linda Hammerich
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
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Wang S, Chen J, Guo XZ. KAI1/CD82 gene and autotaxin-lysophosphatidic acid axis in gastrointestinal cancers. World J Gastrointest Oncol 2022; 14:1388-1405. [PMID: 36160748 PMCID: PMC9412925 DOI: 10.4251/wjgo.v14.i8.1388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/06/2022] [Accepted: 07/22/2022] [Indexed: 02/05/2023] Open
Abstract
The KAI1/CD82 gene inhibits the metastasis of most tumors and is remarkably correlated with tumor invasion and prognosis. Cell metabolism dysregulation is an important cause of tumor occurrence, development, and metastasis. As one of the important characteristics of tumors, cell metabolism dysregulation is attracting increasing research attention. Phospholipids are an indispensable substance in the metabolism in various tumor cells. Phospholipid metabolites have become important cell signaling molecules. The pathological role of lysophosphatidic acid (LPA) in tumors was identified in the early 1990s. Currently, LPA inhibitors have entered clinical trials but are not yet used in clinical treatment. Autotaxin (ATX) has lysophospholipase D (lysoPLD) activity and can regulate LPA levels in vivo. The LPA receptor family and ATX/lysoPLD are abnormally expressed in various gastrointestinal tumors. According to our recent pre-experimental results, KAI1/CD82 might inhibit the migration and metastasis of cancer cells by regulating the ATX-LPA axis. However, no relevant research has been reported. Clarifying the mechanism of ATX-LPA in the inhibition of cancer metastasis by KAI1/CD82 will provide an important theoretical basis for targeted cancer therapy. In this paper, the molecular compositions of the KAI1/CD82 gene and the ATX-LPA axis, their physiological functions in tumors, and their roles in gastrointestinal cancers and target therapy are reviewed.
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Affiliation(s)
- Shuo Wang
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Jiang Chen
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Xiao-Zhong Guo
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
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Petri BJ, Piell KM, Wahlang B, Head KZ, Andreeva K, Rouchka EC, Pan J, Rai SN, Cave MC, Klinge CM. Multiomics analysis of the impact of polychlorinated biphenyls on environmental liver disease in a mouse model. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 94:103928. [PMID: 35803474 DOI: 10.1016/j.etap.2022.103928] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/27/2022] [Accepted: 07/03/2022] [Indexed: 06/15/2023]
Abstract
Exposure to high fat diet (HFD) and persistent organic pollutants including polychlorinated biphenyls (PCBs) is associated with liver injury in human populations and non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in animal models. Previously, exposure of HFD-fed male mice to the non-dioxin-like (NDL) PCB mixture Aroclor1260, dioxin-like (DL) PCB126, or Aroclor1260 + PCB126 co-exposure caused toxicant-associated steatohepatitis (TASH) and differentially altered the liver proteome. Here unbiased mRNA and miRNA sequencing (mRNA- and miRNA- seq) was used to identify biological pathways altered in these liver samples. Fewer transcripts and miRs were up- or down- regulated by PCB126 or Aroclor1260 compared to the combination, suggesting that crosstalk between the receptors activated by these PCBs amplifies changes in the transcriptome. Pathway enrichment analysis identified "positive regulation of Wnt/β-catenin signaling" and "role of miRNAs in cell migration, survival, and angiogenesis" for differentially expressed mRNAs and miRNAs, respectively. We evaluated the five miRNAs increased in human plasma with PCB exposure and suspected TASH and found that miR-192-5p was increased with PCB exposure in mouse liver. Although we observed little overlap between differentially expressed mRNA transcripts and proteins, biological pathway-relevant PCB-induced miRNA-mRNA and miRNA-protein inverse relationships were identified that may explain protein changes. These results provide novel insights into miRNA and mRNA transcriptome changes playing direct and indirect roles in the functional protein pathways in PCB-related hepatic lipid accumulation, inflammation, and fibrosis in a mouse model of TASH and its relevance to human liver disease in exposed populations.
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Affiliation(s)
- Belinda J Petri
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine University of Louisville, Louisville, KY 40292, USA
| | - Kellianne M Piell
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine University of Louisville, Louisville, KY 40292, USA
| | - Banrida Wahlang
- University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; University of Louisville Hepatobiology and Toxicology Center, USA; The University of Louisville Superfund Research Center, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA
| | - Kimberly Z Head
- University of Louisville Hepatobiology and Toxicology Center, USA
| | | | - Eric C Rouchka
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine University of Louisville, Louisville, KY 40292, USA; KY INBRE Bioinformatics Core, University of Louisville, USA
| | - Jianmin Pan
- Biostatistics and Bioinformatics Facility, Brown Cancer Center, USA
| | - Shesh N Rai
- University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; University of Louisville Hepatobiology and Toxicology Center, USA; Biostatistics and Bioinformatics Facility, Brown Cancer Center, USA
| | - Matthew C Cave
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine University of Louisville, Louisville, KY 40292, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; University of Louisville Hepatobiology and Toxicology Center, USA; The University of Louisville Superfund Research Center, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA
| | - Carolyn M Klinge
- Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine University of Louisville, Louisville, KY 40292, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA.
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Artru F, McPhail MJW, Triantafyllou E, Trovato FM. Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids. Front Immunol 2022; 13:867261. [PMID: 35432367 PMCID: PMC9008479 DOI: 10.3389/fimmu.2022.867261] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/08/2022] [Indexed: 12/30/2022] Open
Abstract
Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described.
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Affiliation(s)
- Florent Artru
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Mark J W McPhail
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Evangelos Triantafyllou
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
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Małachowska B, Janikiewicz J, Pietrowska K, Wyka K, Madzio J, Wypyszczak K, Tkaczyk M, Chrul S, Zwiech R, Hogendorf A, Małecki MT, Borowiec M, Krętowski A, Młynarski W, Dobrzyń A, Ciborowski M, Fendler W. Elevated level of lysophosphatidic acid among patients with HNF1B mutations and its role in RCAD syndrome: a multiomic study. Metabolomics 2022; 18:15. [PMID: 35179657 PMCID: PMC8857088 DOI: 10.1007/s11306-022-01873-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 02/01/2022] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Patients with hepatocyte nuclear factor-1 beta (HNF1B) mutations present a variable phenotype with two main symptoms: maturity onset diabetes of the young (MODY) and polycystic kidney disease (PKD). OBJECTIVES Identification of serum metabolites specific for HNF1Bmut and evaluation of their role in disease pathogenesis. METHODS We recruited patients with HNF1Bmut (N = 10), HNF1Amut (N = 10), PKD: non-dialyzed and dialyzed (N = 8 and N = 13); and healthy controls (N = 12). Serum fingerprinting was performed by LC-QTOF-MS. Selected metabolite was validated by ELISA (enzyme-linked immunosorbent assay) measurements and then biologically connected with HNF1B by in silico analysis. HepG2 were stimulated with lysophosphatidic acid (LPA) and HNF1B gene was knocked down (kd) by small interfering RNA. Transcriptomic analysis with microarrays and western blot measurements were performed. RESULTS Serum levels of six metabolites including: arachidonic acid, hydroxyeicosatetraenoic acid, linoleamide and three LPA (18:1, 18:2 and 20:4), had AUC (the area under the curve) > 0.9 (HNF1Bmut vs comparative groups). The increased level of LPA was confirmed by ELISA measurements. In HepG2HNF1Bkd cells LPA stimulation lead to downregulation of many pathways associated with cell cycle, lipid metabolism, and upregulation of steroid hormone metabolism and Wnt signaling. Also, increased intracellular protein level of autotaxin was detected in the cells. GSK-3alpha/beta protein level and its phosphorylated ratio were differentially affected by LPA stimulation in HNF1Bkd and control cells. CONCLUSIONS LPA is elevated in sera of patients with HNF1Bmut. LPA contributes to the pathogenesis of HNF1B-MODY by affecting Wnt/GSK-3 signaling.
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Affiliation(s)
- Beata Małachowska
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 15 Mazowiecka Street, 92-215, Lodz, Poland
| | - Justyna Janikiewicz
- Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology PAS, 3 Pasteur Street, 02-093, Warsaw, Poland
| | - Karolina Pietrowska
- Clinical Research Centre, Medical University of Bialystok, 24a Sklodowska-Curie Street, 15-276, Bialystok, Poland
| | - Krystyna Wyka
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, 36/50 Sporna Street, 91-738, Lodz, Poland
| | - Joanna Madzio
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, 36/50 Sporna Street, 91-738, Lodz, Poland
| | - Kamila Wypyszczak
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, 36/50 Sporna Street, 91-738, Lodz, Poland
| | - Marcin Tkaczyk
- Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, 281/289 Rzgowska Street, 93-338, Lodz, Poland
- Department of Pediatrics Nephrology and Immunology, Medical University of Lodz, 281/289 Rzgowska Street, 93-338, Lodz, Poland
| | - Sławomir Chrul
- Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, 281/289 Rzgowska Street, 93-338, Lodz, Poland
| | - Rafał Zwiech
- Department of Kidney Transplantation/Dialysis Department, Barlicki Memorial Teaching Hospital No. 1, Medical University of Lodz, 22 Kopcinskiego Street, 90-153, Lodz, Poland
| | - Anna Hogendorf
- Department of Pediatrics, Diabetology, Endocrinology, and Nephrology, Medical University of Lodz, 36/50 Sporna Street, 91-738, Lodz, Poland
| | - Maciej T Małecki
- Department of Metabolic Diseases, Medical College, Jagiellonian University, 2 Jakubowskiego Street, 30-688, Cracov, Poland
| | - Maciej Borowiec
- Department of Clinical Genetics, Medical University of Lodz, 251 Pomorska Street, 92-213, Lodz, Poland
| | - Adam Krętowski
- Clinical Research Centre, Medical University of Bialystok, 24a Sklodowska-Curie Street, 15-276, Bialystok, Poland
- Department of Endocrinology, Diabetology, and Internal Medicine, Medical University of Bialystok, 24a Sklodowska-Curie Street, 15-276, Bialystok, Poland
| | - Wojciech Młynarski
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, 36/50 Sporna Street, 91-738, Lodz, Poland
| | - Agnieszka Dobrzyń
- Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology PAS, 3 Pasteur Street, 02-093, Warsaw, Poland
| | - Michał Ciborowski
- Clinical Research Centre, Medical University of Bialystok, 24a Sklodowska-Curie Street, 15-276, Bialystok, Poland
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 15 Mazowiecka Street, 92-215, Lodz, Poland.
- Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.
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10
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Abstract
Lysophospholipids, exemplified by lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are produced by the metabolism and perturbation of biological membranes. Both molecules are established extracellular lipid mediators that signal via specific G protein-coupled receptors in vertebrates. This widespread signaling axis regulates the development, physiological functions, and pathological processes of all organ systems. Indeed, recent research into LPA and S1P has revealed their important roles in cellular stress signaling, inflammation, resolution, and host defense responses. In this review, we focus on how LPA regulates fibrosis, neuropathic pain, abnormal angiogenesis, endometriosis, and disorders of neuroectodermal development such as hydrocephalus and alopecia. In addition, we discuss how S1P controls collective behavior, apoptotic cell clearance, and immunosurveillance of cancers. Advances in lysophospholipid research have led to new therapeutics in autoimmune diseases, with many more in earlier stages of development for a wide variety of diseases, such as fibrotic disorders, vascular diseases, and cancer.
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Affiliation(s)
- Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; , .,AMED-LEAP, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; , .,AMED-LEAP, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan
| | - Timothy Hla
- Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA; .,Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA
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11
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Zhang Y, Zhao M, Liu Y, Liu T, Zhao C, Wang M. Investigation of the therapeutic effect of Yinchen Wuling Powder on CCl 4-induced hepatic fibrosis in rats by 1H NMR and MS-based metabolomics analysis. J Pharm Biomed Anal 2021; 200:114073. [PMID: 33873073 DOI: 10.1016/j.jpba.2021.114073] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/27/2021] [Accepted: 04/10/2021] [Indexed: 02/06/2023]
Abstract
Hepatic fibrosis (HF) is a typical consequence of various chronic liver diseases, and there is still no ideal drug for its treatment. Yinchen Wuling Powder (YCWLP), a famous traditional Chinese medicine prescription, is effective for the treatment of icteric hepatitis, hepatic fibrosis, non-alcoholic fatty liver disease and other liver diseases in clinical practices, however, the underlying mechanisms of YCWLP on HF is still unclear. In this study, 1H NMR and MS-based metabolomics analysis along with body weight change, serum liver function indexes, serum liver fibrosis index and histopathological observations of liver were applied to evaluate the therapeutic effect of YCWLP on hepatic fibrosis and the mechanism associated with this. The results of the pharmacodynamics study show that YCWLP has a significant therapeutic effect on hepatic fibrosis. As for the metabolomics research, 7 metabolites in the plasma samples, 28 in the urine samples and 6 in the liver samples were significantly altered due to the protective effect of YCWLP on CCl4-induced hepatic fibrosis. These endogenous metabolites are involved in amino acid metabolism, carbohydrate metabolism, glycerophospholipid metabolism and gut bacteria metabolism. These findings suggest that YCWLP could treat hepatic fibrosis by promoting urea circulation and reducing blood ammonia accumulation, improving carbohydrate metabolism and reducing oxidative stress, improving glycerophospholipid metabolism and protecting cell membrane, and regulating intestinal flora metabolism.
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Affiliation(s)
- Yumeng Zhang
- School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning, China
| | - Min Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning, China
| | - Yangyang Liu
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning, China
| | - Tingting Liu
- School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning, China
| | - Chunjie Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning, China.
| | - Miao Wang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning, China.
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12
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Nie C, Zhang L, Chen X, Li Y, Ha F, Liu H, Han T. Autotaxin: An Early Warning Biomarker for Acute-on-chronic Liver Failure. J Clin Transl Hepatol 2020; 8:240-245. [PMID: 33083245 PMCID: PMC7562802 DOI: 10.14218/jcth.2020.00045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/09/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023] Open
Abstract
Background and Aims: Recent accumulating evidence indicates the biological actions of autotaxin (ATX) in liver disease. However, the relationship between ATX and liver failure has not been reported. The present study aimed to examine alterations of serum ATX in acute-on-chronic liver failure (ACLF) and evaluate whether serum ATX could be useful as an early warning biomarker of ACLF. Methods: Serum ATX was measured in 50 patients with hepatitis B-related ACLF, 14 patients with alcohol-related ACLF, 11 patients with hepatitis B-related pre-ACLF, 11 patients with alcohol-related Child-Pugh A cirrhosis, 39 patients with hepatitis B-related Child-Pugh A cirrhosis, 26 patients with chronic hepatitis B, and 38 healthy volunteers by enzyme-linked immunosorbent assay. Results: Serum ATX level was significantly higher in the pre-ACLF group than in the Child-Pugh A cirrhosis and chronic hepatitis B groups but lower than in the ACLF group; furthermore, patients with pre-ACLF deteriorated to ACLF had significantly higher serum ATX levels than pre-ACLF patients that did not progress to ACLF. Serum ATX levels were significantly higher among male ACLF patients with preclinical infection, spontaneous bacterial peritonitis or pneumonia, as compared to patients with ACLF but no spontaneous bacterial peritonitis or pneumonia. Serum ATX levels were well correlated with serum biochemical parameters of liver function and model for end-stage liver disease score. Serum ATX ≥ 584.1 ng/mL was a poor prognostic factor for ACLF (hazard ratio of 4.750, 95% confidence interval of 1.106-20.392, p=0.036). Conclusions: Serum ATX level may be a useful early warning biomarker for ACLF.
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Affiliation(s)
- Caiyun Nie
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Lei Zhang
- Department of Clinical Laboratory, Tianjin Third Central Hospital, Tianjin, China
| | - Xiaobing Chen
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Ying Li
- The Third Central Clinical College of Tianjin Medical University, Tianjin, China
- The Affiliated Hospital of Nankai University, Tianjin, China
- Department of Hepatology and Gastroenterology, Tianjin Third Central Hospital, Tianjin, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
- Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Fushuang Ha
- The Affiliated Hospital of Nankai University, Tianjin, China
- Department of Hepatology and Gastroenterology, Tianjin Third Central Hospital, Tianjin, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
- Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Hua Liu
- The Third Central Clinical College of Tianjin Medical University, Tianjin, China
- The Affiliated Hospital of Nankai University, Tianjin, China
- Department of Hepatology and Gastroenterology, Tianjin Third Central Hospital, Tianjin, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
- Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Tao Han
- The Third Central Clinical College of Tianjin Medical University, Tianjin, China
- The Affiliated Hospital of Nankai University, Tianjin, China
- Department of Hepatology and Gastroenterology, Tianjin Third Central Hospital, Tianjin, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
- Tianjin Institute of Hepatobiliary Disease, Tianjin, China
- Correspondence to: Tao Han, Department of Hepatology and Gastroenterology, Tianjin Institute of Hepatobiliary Disease, Tianjin Key Laboratory of Artificial Cells, Tianjin Third Central Hospital, 83 Jintang Road, Tianjin 300170, China. Tel: +86-22-84112298, Fax: +86-22-84112208, E-mail:
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13
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Szóstek-Mioduchowska A, Leciejewska N, Zelmańska B, Staszkiewicz-Chodor J, Ferreira-Dias G, Skarzynski D. Lysophosphatidic acid as a regulator of endometrial connective tissue growth factor and prostaglandin secretion during estrous cycle and endometrosis in the mare. BMC Vet Res 2020; 16:343. [PMID: 32943074 PMCID: PMC7499873 DOI: 10.1186/s12917-020-02562-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 09/08/2020] [Indexed: 12/22/2022] Open
Abstract
Background Equine endometrosis is a chronic degenerative condition, described as endometrial fibrosis that forms in the stroma, under the basement membrane and around the endometrial glands. The role of lysophosphatidic acid (LPA) in the development of tissue fibrosis varies depending on the organ, and its profibrotic role in mare endometrosis remains unclear. The study aimed to establish the endometrial presence of LPA and its receptors (LPAR1–4), together with its effects on connective tissue growth factor (CTGF) and prostaglandins (PG) secretion from equine endometrium under physiological (estrous cycle), or pathological conditions (endometrosis). Mare endometria in the mid-luteal phase (n = 5 for each category I, IIA, IIB, III of Kenney and Doig) and in the follicular phase (n = 5 for each category I, IIA, III and n = 4 for IIB) were used. In experiment 1, the levels of LPA, LPAR1–4 mRNA level and protein abundance were investigated in endometria at different stages of endometrosis. In experiment 2, the in vitro effect of LPA (10− 9 M) on the secretion of CTGF and PGs from endometrial tissue explants at different stages of endometrosis were determined. Results Endometrial LPA concentration was higher in the mid-luteal phase compared to the follicular phase in category I endometrium (P < 0.01). There was an alteration in endometrial concentrations of LPA and LPAR1–4 protein abundance in the follicular phase at different stages of endometrosis (P < 0.05). Additionally, LPA increased the secretion of PGE2 from category I endometrium in both phases of the estrous cycle (P < 0.05). The effect of LPA on the secretion of CTGF and PGF2α from endometrial tissue was altered depending on different stages of endometrosis (P < 0.05). Conclusion Our data indicate that endometrosis disturbs proper endometrial function and is associated with altered endometrial LPA concentration, its receptor expression and protein abundance, PGE2/PGF2α ratio, and CTGF secretion in response to LPA. These changes could influence several physiological events occurring in endometrium in mare during estrous cycle and early pregnancy.
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Affiliation(s)
- Anna Szóstek-Mioduchowska
- Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Olsztyn, Tuwima-st 10, 10-748, Olsztyn, Poland.
| | - Natalia Leciejewska
- Department of Animal Physiology and Biochemistry and Biostructure, Faculty of Veterinary Medicine and Animal Science, Poznan University of Life Sciences, Poznan, Poland
| | - Beata Zelmańska
- Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Olsztyn, Tuwima-st 10, 10-748, Olsztyn, Poland
| | - Joanna Staszkiewicz-Chodor
- Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Olsztyn, Tuwima-st 10, 10-748, Olsztyn, Poland
| | - Graça Ferreira-Dias
- CIISA, Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal
| | - Dariusz Skarzynski
- Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Olsztyn, Tuwima-st 10, 10-748, Olsztyn, Poland
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14
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Morita Y, Kurano M, Morita E, Shimamoto S, Igarashi K, Sawabe M, Aoki J, Yatomi Y. Urinary autotaxin concentrations are associated with kidney injury. Clin Chim Acta 2020; 509:156-165. [PMID: 32540127 DOI: 10.1016/j.cca.2020.06.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 06/03/2020] [Accepted: 06/09/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND While basic researches have shown the involvement of the autotaxin-lysophosphatidic acid (ATX-LPA) axis in the pathogenesis of kidney diseases, no clinical studies have revealed the association between urinary ATX concentrations and kidney disease yet. We investigate the clinical characteristics in relation to the urinary ATX concentrations and the potential association between urinary ATX concentrations and various kidney diseases. METHODS We measured the urinary ATX concentrations in residual urine samples after routine clinical testing from a total of 326 subjects with various kidney diseases and healthy subjects. We compared the urinary ATX concentrations in relation to clinical parameters and urinary biomarkers, and investigated their association with various kidney diseases. RESULTS The urinary ATX concentrations were associated with the gender, eGFR, presence/absence of hematuria, serum ATX, urinary concentrations of total protein (TP), microalbumin, N-acetyl-β-D-glucosaminidase (NAG), α1-microglobulin (α1-MG), and transforming growth factor-β. Multiple regression analyses identified urinary α1-MG, age, urinary TP, NAG, and hematuria as being significantly associated with the urinary ATX concentrations. Urinary ATX concentrations were higher in subjects with membranous nephropathy and systemic lupus erythematosus than in the control subjects. CONCLUSIONS Urinary ATX might be associated with pathological conditions of the kidney associated with kidney injury.
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Affiliation(s)
- Yoshifumi Morita
- Department of Clinical Laboratory, the University of Tokyo Hospital, Tokyo, Japan; Department of Molecular Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Makoto Kurano
- Department of Clinical Laboratory, the University of Tokyo Hospital, Tokyo, Japan; Department of Clinical Laboratory Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
| | - Eriko Morita
- Department of Clinical Laboratory, the University of Tokyo Hospital, Tokyo, Japan
| | | | - Koji Igarashi
- Bioscience Division, TOSOH Corporation, Kanagawa, Japan
| | - Motoji Sawabe
- Department of Molecular Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Junken Aoki
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory, the University of Tokyo Hospital, Tokyo, Japan; Department of Clinical Laboratory Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
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15
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Strumwasser A, Cohan CM, Beattie G, Chong V, Victorino GP. Autotaxin inhibition attenuates endothelial permeability after ischemia-reperfusion injury. Clin Hemorheol Microcirc 2020; 75:399-407. [PMID: 32390607 DOI: 10.3233/ch-190732] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autotaxin (ATX-secretory lysophospholipase D) is the primary lysophosphatidic acid (LPA) producing enzyme. LPA promotes endothelial hyper-permeability and microvascular dysfunction following cellular stress. OBJECTIVE We sought to assess whether ATX inhibition would attenuate endothelial monolayer permeability after anoxia-reoxygenation (A-R) in vitro and attenuate the increase in hydraulic permeability observed after ischemia-reperfusion injury (IRI) in vivo. METHODS A permeability assay assessed bovine endothelial monolayer permeability during anoxia-reoxygenation with/without administration of pipedimic acid, a specific inhibitor of ATX, administered either pre-anoxia or post-anoxia. Hydraulic permeability (Lp) of rat mesenteric post-capillary venules was evaluated after IRI, with and without ATX inhibition. Lastly, Lp was evaluated after the administration of ATX alone. RESULTS Anoxia-reoxygenation increased monolayer permeability 4-fold (p < 0.01). Monolayer permeability was reduced to baseline similarly in both the pre-anoxia and post-anoxia ATX inhibition groups (each p < 0.01, respectively). Lp was attenuated by 24% with ATX inhibition (p < 0.01). ATX increased Lp from baseline in a dose dependent manner (p < 0.05). CONCLUSIONS Autotaxin inhibition attenuated increases in endothelial monolayer permeability during A-R in vitro and hydraulic permeability during IRI in vivo. Targeting ATX may be especially beneficial by limiting its downstream mediators that contribute to mechanisms associated with endothelial permeability. ATX inhibitors may therefore have potential for pharmacotherapy during IRI.
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Affiliation(s)
- Aaron Strumwasser
- University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.,Department of Surgery, University of California San Francisco East Bay, Oakland, CA, USA
| | - Caitlin M Cohan
- Department of Surgery, University of California San Francisco East Bay, Oakland, CA, USA
| | - Genna Beattie
- Department of Surgery, University of California San Francisco East Bay, Oakland, CA, USA
| | - Vincent Chong
- Department of Surgery, University of California San Francisco East Bay, Oakland, CA, USA
| | - Gregory P Victorino
- Department of Surgery, University of California San Francisco East Bay, Oakland, CA, USA
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16
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Xiang H, Lu Y, Shao M, Wu T. Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases. J Cancer 2020; 11:3519-3535. [PMID: 32284748 PMCID: PMC7150451 DOI: 10.7150/jca.41841] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 02/25/2020] [Indexed: 12/21/2022] Open
Abstract
Lysophosphatidic acid (LPA, 1-acyl-2-hemolytic-sn-glycerol-3-phosphate) extracted from membrane phospholipid is a kind of simple bioactive glycophospholipid, which has many biological functions such as stimulating cell multiplication, cytoskeleton recombination, cell survival, drug-fast, synthesis of DNA and ion transport. Current studies have shown that six G-coupled protein receptors (LPAR1-6) can be activated by LPA. They stimulate a variety of signal transduction pathways through heterotrimeric G-proteins (such as Gα12/13, Gαq/11, Gαi/o and GαS). LPA and its receptors play vital roles in cancers, nervous system diseases, cardiovascular diseases, liver diseases, metabolic diseases, etc. In this article, we discussed the structure of LPA receptors and elucidated their functions in various diseases, in order to better understand them and point out new therapeutic schemes for them.
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Affiliation(s)
- Hongjiao Xiang
- Center of Chinese Medical Therapy and Systems Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yifei Lu
- Center of Chinese Medical Therapy and Systems Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Mingmei Shao
- Center of Chinese Medical Therapy and Systems Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tao Wu
- Center of Chinese Medical Therapy and Systems Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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17
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Khomich O, Ivanov AV, Bartosch B. Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis. Cells 2019; 9:24. [PMID: 31861818 PMCID: PMC7016711 DOI: 10.3390/cells9010024] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/09/2019] [Accepted: 12/18/2019] [Indexed: 12/17/2022] Open
Abstract
Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.
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Affiliation(s)
- Olga Khomich
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, CEDEX 03, 69424 Lyon, France;
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Alexander V. Ivanov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Birke Bartosch
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, CEDEX 03, 69424 Lyon, France;
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18
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Tabbai S, Moreno-Fernández RD, Zambrana-Infantes E, Nieto-Quero A, Chun J, García-Fernández M, Estivill-Torrús G, Rodríguez de Fonseca F, Santín LJ, Oliveira TG, Pérez-Martín M, Pedraza C. Effects of the LPA 1 Receptor Deficiency and Stress on the Hippocampal LPA Species in Mice. Front Mol Neurosci 2019; 12:146. [PMID: 31244601 PMCID: PMC6580287 DOI: 10.3389/fnmol.2019.00146] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 05/17/2019] [Indexed: 12/29/2022] Open
Abstract
Lysophosphatidic acid (LPA) is an important bioactive lipid species that functions in intracellular signaling through six characterized G protein-coupled receptors (LPA1-6). Among these receptors, LPA1 is a strong candidate to mediate the central effects of LPA on emotion and may be involved in promoting normal emotional behaviors. Alterations in this receptor may induce vulnerability to stress and predispose an individual to a psychopathological disease. In fact, mice lacking the LPA1 receptor exhibit emotional dysregulation and cognitive alterations in hippocampus-dependent tasks. Moreover, the loss of this receptor results in a phenotype of low resilience with dysfunctional coping in response to stress and induces anxiety and several behavioral and neurobiological changes that are strongly correlated with mood disorders. In fact, our group proposes that maLPA1-null mice represent an animal model of anxious depression. However, despite the key role of the LPA-LPA1-pathway in emotion and stress coping behaviors, the available information describing the mechanisms by which the LPA-LPA1-pathway regulates emotion is currently insufficient. Because activation of LPA1 requires LPA, here, we used a Matrix-Assisted Laser Desorption/ Ionization mass spectrometry-based approach to evaluate the effects of an LPA1 receptor deficiency on the hippocampal levels of LPA species. Additionally, the impact of stress on the LPA profile was also examined in both wild-type (WT) and the Malaga variant of LPA1-null mice (maLPA1-null mice). Mice lacking LPA1 did not exhibit gross perturbations in the hippocampal LPA species, but the LPA profile was modified, showing an altered relative abundance of 18:0 LPA. Regardless of the genotype, restraint stress produced profound changes in all LPA species examined, revealing that hippocampal LPA species are a key target of stress. Finally, the relationship between the hippocampal levels of LPA species and performance in the elevated plus maze was established. To our knowledge, this study is the first to detect, identify and profile LPA species in the hippocampus of both LPA1-receptor null mice and WT mice at baseline and after acute stress, as well as to link these LPA species with anxiety-like behaviors. In conclusion, the hippocampal LPA species are a key target of stress and may be involved in psychopathological conditions.
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Affiliation(s)
- Sara Tabbai
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Román Dario Moreno-Fernández
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Emma Zambrana-Infantes
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Andrea Nieto-Quero
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Jerold Chun
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - Maria García-Fernández
- Departamento de Fisiología y Medicina Deportiva, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Guillermo Estivill-Torrús
- Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Fernando Rodríguez de Fonseca
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Luis Javier Santín
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Tiago Gil Oliveira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga, Portugal
| | - Margarita Pérez-Martín
- Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
| | - Carmen Pedraza
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain
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Lei L, Su J, Chen J, Chen W, Chen X, Peng C. The role of lysophosphatidic acid in the physiology and pathology of the skin. Life Sci 2018; 220:194-200. [PMID: 30584899 DOI: 10.1016/j.lfs.2018.12.040] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/25/2018] [Accepted: 12/21/2018] [Indexed: 12/13/2022]
Abstract
Lysophosphatidic acid (LPA) is the simplest phospholipid found in nature. LPA is mainly biosynthesized in tissues and cells by autotoxin and PA-PLA1α/PA-PLA1β and is degraded by lipid phosphate phosphatases (LPPs). It is an important component of biofilm, an extracellular signal transmitter and intracellular second messenger. After targeting to endothelial differentiation gene (Edg) family LPA receptors (LPA1, LPA2, LPA3) and non-Edg family LPA receptors (LPA4, LPA5, LPA6), LPA mediates physiological and pathological processes such as embryonic development, angiogenesis, tumor progression, fibrogenesis, wound healing, ischemia/reperfusion injury, and inflammatory reactions. These processes are induced through signaling pathways including mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K)/Akt, protein kinase C (PKC)-GSK3β-β-catenin, Rho, Stat, and hypoxia-inducible factor 1-alpha (HIF-1α). LPA is involved in multiple physiological and pathological processes in the skin. It not only regulates skin function but also plays an important role in hair follicle development, skin wound healing, pruritus, skin tumors, and scleroderma. Pharmacological inhibition of LPA synthesis or antagonization of LPA receptors is a new strategy for the treatment of various skin disorders. This review focuses on the current understanding of the pathophysiologic role of LPA in the skin.
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Affiliation(s)
- Li Lei
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Juan Su
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Junchen Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Wangqing Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China.
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China.
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20
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Matralis AN, Afantitis A, Aidinis V. Development and therapeutic potential of autotaxin small molecule inhibitors: From bench to advanced clinical trials. Med Res Rev 2018; 39:976-1013. [PMID: 30462853 DOI: 10.1002/med.21551] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/21/2018] [Accepted: 10/19/2018] [Indexed: 12/11/2022]
Abstract
Several years after its isolation from melanoma cells, an increasing body of experimental evidence has established the involvement of Autotaxin (ATX) in the pathogenesis of several diseases. ATX, an extracellular enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) into the bioactive lipid lysophosphatidic acid (LPA), is overexpressed in a variety of human metastatic cancers and is strongly implicated in chronic inflammation and liver toxicity, fibrotic diseases, and thrombosis. Accordingly, the ATX-LPA signaling pathway is considered a tractable target for therapeutic intervention substantiated by the multitude of research campaigns that have been successful in identifying ATX inhibitors by both academia and industry. Furthermore, from a therapeutic standpoint, the entry and the so far promising results of the first ATX inhibitor in advanced clinical trials against idiopathic pulmonary fibrosis (IPF) lends support to the viability of this approach, bringing it to the forefront of drug discovery efforts. The present review article aims to provide a comprehensive overview of the most important series of ATX inhibitors developed so far. Special weight is lent to the design, structure activity relationship and mode of binding studies carried out, leading to the identification of advanced leads. The most significant in vitro and in vivo pharmacological results of these advanced leads are also summarized. Lastly, the development of the first ATX inhibitor entered in clinical trials accompanied by its phase 1 and 2a clinical trial data is disclosed.
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Affiliation(s)
- Alexios N Matralis
- Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens, Greece
| | - Antreas Afantitis
- Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens, Greece.,NovaMechanics Ltd Cheminformatics Company, Nicosia, Cyprus
| | - Vassilis Aidinis
- Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens, Greece
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21
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Yang F, Chen GX. Production of extracellular lysophosphatidic acid in the regulation of adipocyte functions and liver fibrosis. World J Gastroenterol 2018; 24:4132-4151. [PMID: 30271079 PMCID: PMC6158478 DOI: 10.3748/wjg.v24.i36.4132] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 04/24/2018] [Accepted: 05/06/2018] [Indexed: 02/06/2023] Open
Abstract
Lysophosphatidic acid (LPA), a glycerophospholipid, consists of a glycerol backbone connected to a phosphate head group and an acyl chain linked to sn-1 or sn-2 position. In the circulation, LPA is in sub-millimolar range and mainly derived from hydrolysis of lysophosphatidylcholine, a process mediated by lysophospholipase D activity in proteins such as autotaxin (ATX). Intracellular and extracellular LPAs act as bioactive lipid mediators with diverse functions in almost every mammalian cell type. The binding of LPA to its receptors LPA1-6 activates multiple cellular processes such as migration, proliferation and survival. The production of LPA and activation of LPA receptor signaling pathways in the events of physiology and pathophysiology have attracted the interest of researchers. Results from studies using transgenic and gene knockout animals with alterations of ATX and LPA receptors genes, have revealed the roles of LPA signaling pathways in metabolic active tissues and organs. The present review was aimed to summarize recent progresses in the studies of extracellular and intracellular LPA production pathways. This includes the functional, structural and biochemical properties of ATX and LPA receptors. The potential roles of LPA production and LPA receptor signaling pathways in obesity, insulin resistance and liver fibrosis are also discussed.
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Affiliation(s)
- Fang Yang
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, TN 37996, United States
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22
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Lysophosphatidic acid receptor, LPA 6, regulates endothelial blood-brain barrier function: Implication for hepatic encephalopathy. Biochem Biophys Res Commun 2018; 501:1048-1054. [PMID: 29778535 DOI: 10.1016/j.bbrc.2018.05.106] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 05/15/2018] [Indexed: 11/22/2022]
Abstract
Cerebral edema is a life-threatening neurological condition characterized by brain swelling due to the accumulation of excess fluid both intracellularly and extracellularly. Fulminant hepatic failure (FHF) develops cerebral edema by disrupting blood-brain barrier (BBB). However, the mechanisms by which mediator induces brain edema in FHF remain to be elucidated. Here, we assessed a linkage between brain edema and lysophosphatidic acid (LPA) signaling by utilizing an animal model of FHF and in vitro BBB model. Azoxymethane-treated mice developed FHF and hepatic encephalopathy, associated with higher autotaxin (ATX) activities in serum than controls. Using in vitro BBB model, LPA disrupted the structural integrity of tight junction proteins including claudin-5, occludin, and ZO-1. Furthermore, LPA decreased transendothelial electrical resistances in in vitro BBB model, and induced cell contraction in brain endothelial monolayer cultures, both being inhibited by a Rho-associated protein kinase inhibitor, Y-27632. The brain capillary endothelial cells predominantly expressed LPA6 mRNA, whose knockdown blocked the LPA-induced endothelial cell contraction. Taken together, the up-regulation of serum ATX in hepatic encephalopathy may activate the LPA-LPA6-G12/13-Rho pathway in brain capillary endothelial cells, leading to enhancement of BBB permeability and brain edema.
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Eraky SM, El-Mesery M, El-Karef A, Eissa LA, El-Gayar AM. Silymarin and caffeine combination ameliorates experimentally-induced hepatic fibrosis through down-regulation of LPAR1 expression. Biomed Pharmacother 2018; 101:49-57. [PMID: 29477472 DOI: 10.1016/j.biopha.2018.02.064] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/14/2018] [Accepted: 02/15/2018] [Indexed: 01/08/2023] Open
Abstract
AIMS Lysophosphatidic acid is a lipid mediator that is supposed to be implicated in hepatic fibrosis. Silymarin and caffeine are natural compounds known for their anti-inflammatory and antioxidant effects. Our study aimed to explore the effect of silymarin, caffeine, and their combination on lysophosphatidic acid receptor 1 (LPAR1) pathway in thioacetamide (TAA)-induced hepatic fibrosis. MAIN METHODS Hepatic fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 200 mg/kg of TAA twice a week for 8 weeks. Silymarin (50 mg/kg), caffeine (50 mg/kg), and their combination (50 mg/kg silymarin + 50 mg/kg caffeine) were orally given to rats every day for 8 weeks along with TAA injection. Liver functions were measured. Histopathological examination of liver tissues was performed using hematoxylin and eosin and Masson's trichrome staining. mRNA expressions of LPAR1, transforming growth factor beta 1 (TGF-β1), connective tissue growth factor (CTGF), and alpha smooth muscle actin (α-SMA) were measured using RT-PCR. LPAR1 tissue expression was scored using immunohistochemistry. KEY FINDINGS Silymarin, caffeine, and their combination significantly improved liver function. They caused significant decrease in fibrosis and necro-inflammatory scores. Combination of silymain and caffeine caused a significant decrease in the necro-inflammatory score than the single treatment with silymarin or caffeine. In addition, silymarin, caffeine, and their combination significantly decreased hepatic LPAR1, TGF-β1, CTGF, and α-SMA gene expressions and LPAR1 tissue expression. SIGNIFICANCE Silymarin, caffeine, and their combination protect against liver fibrosis through down-regulation of LPAR1, TGF-β1, and CTGF.
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Affiliation(s)
- Salma M Eraky
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Mohamed El-Mesery
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Amro El-Karef
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Laila A Eissa
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Amal M El-Gayar
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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24
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Yamazaki T, Joshita S, Umemura T, Usami Y, Sugiura A, Fujimori N, Kimura T, Matsumoto A, Igarashi K, Ota M, Tanaka E. Changes in serum levels of autotaxin with direct-acting antiviral therapy in patients with chronic hepatitis C. PLoS One 2018; 13:e0195632. [PMID: 29617443 PMCID: PMC5884565 DOI: 10.1371/journal.pone.0195632] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 03/25/2018] [Indexed: 12/25/2022] Open
Abstract
Sustained virological response (SVR) rates have increased remarkably since the introduction of direct-acting antiviral agents (DAAs) for chronic hepatitis C. Autotaxin (ATX) is a secreted enzyme converting lysophosphatidylcholine to lysophosphatidic acid and a newly established biomarker for liver fibrosis. Interferon-free DAA regimens for chronic hepatitis C could improve liver stiffness in SVR patients according to several non-invasive evaluation methods, but the clinical response and significance of ATX in this context have not yet been defined. We therefore investigated sequential serum ATX levels at baseline, 4 weeks after the start of treatment, and 24 weeks after treatment in 159 hepatitis C virus (HCV)-infected patients who received DAA therapy. Other non-invasive fibrosis markers (aspartate aminotransferase-to-platelet ratio and FIB-4 index) were examined as well. Baseline median ATX levels were comparable between the 144 patients who achieved a SVR and the 15 who did not (1.54 vs. 1.62 mg/L), but median ATX levels became significantly decreased during and after DAA therapy in the SVR group only (from 1.54 to 1.40 and 1.31 mg/L, respectively; P < 0.001). ATX was significantly decreased between baseline and 4 weeks of treatment in overall, male, and female SVR patients (all P < 0.001). In subjects with low necroinflammatory activity in the liver (i.e., alanine aminotransferase < 30 U/L), ATX levels were significantly reduced from baseline to 4 weeks of treatment and remained low (P < 0.001) in patients with a SVR. Thus, interferon-free DAA therapy was associated with a significant decrease in serum ATX levels in patients achieving a SVR, suggesting early regression of liver fibrosis in addition to inflammation treatment.
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Affiliation(s)
- Tomoo Yamazaki
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
- Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
- Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan
- * E-mail:
| | - Yoko Usami
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Ayumi Sugiura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Naoyuki Fujimori
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takefumi Kimura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akihiro Matsumoto
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Koji Igarashi
- Bioscience Division, TOSOH Corporation, Ayase, Japan
| | - Masao Ota
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Eiji Tanaka
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
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Lysophosphatidic acid (LPA) as a pro-fibrotic and pro-oncogenic factor: a pivotal target to improve the radiotherapy therapeutic index. Oncotarget 2018; 8:43543-43554. [PMID: 28402936 PMCID: PMC5522168 DOI: 10.18632/oncotarget.16672] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 03/08/2017] [Indexed: 12/21/2022] Open
Abstract
Radiation-induced fibrosis is widely considered as a common but forsaken phenomenon that can lead to clinical sequela and possibly vital impairments. Lysophosphatidic acid is a bioactive lipid involved in fibrosis and probably in radiation-induced fibrosis as suggested in recent studies. Lysophosphatidic acid is also a well-described pro-oncogenic factor, involved in carcinogenesis processes (proliferation, survival, angiogenesis, invasion, migration). The present review highlights and summarizes the links between lysophosphatidic acid and radiation-induced fibrosis, lysophosphatidic acid and radioresistance, and proposes lysophosphatidic acid as a potential central actor of the radiotherapy therapeutic index. Besides, we hypothesize that following radiotherapy, the newly formed tumour micro-environment, with increased extracellular matrix and increased lysophosphatidic acid levels, is a favourable ground to metastasis development. Lysophosphatidic acid could therefore be an exciting therapeutic target, minimizing radio-toxicities and radio-resistance effects.
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26
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Baader M, Bretschneider T, Broermann A, Rippmann JF, Stierstorfer B, Kuttruff CA, Mark M. Characterization of the properties of a selective, orally bioavailable autotaxin inhibitor in preclinical models of advanced stages of liver fibrosis. Br J Pharmacol 2018; 175:693-707. [PMID: 29197066 DOI: 10.1111/bph.14118] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 11/13/2017] [Accepted: 11/21/2017] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND AND PURPOSE Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine to generate lysophosphatidic acid (LPA). The extracellular signalling molecule LPA exerts its biological actions through activation of six GPCRs expressed in various cell types including fibroblasts. Multiple preclinical studies using knockout animals, LPA receptor antagonists or ATX inhibitors have provided evidence for a potential role of the ATX/LPA axis in tissue fibrosis. Despite growing evidence for a correlation between ATX levels and the degree of fibrosis in chronic liver diseases, including viral hepatitis and hepatocellular carcinoma, the role of ATX in non-alcoholic steatohepatitis (NASH) remains unclear. EXPERIMENTAL APPROACH The relevance of ATX in the pathogenesis of liver fibrosis was investigated by oral administration of Ex_31, a selective ATX inhibitor, in a 10 week model of carbon tetrachloride-induced liver injury and in a 14 week model of choline-deficient amino acid-defined diet-induced liver injury in rats. KEY RESULTS Oral administration of Ex_31, a selective ATX inhibitor, at 15 mg·kg-1 twice daily in therapeutic intervention mode resulted in efficient ATX inhibition and more than 95% reduction in plasma LPA levels in both studies. Treatment with Ex_31 had no effect on biomarkers of liver function, inflammation, or fibrosis and did not result in histological improvements in diseased animals. CONCLUSIONS AND IMPLICATIONS Our findings question the role of ATX in the pathogenesis of hepatic fibrosis and the potential of small molecule ATX inhibitors for the treatment of patients with NASH and advanced stages of liver fibrosis.
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Affiliation(s)
- Manuel Baader
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Tom Bretschneider
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Andre Broermann
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Joerg F Rippmann
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | | | | | - Michael Mark
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
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YATOMI Y, KURANO M, IKEDA H, IGARASHI K, KANO K, AOKI J. Lysophospholipids in laboratory medicine. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2018; 94:373-389. [PMID: 30541965 PMCID: PMC6374142 DOI: 10.2183/pjab.94.025] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Lysophospholipids (LPLs), such as lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), and lysophosphatidylserine (LysoPS), are attracting attention as second-generation lipid mediators. In our laboratory, the functional roles of these lipid mediators and the mechanisms by which the levels of these mediators are regulated in vivo have been studied. Based on these studies, the clinical introduction of assays for LPLs and related proteins has been pursued and will be described in this review. Although assays of these lipids themselves are possible, autotaxin (ATX), apolipoprotein M (ApoM), and phosphatidylserine-specific phospholipase A1 (PS-PLA1) are more promising as alternate biomarkers for LPA, S1P, and LysoPS, respectively. Presently, ATX, which produces LPA through its lysophospholipase D activity, has been shown to be a useful laboratory test for the diagnosis and staging of liver fibrosis, whereas PS-PLA1 and ApoM are considered to be promising clinical markers reflecting the in vivo actions induced by LysoPS and S1P.
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Affiliation(s)
- Yutaka YATOMI
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Correspondence should be addressed: Y. Yatomi, Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan (e-mail: )
| | - Makoto KURANO
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hitoshi IKEDA
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Koji IGARASHI
- Bioscience Division, TOSOH Corporation, Kanagawa, Japan
| | - Kuniyuki KANO
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
| | - Junken AOKI
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
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Bae GH, Lee SK, Kim HS, Lee M, Lee HY, Bae YS. Lysophosphatidic acid protects against acetaminophen-induced acute liver injury. Exp Mol Med 2017; 49:e407. [PMID: 29217823 PMCID: PMC5750472 DOI: 10.1038/emm.2017.203] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 06/01/2017] [Accepted: 06/05/2017] [Indexed: 01/04/2023] Open
Abstract
We investigated the effect of lysophosphatidic acid (LPA) in experimental acetaminophen (APAP)-induced acute liver injury. LPA administration significantly reduced APAP-challenged acute liver injury, showing attenuated liver damage, liver cell death and aspartate aminotransferase and alanine aminotransferase levels. APAP overdose-induced mortality was also significantly decreased by LPA administration. Regarding the mechanism involved in LPA-induced protection against acute liver injury, LPA administration significantly increased the glutathione level, which was markedly decreased in APAP challenge-induced acute liver injury. LPA administration also strongly blocked the APAP challenge-elicited phosphorylation of JNK, ERK and GSK3β, which are involved in the pathogenesis of acute liver injury. Furthermore, LPA administration decreased the production of TNF-α and IL-1β in an experimental drug-induced liver injury animal model. Mouse primary hepatocytes express LPA1,3-6, and injection of the LPA receptor antagonist KI16425 (an LPA1,3-selective inhibitor) or H2L 5765834 (an LPA1,3,5-selective inhibitor) did not reverse the LPA-induced protective effects against acute liver injury. The therapeutic administration of LPA also blocked APAP-induced liver damage, leading to an increased survival rate. Collectively, these results indicate that the well-known bioactive lipid LPA can block the pathogenesis of APAP-induced acute liver injury by increasing the glutathione level but decreasing inflammatory cytokines in an LPA1,3,5-independent manner. Our results suggest that LPA might be an important therapeutic agent for drug-induced liver injury.
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Affiliation(s)
- Geon Ho Bae
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
| | - Sung Kyun Lee
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
| | - Hyung Sik Kim
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
| | - Mingyu Lee
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Seoul, Republic of Korea
| | - Ha Young Lee
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
| | - Yoe-Sik Bae
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Seoul, Republic of Korea
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29
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Ikeda H, Kobayashi M, Kumada H, Enooku K, Koike K, Kurano M, Sato M, Nojiri T, Kobayashi T, Ohkawa R, Shimamoto S, Igarashi K, Aoki J, Yatomi Y. Performance of autotaxin as a serum marker for liver fibrosis. Ann Clin Biochem 2017; 55:469-477. [PMID: 29065699 DOI: 10.1177/0004563217741509] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Background Because autotaxin reportedly has a better performance than hyaluronic acid as a marker for liver fibrosis for the prediction of cirrhosis caused by hepatitis C, we aimed to further evaluate the role of autotaxin in liver fibrosis of other aetiologies. Methods Autotaxin antigen was measured in serum samples from 108 patients with chronic hepatitis B and 128 patients with non-alcoholic fatty liver disease who had undergone a liver biopsy as well as healthy subjects and patients with chronic kidney disease, diabetes mellitus, rheumatoid arthritis and cardiac dysfunction. Results When evaluated using receiver operator characteristics curves, the performance of autotaxin for the prediction of significant fibrosis (F2-F4) in chronic hepatitis B patients was better than that of hyaluronic acid or type IV collagen 7S. In non-alcoholic fatty liver disease patients, however, the performance of autotaxin for the prediction of significant fibrosis was poorer than that of hyaluronic acid or type IV collagen 7S. The increase in the serum autotaxin concentrations was less notable than that of hyaluronic acid or type IV collagen in patients with chronic kidney disease, diabetes mellitus, rheumatoid arthritis or cardiac dysfunction. Food intake did not affect the serum autotaxin concentrations. Conclusions Autotaxin is useful as a serum marker for liver fibrosis caused by not only chronic viral hepatitis C but also by hepatitis B, although it was less useful in patients with non-alcoholic fatty liver disease. The increase in serum autotaxin concentrations is fairly specific for liver fibrosis, and the serum autotaxin concentrations can be analysed without consideration of food intake before blood collection.
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Affiliation(s)
- Hitoshi Ikeda
- 1 Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mariko Kobayashi
- 2 Department of Hepatology, Toranomon Hospital, Minato-ku, Tokyo, Japan
| | - Hiromitsu Kumada
- 2 Department of Hepatology, Toranomon Hospital, Minato-ku, Tokyo, Japan
| | - Kenichiro Enooku
- 3 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Kazuhiko Koike
- 3 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Makoto Kurano
- 1 Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaya Sato
- 1 Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,3 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Takahiro Nojiri
- 4 Department of Clinical Laboratory, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan
| | - Tamaki Kobayashi
- 4 Department of Clinical Laboratory, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan
| | - Ryunosuke Ohkawa
- 5 Analytical Laboratory Chemistry, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Satoshi Shimamoto
- 6 Bioscience Division, Reagent Development Department, AIA Research Group, TOSOH Corporation, Ayase, Kanagawa, Japan
| | - Koji Igarashi
- 6 Bioscience Division, Reagent Development Department, AIA Research Group, TOSOH Corporation, Ayase, Kanagawa, Japan
| | - Junken Aoki
- 7 Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan
| | - Yutaka Yatomi
- 1 Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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30
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Funke M, Knudsen L, Lagares D, Ebener S, Probst CK, Fontaine BA, Franklin A, Kellner M, Kühnel M, Matthieu S, Grothausmann R, Chun J, Roberts JD, Ochs M, Tager AM. Lysophosphatidic Acid Signaling through the Lysophosphatidic Acid-1 Receptor Is Required for Alveolarization. Am J Respir Cell Mol Biol 2017; 55:105-16. [PMID: 27082727 DOI: 10.1165/rcmb.2015-0152oc] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Lysophosphatidic acid (LPA) signaling through one of its receptors, LPA1, contributes to both the development and the pathological remodeling after injury of many organs. Because we found previously that LPA-LPA1 signaling contributes to pulmonary fibrosis, here we investigated whether this pathway is also involved in lung development. Quantitative assessment of lung architecture of LPA1-deficient knock-out (KO) and wild-type (WT) mice at 3, 12, and 24 weeks of age using design-based stereology suggested the presence of an alveolarization defect in LPA1 KO mice at 3 weeks, which persisted as alveolar numbers increased in WT mice into adulthood. Across the ages examined, the lungs of LPA1 KO mice exhibited decreased alveolar numbers, septal tissue volumes, and surface areas, and increased volumes of the distal airspaces. Elastic fibers, critical to the development of alveolar septa, appeared less organized and condensed and more discontinuous in KO alveoli starting at P4. Tropoelastin messenger RNA expression was decreased in KO lungs, whereas expression of matrix metalloproteinases degrading elastic fibers was either decreased or unchanged. These results are consistent with the abnormal lung phenotype of LPA1 KO mice, being attributable to reduced alveolar septal formation during development, rather than to increased septal destruction as occurs in the emphysema of chronic obstructive pulmonary disease. Peripheral septal fibroblasts and myofibroblasts, which direct septation in late alveolarization, demonstrated reduced production of tropoelastin and matrix metalloproteinases, and diminished LPA-induced migration, when isolated from LPA1 KO mice. Taken together, our data suggest that LPA-LPA1 signaling is critically required for septation during alveolarization.
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Affiliation(s)
- Manuela Funke
- 1 Departments of Pulmonary Medicine, Inselspital Berne, and.,2 Clinical Research, University of Berne, Berne, Switzerland.,3 Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases, and
| | - Lars Knudsen
- 4 Institute of Functional and Applied Anatomy, Hannover Medical School, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, REBIRTH Cluster of Excellence, Hannover, Germany; and
| | - David Lagares
- 3 Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases, and
| | - Simone Ebener
- 1 Departments of Pulmonary Medicine, Inselspital Berne, and.,2 Clinical Research, University of Berne, Berne, Switzerland
| | - Clemens K Probst
- 3 Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases, and
| | - Benjamin A Fontaine
- 3 Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases, and
| | - Alicia Franklin
- 3 Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases, and
| | - Manuela Kellner
- 4 Institute of Functional and Applied Anatomy, Hannover Medical School, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, REBIRTH Cluster of Excellence, Hannover, Germany; and
| | - Mark Kühnel
- 4 Institute of Functional and Applied Anatomy, Hannover Medical School, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, REBIRTH Cluster of Excellence, Hannover, Germany; and
| | - Stephanie Matthieu
- 4 Institute of Functional and Applied Anatomy, Hannover Medical School, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, REBIRTH Cluster of Excellence, Hannover, Germany; and
| | - Roman Grothausmann
- 4 Institute of Functional and Applied Anatomy, Hannover Medical School, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, REBIRTH Cluster of Excellence, Hannover, Germany; and
| | - Jerold Chun
- 5 Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, Scripps Research Institute, La Jolla, California
| | - Jesse D Roberts
- 6 Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Matthias Ochs
- 4 Institute of Functional and Applied Anatomy, Hannover Medical School, and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, REBIRTH Cluster of Excellence, Hannover, Germany; and
| | - Andrew M Tager
- 3 Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases, and
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31
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Lopane C, Agosti P, Gigante I, Sabbà C, Mazzocca A. Implications of the lysophosphatidic acid signaling axis in liver cancer. Biochim Biophys Acta Rev Cancer 2017; 1868:277-282. [PMID: 28591560 DOI: 10.1016/j.bbcan.2017.06.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 05/30/2017] [Accepted: 06/01/2017] [Indexed: 01/25/2023]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in western countries. The major risk factors for HCC are hepatitis C or B viruses, alcohol and metabolic disorders. The increasing risk of HCC in patients with metabolic disorders (i.e. obesity, diabetes and non-alcoholic steatohepatitis/NASH) regardless of the presence of liver cirrhosis is becoming relevant. Nevertheless, molecular mechanisms linking these risk factors to liver oncogenesis are unclear. This review focuses on the pathogenic role of the lysophosphatidic acid (LPA) pathway in HCC, highlighting the implications of this bioactive phospholipid in liver cancer biology and metabolism and as potential therapeutic target.
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Affiliation(s)
- Chiara Lopane
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy
| | - Pasquale Agosti
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy
| | - Isabella Gigante
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy
| | - Carlo Sabbà
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy
| | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11, 70124 Bari, Italy.
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32
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Nikolaou A, Kokotou MG, Limnios D, Psarra A, Kokotos G. Autotaxin inhibitors: a patent review (2012-2016). Expert Opin Ther Pat 2017; 27:815-829. [DOI: 10.1080/13543776.2017.1323331] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Aikaterini Nikolaou
- Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Maroula G. Kokotou
- Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitris Limnios
- Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasia Psarra
- Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - George Kokotos
- Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
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33
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Bain G, Shannon KE, Huang F, Darlington J, Goulet L, Prodanovich P, Ma GL, Santini AM, Stein AJ, Lonergan D, King CD, Calderon I, Lai A, Hutchinson JH, Evans JF. Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis. J Pharmacol Exp Ther 2017; 360:1-13. [PMID: 27754931 DOI: 10.1124/jpet.116.237156] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 10/14/2016] [Indexed: 03/08/2025] Open
Abstract
Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]. PAT-505 is a potent, selective, noncompetitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a Stelic Mouse Animal Model of nonalcoholic steatohepatitis (NASH), PAT-505 treatment resulted in a small but significant improvement in fibrosis with only minor improvements in hepatocellular ballooning and hepatic inflammation. In a choline-deficient, high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning, or inflammation. These data demonstrate that inhibiting autotaxin is antifibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH.
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Affiliation(s)
- Gretchen Bain
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Kristen E Shannon
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Fei Huang
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Janice Darlington
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Lance Goulet
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Patricia Prodanovich
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Gina L Ma
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Angelina M Santini
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Adam J Stein
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Dave Lonergan
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Christopher D King
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Imelda Calderon
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Andiliy Lai
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - John H Hutchinson
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Jilly F Evans
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Zuckerman V, Sokolov E, Swet JH, Ahrens WA, Showlater V, Iannitti DA, Mckillop IH. Expression and function of lysophosphatidic acid receptors (LPARs) 1 and 3 in human hepatic cancer progenitor cells. Oncotarget 2016; 7:2951-67. [PMID: 26701886 PMCID: PMC4823083 DOI: 10.18632/oncotarget.6696] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 11/16/2015] [Indexed: 01/26/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and is characterized by rapid tumor expansion and metastasis. Lysophosphatidic acid (LPA) signaling, via LPA receptors 1–6 (LPARs1–6), regulates diverse cell functions including motility, migration, and proliferation, yet the role of LPARs in hepatic tumor pathology is poorly understood. We sought to determine the expression and function of endothelial differentiation gene (EDG) LPARs (LPAR1–3) in human HCC and complimentary in vitro models. Human HCC were characterized by significantly elevated LPAR1/LPAR3 expression in the microenvironment between the tumor and non-tumor liver (NTL), a finding mirrored in human SKHep1 cells. Analysis of human tissue and human hepatic tumor cells in vitro revealed cells that express LPAR3 (HCC-NTL margin in vivo and SKHep1 in vitro) also express cancer stem cell markers in the absence of hepatocyte markers. Treatment of SKHep1 cells with exogenous LPA led to significantly increased cell motility but not proliferation. Using pharmacological agents and cells transfected to knock-down LPAR1 or LPAR3 demonstrated LPA-dependent cell migration occurs via an LPAR3-Gi-ERK-pathway independent of LPAR1. These data suggest cells that stain positive for both LPAR3 and cancer stem cell markers are distinct from the tumor mass per se, and may mediate tumor invasiveness/expansion via LPA-LPAR3 signaling.
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Affiliation(s)
| | - Eugene Sokolov
- Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA 28203
| | - Jacob H Swet
- Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA 28203
| | - William A Ahrens
- Department of Pathology, Carolinas Medical Center, Charlotte, NC, USA 28203
| | - Victor Showlater
- Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA 28203
| | - David A Iannitti
- Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA 28203
| | - Iain H Mckillop
- Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA 28203
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35
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Enooku K, Uranbileg B, Ikeda H, Kurano M, Sato M, Kudo H, Maki H, Koike K, Hasegawa K, Kokudo N, Yatomi Y. Higher LPA2 and LPA6 mRNA Levels in Hepatocellular Carcinoma Are Associated with Poorer Differentiation, Microvascular Invasion and Earlier Recurrence with Higher Serum Autotaxin Levels. PLoS One 2016; 11:e0161825. [PMID: 27583415 PMCID: PMC5008774 DOI: 10.1371/journal.pone.0161825] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 08/14/2016] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) commonly develops in patients with liver fibrosis; in these patients, the blood levels of lysophosphatidic acid (LPA) and its generating enzyme autotaxin (ATX) increase with the liver fibrosis stage. We aimed to examine the potential relevance of ATX and LPA in HCC. Fifty-eight HCC patients who underwent surgical treatment were consecutively enrolled in the study. Among the LPA receptors in HCC, higher LPA2 mRNA levels correlated with poorer differentiation, and higher LPA6 mRNA levels correlated with microvascular invasion, which suggested a higher malignant potential of HCC with increased LPA2 and LPA6 expression. In patients with primary HCC, neither LPA2 nor LPA6 mRNA levels were associated with recurrence. However, when serum ATX levels were combined for analysis as a surrogate for plasma LPA levels, the cumulative intra-hepatic recurrence rate was higher in patients in whom both serum ATX levels and LPA2 or LPA6 mRNA levels were higher than the median. However, the mRNA level of phosphatidic acid-selective phospholipase A1ɑ, another LPA-generating enzyme, in HCC patients was not associated with pathological findings or recurrence, even in combination with the expression of LPA receptors. Higher LPA2 mRNA levels were associated with poorer differentiation, and higher LPA6 levels were associated with microvascular invasion in HCC; both became a risk factor for recurrence after surgical treatment when combined with increased serum ATX levels. ATX and LPA receptors merit consideration as therapeutic targets of HCC.
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Affiliation(s)
- Kenichiro Enooku
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Baasanjav Uranbileg
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Hitoshi Ikeda
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
- * E-mail:
| | - Makoto Kurano
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaya Sato
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroki Kudo
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Harufumi Maki
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
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36
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Wang G, Li Z, Li H, Li L, Li J, Yu C. Metabolic Profile Changes of CCl₄-Liver Fibrosis and Inhibitory Effects of Jiaqi Ganxian Granule. Molecules 2016; 21:molecules21060698. [PMID: 27248993 PMCID: PMC6273034 DOI: 10.3390/molecules21060698] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 05/18/2016] [Accepted: 05/20/2016] [Indexed: 01/08/2023] Open
Abstract
Jiaqi Ganxian Granule (JGG) is a famous traditional Chinese medicine, which has been long used in clinical practice for treating liver fibrosis. However, the mechanism underlying its anti-hepatic fibrosis is still not clear. In this study, an Ultra-Performance Liquid Chromatography-Time-Of-Flight Mass Spectrometry (UPLC-TOF-MS)-based metabolomics strategy was used to profile the metabolic characteristic of serum obtained from a carbon tetrachloride (CCl4)-induced hepatic fibrosis model in Sprague-Dawley (SD) rats with JGG treatment. Through Principal Component Analysis (PCA) and Partial Least Square Discriminant Analysis (PLS-DA), it was shown that metabolic perturbations induced by CCl4 were inhibited after treatment of JGG, for 17 different metabolites related to CCl4. Among these compounds, the change tendency of eight potential drug targets was restored after the intervention with JGG. The current study indicates that JGG has a significant anti-fibrosis effect on CCl4-induced liver fibrosis in rats, which might be by regulating the dysfunction of sphingolipid metabolism, glycerophospholipid metabolism, N-acylethanolamine biosynthesis, fat digestion and absorption, while glycerophospholipid metabolism played vital roles in the inhibitory effects of JGG on hepatic fibrosis according to Metabolic Pathway Analysis (MetPA). Our findings indicated that the metabolomics approach may provide a useful tool for exploring potential biomarkers involved in hepatic fibrosis and elucidate the mechanisms underlying the action of therapies used in traditional Chinese medicine.
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Affiliation(s)
- Ge Wang
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
| | - Zehao Li
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
| | - Hao Li
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
| | - Lidan Li
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
| | - Jian Li
- School of Basic Medical Science, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Changyuan Yu
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
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Bolier R, Tolenaars D, Kremer AE, Saris J, Parés A, Verheij J, Bosma PJ, Beuers U, Oude Elferink RP. Enteroendocrine cells are a potential source of serum autotaxin in men. Biochim Biophys Acta Mol Basis Dis 2016; 1862:696-704. [DOI: 10.1016/j.bbadis.2016.01.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 12/22/2015] [Accepted: 01/12/2016] [Indexed: 12/26/2022]
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Ohashi T, Yamamoto T. Antifibrotic effect of lysophosphatidic acid receptors LPA1and LPA3antagonist on experimental murine scleroderma induced by bleomycin. Exp Dermatol 2015; 24:698-702. [DOI: 10.1111/exd.12752] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/28/2015] [Indexed: 12/18/2022]
Affiliation(s)
- Takenobu Ohashi
- Department of Dermatology; Fukushima Medical University; Fukushima Japan
| | - Toshiyuki Yamamoto
- Department of Dermatology; Fukushima Medical University; Fukushima Japan
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Rachakonda VP, Reeves VL, Aljammal J, Wills RC, Trybula JS, DeLany JP, Kienesberger PC, Kershaw EE. Serum autotaxin is independently associated with hepatic steatosis in women with severe obesity. Obesity (Silver Spring) 2015; 23:965-72. [PMID: 25865747 PMCID: PMC4414671 DOI: 10.1002/oby.20960] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 10/13/2014] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Autotaxin (ATX) is an adipocyte-derived lysophospholipase that generates the lipid signaling molecule lysophosphatidic acid (LPA). The aim of this study was to determine the relationship between serum ATX and nonalcoholic fatty liver disease (NAFLD) in females with obesity. METHODS 101 nondiabetic women with obesity (age: 31.5-55.8 years; BMI: 35.0-64.5 kg/m2) were classified as having NAFLD (36.3%) or not having NAFLD (63.7%) based on the degree of hepatic steatosis on abdominal CT. Subjects were characterized for metabolic phenotype including measures of energy, glucose, and lipid homeostasis. Fasting serum adipokines and inflammatory markers were determined by ELISA. Linear regression analysis was used to determine features independently associated with NAFLD. RESULTS Subjects with and without NAFLD differed in several key features of metabolic phenotype including BMI, waist circumference, fasting glucose and insulin, HOMA-IR, VLDL, triglycerides, and ALT. Serum adipokines, including ATX and leptin, were higher in subjects with NAFLD. Serum ATX was significantly correlated with alkaline phosphatase, fasting glucose, fasting insulin, and HOMA-IR. Linear regression analysis revealed that serum triglycerides and log-transformed ATX were independently associated with hepatic steatosis. CONCLUSIONS Serum ATX may be a potential pathogenic factor and/or biomarker for NAFLD in nondiabetic women with obesity.
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Affiliation(s)
- Vikrant P. Rachakonda
- Division of Gastroenterology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Valerie L. Reeves
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jules Aljammal
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Rachel C. Wills
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Joy S. Trybula
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - James P. DeLany
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Petra C. Kienesberger
- Department of Biochemistry and Molecular Biology, Dalhousie Medicine New Brunswick, Saint John, NB E2L 4L5 Canada
| | - Erin E. Kershaw
- Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Barbayianni E, Kaffe E, Aidinis V, Kokotos G. Autotaxin, a secreted lysophospholipase D, as a promising therapeutic target in chronic inflammation and cancer. Prog Lipid Res 2015; 58:76-96. [DOI: 10.1016/j.plipres.2015.02.001] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 01/20/2015] [Accepted: 02/12/2015] [Indexed: 02/07/2023]
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Udomsinprasert W, Honsawek S, Anomasiri W, Chongsrisawat V, Vejchapipat P, Poovorawan Y. Serum autotaxin levels correlate with hepatic dysfunction and severity in postoperative biliary atresia. Biomarkers 2015; 20:89-94. [PMID: 25536867 DOI: 10.3109/1354750x.2014.994564] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To investigate correlation of serum autotaxin and disease severity in biliary atresia (BA). METHODS Eighty postoperative BA patients and 15 controls were recruited. Serum autotaxin levels were determined by enzyme-linked immunosorbent assay. RESULTS BA patients had greater serum autotaxin and liver stiffness than controls. Serum autotaxin and liver stiffness were markedly elevated in BA patients with jaundice compared to those without jaundice. Furthermore, serum autotaxin was correlated with liver stiffness and biochemical parameters in BA. CONCLUSIONS Elevated serum autotaxin was correlated with hepatic dysfunction in BA. Accordingly, serum autotaxin is a promising biomarker reflecting the severity in BA.
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Affiliation(s)
- Wanvisa Udomsinprasert
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society , Bangkok , Thailand
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Pleli T, Martin D, Kronenberger B, Brunner F, Köberle V, Grammatikos G, Farnik H, Martinez Y, Finkelmeier F, Labocha S, Ferreirós N, Zeuzem S, Piiper A, Waidmann O. Serum autotaxin is a parameter for the severity of liver cirrhosis and overall survival in patients with liver cirrhosis--a prospective cohort study. PLoS One 2014; 9:e103532. [PMID: 25062038 PMCID: PMC4111595 DOI: 10.1371/journal.pone.0103532] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 06/29/2014] [Indexed: 12/25/2022] Open
Abstract
Background Autotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients. Methods Patients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact. Blood samples drawn at the day of inclusion in the study were assessed for ATX content by an enzyme-linked immunosorbent assay. ATX levels were correlated with the stage as well as complications of cirrhosis. The prognostic value of ATX was investigated by uni- and multivariate Cox regression analyses. LPA concentration was determined by liquid chromatography-tandem mass spectrometry. Results 270 patients were enrolled. Subjects with liver cirrhosis showed elevated serum levels of ATX as compared to healthy subjects (0.814±0.42 mg/l vs. 0.258±0.40 mg/l, P<0.001). Serum ATX levels correlated with the Child-Pugh stage and the MELD (model of end stage liver disease) score and LPA levels (r = 0.493, P = 0.027). Patients with hepatic encephalopathy (P = 0.006), esophageal varices (P = 0.002) and portal hypertensive gastropathy (P = 0.008) had higher ATX levels than patients without these complications. Low ATX levels were a parameter independently associated with longer overall survival (hazard ratio 0.575, 95% confidence interval 0.365–0.905, P = 0.017). Conclusion Serum ATX is an indicator for the severity of liver disease and the prognosis of cirrhotic patients.
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Affiliation(s)
- Thomas Pleli
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt, Germany
| | - Daniel Martin
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt, Germany
| | - Bernd Kronenberger
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt, Germany
| | - Friederike Brunner
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt, Germany
| | - Verena Köberle
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt, Germany
| | - Georgios Grammatikos
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt, Germany
| | - Harald Farnik
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt, Germany
| | - Yolanda Martinez
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt, Germany
| | - Fabian Finkelmeier
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt, Germany
| | - Sandra Labocha
- pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Nerea Ferreirós
- pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Stefan Zeuzem
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt, Germany
| | - Albrecht Piiper
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt, Germany
- * E-mail: (AP); (OW)
| | - Oliver Waidmann
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt, Germany
- * E-mail: (AP); (OW)
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Simo KA, Niemeyer DJ, Hanna EM, Swet JH, Thompson KJ, Sindram D, Iannitti DA, Eheim AL, Sokolov E, Zuckerman V, McKillop IH. Altered lysophosphatidic acid (LPA) receptor expression during hepatic regeneration in a mouse model of partial hepatectomy. HPB (Oxford) 2014; 16:534-42. [PMID: 24750398 PMCID: PMC4048075 DOI: 10.1111/hpb.12176] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 07/28/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatic regeneration requires coordinated signal transduction for efficient restoration of functional liver mass. This study sought to determine changes in lysophosphatidic acid (LPA) and LPA receptor (LPAR) 1-6 expression in regenerating liver following two-thirds partial hepatectomy (PHx). METHODS Liver tissue and blood were collected from male C57BL/6 mice following PHx. Circulating LPA was measured by enzyme-linked immunosorbent assay (ELISA) and hepatic LPAR mRNA and protein expression were determined. RESULTS Circulating LPA increased 72 h after PHx and remained significantly elevated for up to 7 days post-PHx. Analysis of LPAR expression after PHx demonstrated significant increases in LPAR1, LPAR3 and LPAR6 mRNA and protein in a time-dependent manner for up to 7 days post-PHx. Conversely, LPAR2, LPAR4 and LPAR5 mRNA were barely detected in normal liver and did not significantly change after PHx. Changes in LPAR1 expression were confined to non-parenchymal cells following PHx. CONCLUSIONS Liver regeneration following PHx is associated with significant changes in circulating LPA and hepatic LPAR1, LPAR3 and LPAR6 expression in a time- and cell-dependent manner. Furthermore, changes in LPA-LPAR post-PHx occur after the first round of hepatocyte division is complete.
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Affiliation(s)
- Kerri A Simo
- Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA
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Ho YY, Lagares D, Tager AM, Kapoor M. Fibrosis--a lethal component of systemic sclerosis. Nat Rev Rheumatol 2014; 10:390-402. [PMID: 24752182 DOI: 10.1038/nrrheum.2014.53] [Citation(s) in RCA: 242] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Fibrosis is a pathological process characterized by excessive accumulation of connective tissue components in an organ or tissue. Fibrosis is produced by deregulated wound healing in response to chronic tissue injury or chronic inflammation, the hallmarks of rheumatic diseases. Progressive fibrosis, which distorts tissue architecture and results in progressive loss of organ function, is now recognized to be one of the major causes of morbidity and mortality in individuals with one of the most lethal rheumatic disease, systemic sclerosis (SSc). In this Review, we discuss the pathological role of fibrosis in SSc. We discuss the involvement of endothelium and pericyte activation, aberrant immune responses, endoplasmic reticulum stress and chronic tissue injury in the initiation of fibrosis in SSc. We then discuss fibroblast activation and myofibroblast differentiation that occurs in response to these initiating processes and is responsible for excessive accumulation of extracellular matrix. Finally, we discuss the chemical and mechanical signals that drive fibroblast activation and myofibroblast differentiation, which could serve as targets for new therapies for fibrosis in SSc.
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Affiliation(s)
- Yuen Yee Ho
- Shriners Hospital for Children, Division of Surgical Research, McGill University, 1529 Cedar Avenue, Montreal, QC H3G1A6, Canada
| | - David Lagares
- Pulmonary and Critical Care Unit and Centre for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA
| | - Andrew M Tager
- Pulmonary and Critical Care Unit and Centre for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA
| | - Mohit Kapoor
- The Toronto Western Research Institute, Division of Orthopaedics, Toronto Western Hospital, The University Health Network, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada
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Tsou PS, Haak AJ, Khanna D, Neubig RR. Cellular mechanisms of tissue fibrosis. 8. Current and future drug targets in fibrosis: focus on Rho GTPase-regulated gene transcription. Am J Physiol Cell Physiol 2014; 307:C2-13. [PMID: 24740541 DOI: 10.1152/ajpcell.00060.2014] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Tissue fibrosis occurs with excessive extracellular matrix deposition from myofibroblasts, resulting in tissue scarring and inflammation. It is driven by multiple mediators, such as the G protein-coupled receptor ligands lysophosphatidic acid and endothelin, as well as signaling by transforming growth factor-β, connective tissue growth factor, and integrins. Fibrosis contributes to 45% of deaths in the developed world. As current therapeutic options for tissue fibrosis are limited and organ transplantation is the only effective treatment for end-stage disease, there is an imminent need for efficacious antifibrotic therapies. This review discusses the various molecular pathways involved in fibrosis. It highlights the Rho GTPase signaling pathway and its downstream gene transcription output through myocardin-related transcription factor and serum response factor as a convergence point for targeting this complex set of diseases.
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Affiliation(s)
- Pei-Suen Tsou
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Scleroderma Program, Ann Arbor, Michigan
| | - Andrew J Haak
- Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan; and
| | - Dinesh Khanna
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Scleroderma Program, Ann Arbor, Michigan
| | - Richard R Neubig
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan
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Paschos KA, Majeed AW, Bird NC. Natural history of hepatic metastases from colorectal cancer - pathobiological pathways with clinical significance. World J Gastroenterol 2014; 20:3719-3737. [PMID: 24744570 PMCID: PMC3983432 DOI: 10.3748/wjg.v20.i14.3719] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/12/2013] [Accepted: 01/06/2014] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer hepatic metastases represent the final stage of a multi-step biological process. This process starts with a series of mutations in colonic epithelial cells, continues with their detachment from the large intestine, dissemination through the blood and/or lymphatic circulation, attachment to the hepatic sinusoids and interactions with the sinusoidal cells, such as sinusoidal endothelial cells, Kupffer cells, stellate cells and pit cells. The metastatic sequence terminates with colorectal cancer cell invasion, adaptation and colonisation of the hepatic parenchyma. All these events, termed the colorectal cancer invasion-metastasis cascade, include multiple molecular pathways, intercellular interactions and expression of a plethora of chemokines and growth factors, and adhesion molecules, such as the selectins, the integrins or the cadherins, as well as enzymes including matrix metalloproteinases. This review aims to present recent advances that provide insights into these cell-biological events and emphasizes those that may be amenable to therapeutic targeting.
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Yung YC, Stoddard NC, Chun J. LPA receptor signaling: pharmacology, physiology, and pathophysiology. J Lipid Res 2014; 55:1192-214. [PMID: 24643338 DOI: 10.1194/jlr.r046458] [Citation(s) in RCA: 556] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Indexed: 12/18/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a small ubiquitous lipid found in vertebrate and nonvertebrate organisms that mediates diverse biological actions and demonstrates medicinal relevance. LPA's functional roles are driven by extracellular signaling through at least six 7-transmembrane G protein-coupled receptors. These receptors are named LPA1-6 and signal through numerous effector pathways activated by heterotrimeric G proteins, including Gi/o, G12/13, Gq, and Gs LPA receptor-mediated effects have been described in numerous cell types and model systems, both in vitro and in vivo, through gain- and loss-of-function studies. These studies have revealed physiological and pathophysiological influences on virtually every organ system and developmental stage of an organism. These include the nervous, cardiovascular, reproductive, and pulmonary systems. Disturbances in normal LPA signaling may contribute to a range of diseases, including neurodevelopmental and neuropsychiatric disorders, pain, cardiovascular disease, bone disorders, fibrosis, cancer, infertility, and obesity. These studies underscore the potential of LPA receptor subtypes and related signaling mechanisms to provide novel therapeutic targets.
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Affiliation(s)
- Yun C Yung
- Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037
| | - Nicole C Stoddard
- Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037 Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, CA 92037
| | - Jerold Chun
- Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037
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Increased serum autotaxin levels in hepatocellular carcinoma patients were caused by background liver fibrosis but not by carcinoma. Clin Chim Acta 2014; 433:128-34. [PMID: 24642343 DOI: 10.1016/j.cca.2014.03.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 02/26/2014] [Accepted: 03/10/2014] [Indexed: 01/06/2023]
Abstract
BACKGROUND Controversy exists as to whether autotaxin (ATX) may be importantly associated with pathophysiology of hepatocellular carcinoma (HCC). METHODS We evaluated serum ATX levels and its mRNA expression in consecutive 148 HCC patients treated with radiofrequency ablation (RFA) and 30 patients with hepatic resection. RESULTS Although increased serum ATX levels were observed in almost all the patients treated with RFA, they were not reduced after RFA. Furthermore, serum ATX levels were associated not with tumor burden but with the parameters predicting for liver fibrosis, such as liver stiffness values. Then, in surgically-treated patients, there was no significant correlation between serum ATX levels and ATX mRNA expression levels in HCC tissues. Notably, ATX mRNA expression levels in HCC tissues were not higher than those in peri-tumorous tissues. Finally, serum ATX levels in surgically-treated HCC patients were rather correlated with ATX mRNA expression levels in peri-tumorous tissues as well as with liver fibrosis stage. CONCLUSION The increase in serum ATX levels in HCC patients may not be caused by abundant ATX production in HCC tissues but by fibrosis in the background livers.
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Methods for quantifying lysophosphatidic acid in body fluids: a review. Anal Biochem 2014; 453:38-43. [PMID: 24613261 DOI: 10.1016/j.ab.2014.02.021] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 02/10/2014] [Accepted: 02/21/2014] [Indexed: 11/23/2022]
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid involved in cellular signal transduction. LPA plays a role in both physiological and pathological processes. Elevated levels of LPA are observed in the plasma of patients with epithelial ovarian cancer, indicating its potential as a diagnostic marker. Quantification of total LPA can be performed by radioenzymatic, fluorometric, colorimetric, or immunoezymatic assay. Determination of individual LPA molecular species requires the use of capillary electrophoresis, gas chromatography, thin layer chromatography, liquid chromatography, or a matrix-assisted laser desorption/ionization time-of-flight method connected to an appropriate detection system.
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Autotaxin in the crosshairs: taking aim at cancer and other inflammatory conditions. FEBS Lett 2014; 588:2712-27. [PMID: 24560789 DOI: 10.1016/j.febslet.2014.02.009] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 02/11/2014] [Accepted: 02/12/2014] [Indexed: 02/07/2023]
Abstract
Autotaxin is a secreted enzyme that produces most of the extracellular lysophosphatidate from lysophosphatidylcholine, the most abundant phospholipid in blood plasma. Lysophosphatidate mediates many physiological and pathological processes by signaling through at least six G-protein coupled receptors to promote cell survival, proliferation and migration. The autotaxin/lysophosphatidate signaling axis is involved in wound healing and tissue remodeling, and it drives many chronic inflammatory conditions from fibrosis to colitis, asthma and cancer. In cancer, lysophosphatidate signaling promotes resistance to chemotherapy and radiotherapy, and increases both angiogenesis and metastasis. Research into autotaxin inhibitors is accelerating, both as primary and adjuvant therapy. Historically, autotaxin inhibitors had poor bioavailability profiles and thus had limited efficacy in vivo. This situation is now changing, especially since the recent crystal structure of autotaxin is now enabling rational inhibitor design. In this review, we will summarize current knowledge on autotaxin-mediated disease processes including cancer, and discuss recent advancements in the development of autotaxin-targeting strategies. We will also provide new insights into autotaxin as an inflammatory mediator in the tumor microenvironment that promotes cancer progression and therapy resistance.
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