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1
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Choi MA, Rose S, Langouët S. Per- and polyfluoroalkyl substances as potentiators of hepatotoxicity in an exposome framework: Current challenges of environmental toxicology. Toxicology 2025; 515:154167. [PMID: 40300710 DOI: 10.1016/j.tox.2025.154167] [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: 02/05/2025] [Revised: 04/17/2025] [Accepted: 04/26/2025] [Indexed: 05/01/2025]
Abstract
Chronic liver diseases, including metabolic dysfunction-associated steatosic liver disease (MASLD) and hepatocellular carcinoma (HCC), are on the rise, potentially due to daily exposure to complex mixtures of chemical compounds forming part of the exposome. Understanding the mechanisms involved in hepatotoxicity of these mixtures is essential to identify common molecular targets that may highlight potential interactions at the molecular level. We illustrated this issue with two families of environmental contaminants, per- and polyfluoroalkyl substances (PFAS) and heterocyclic aromatic amines (HAAs), both of which could be involved in the progression of chronic liver diseases, and whose toxicity may be potentiated by interactions at the level of xenobiotic metabolism. In the study of exposome effects on chronic liver disease, New Approach Methodologies (NAMs) including omics analyses and data from various in vitro, in vivo and in silico approaches, are crucial for improving predictivity of toxicological studies in humans while reducing animal experimentation. Additionally, the development of complex in vitro human liver cell models, such as organoids, is essential to avoid interspecies differences that minimize the risk for humans. All together, these approaches will contribute to construct Adverse Outcome Pathways (AOPs) and could be applied not only to PFAS mixtures but also to other chemical families, providing valuable insights into mixture hepatotoxicity prediction in the study of the exposome. A better understanding of toxicological mechanisms will clarify the role of environmental contaminant mixtures in the development of MASLD and HCC, supporting risk assessment for better treatment, monitoring and prevention strategies.
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Affiliation(s)
- Minna A Choi
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes 35000, France
| | - Sophie Rose
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes 35000, France
| | - Sophie Langouët
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes 35000, France.
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2
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Yang T, Gu Z, Feng J, Shan J, Qian C, Zhuang N. Non-parenchymal cells: key targets for modulating chronic liver diseases. Front Immunol 2025; 16:1576739. [PMID: 40568596 PMCID: PMC12187809 DOI: 10.3389/fimmu.2025.1576739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Accepted: 05/13/2025] [Indexed: 06/28/2025] Open
Abstract
Non-neoplastic chronic liver diseases (CLDs), including alcoholic liver disease, metabolic-associated fatty liver disease, viral hepatitis, fibrosis, and cirrhosis, pose a global health challenge due to progressive fibro-inflammatory remodeling. Emerging evidence highlights the pivotal roles of non-parenchymal cells (NPCs)-liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KCs), and innate immune lymphocytes such as natural killer (NK) and natural killer T (NKT) cells-in driving disease progression. Chronic liver injury triggers LSEC capillarization, HSC transdifferentiation into collagen-producing myofibroblasts, and KC polarization toward pro-inflammatory phenotypes, collectively exacerbating extracellular matrix deposition and immune dysregulation. Dysfunctional NK/NKT cells play dual roles in antiviral defense and fibrosis amplification through excessive cytokine production. This review summarizes recent advances in understanding NPC-driven mechanisms underlying chronic liver injury and fibrosis, with a focus on LSEC dysfunction, HSC activation, and inflammation mediated by KCs and NK/NKT cells. Furthermore, we delve into emerging therapeutic strategies aimed at targeting NPC-specific pathways, including mechanotransduction modulation in LSECs, metabolic reprogramming of HSCs, and regulation of KC polarization. These approaches provide valuable insights into halting CLD progression and advancing the development of innovative antifibrotic therapies.
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Affiliation(s)
| | | | | | | | - Cheng Qian
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Na Zhuang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
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3
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Zhou Q, Lu Z, Wang B, Wang Y, Li L, You M, Wang L, Cao T, Tong D, Xiang J, Zhao Y, Li Q, Mou A, Shu W, He H, Zhao Z, Liu D, Zhu Z, Gao P, Yan Z. Endothelial SIRT3 deficiency predisposes brown adipose tissue to whitening in diet-induced obesity. Int J Biol Sci 2025; 21:3444-3460. [PMID: 40520025 PMCID: PMC12160546 DOI: 10.7150/ijbs.110741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 04/16/2025] [Indexed: 06/18/2025] Open
Abstract
Endothelial dysfunction and vascular rarefaction are supposed to be secondary to metabolic diseases, while recent evidence has revealed the primary roles of endothelium in initiating and accelerating metabolic disorders. Here, the effects and underlying mechanisms of endothelial SIRT3 in modulating the whitening of BAT during obesity progression were explored. Therefore, mice with global or BAT regional endothelium-specific Sirt3 knockout were constructed and fed with high-fat diet (HFD). The results showed that both global and BAT regional endothelium-specific Sirt3 knockout accelerated diet-induced weight gain, accompanied by glucose intolerance, insulin resistance, and BAT whitening. In vitro results revealed that the inhibition or knockdown of endothelial Sirt3 impeded palmitic acid-induced angiogenesis deficiency, while the overexpression of Sirt3 exhibited the opposite effects. Furtherly, endothelial Sirt3 overexpression ameliorated palmitic acid-induced adipocyte dysfunction and proinflammatory macrophages polarization in a paracrine way. Mechanistically, endothelial SIRT3 deficiency increased the acetylation of fatty acid synthase (FASN), which disturbed the fatty acid metabolism and thus, leading to angiogenesis insufficiency. Moreover, loss of SIRT3 promoted adipocytes dysfunction and proinflammatory macrophage polarization via CASP1-mediated pyroptosis. Endothelial SIRT3 loss contributed to diet-induced BAT whitening and obesity progression and thus, could be a therapeutic target in treating obesity and associated metabolic diseases.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Zhiming Zhu
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Peng Gao
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Zhencheng Yan
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
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4
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Dai Q, Ain Q, Seth N, Rooney M, Zipprich A. Liver sinusoidal endothelial cells: Friend or foe in metabolic dysfunction- associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis. Dig Liver Dis 2025; 57:493-503. [PMID: 39904692 DOI: 10.1016/j.dld.2025.01.189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/27/2024] [Accepted: 01/15/2025] [Indexed: 02/06/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the predominant liver disease and is becoming the paramount contributor to end-stage liver disease and liver-related deaths. Liver sinusoidal endothelial cells (LSECs) located between the hepatic parenchyma and blood from viscera and gastrointestinal tract are the gatekeepers for the hepatic microenvironment and normal function. In normal physiological conditions, LSECs govern the substance exchange between hepatic parenchyma and blood through dynamic regulation of fenestration and maintain the quiescent state of Kupffer cells (KCs) and hepatic stellate cells. In MASLD, lipotoxicity, insulin resistance, gastrointestinal microbiota dysbiosis, and mechanical compression caused by fat-laden hepatocytes result in LSECs capillarization and dysfunction. The altered LSECs progressively shift from healer to injurer, exacerbating liver inflammation and advancing liver fibrosis. This review focuses on the deteriorative roles of LSECs and related molecular mechanisms involved in MASLD and their contribution to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis development and progression. Furthermore, in this review, we propose that targeting LSECs dysfunction is a prospective therapeutic strategy to restore the physiological function of LSECs and mitigate MASLD progression.
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Affiliation(s)
- Qingqing Dai
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, 07747, Jena, Thuringia, Germany
| | - Quratul Ain
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, 07747, Jena, Thuringia, Germany
| | - Navodita Seth
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, 07747, Jena, Thuringia, Germany
| | - Michael Rooney
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, 07747, Jena, Thuringia, Germany
| | - Alexander Zipprich
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, 07747, Jena, Thuringia, Germany.
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5
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Lee W, Bates EA, Kipp ZA, Pauss SN, Martinez GJ, Blair CA, Hinds TD. Insulin receptor responsiveness governs TGFβ-induced hepatic stellate cell activation: Insulin resistance instigates liver fibrosis. FASEB J 2025; 39:e70427. [PMID: 40022609 PMCID: PMC11871568 DOI: 10.1096/fj.202402169r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 12/21/2024] [Accepted: 02/19/2025] [Indexed: 03/03/2025]
Abstract
The insulin receptor (INSR) has been shown to be hyperactive in hepatic stellate cells (HSCs) in humans and rodents with liver fibrosis. To explore HSC cellular mechanisms that INSR regulates during pro-fibrotic stimulation, we used CRISPR-Cas9 technology. We knocked out a portion of the INSR gene in human LX2 HSC cells (INSRe5-8 KO) that regulates insulin responsiveness but not the insulin-like growth factor (IGF) or transforming growth factor-β (TGFβ) signaling. The INSRe5-8 KO HSCs had significantly higher cell growth, BrdU incorporation, and lower TP53 expression that suppresses growth, and they also exhibited increased migration compared to the Scramble control. We treated the scramble control and INSRe5-8 KO HSCs with insulin or TGFβ and profiled hundreds of kinase activities using the PamGene PamStation kinome technology. Our analysis showed that serine/threonine kinase (STK) activities were reduced, and most of the protein-tyrosine kinase (PTK) activities were increased in the INSRe5-8 KO compared to the Scramble control HSCs. To study gene transcripts altered in activated Scramble control and INSRe5-8 KO HSCs, we treated them with TGFβ for 24 h. We isolated RNA for sequencing and found that the INSRe5-8 KO cells, compared to control HSCs, had altered transcriptional responsiveness to TGFβ stimulation, collagen-activated signaling, smooth muscle cell differentiation pathways, SMAD protein signaling, collagen metabolic process, integrin-mediated cell adhesion, and notch signaling. This study demonstrates that reduced INSR responsiveness enhances HSC growth and selectively mediates TGFβ-induced HSC activation. These findings provide new insights into the development of more effective treatments for liver fibrosis.
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Grants
- R01DK121797 HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)
- R01DA058933 HHS | NIH | National Institute on Drug Abuse (NIDA)
- F31HL170972 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- F31HL175979 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- 25PRE1374495 American Heart Association (AHA)
- HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)
- HHS | NIH | National Institute on Drug Abuse (NIDA)
- HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- American Heart Association (AHA)
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Affiliation(s)
- Wang‐Hsin Lee
- Drug & Disease Discovery D3 Research CenterUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
- Department of Pharmacology and Nutritional SciencesUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Evelyn A. Bates
- Drug & Disease Discovery D3 Research CenterUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
- Department of Pharmacology and Nutritional SciencesUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Zachary A. Kipp
- Drug & Disease Discovery D3 Research CenterUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
- Department of Pharmacology and Nutritional SciencesUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Sally N. Pauss
- Drug & Disease Discovery D3 Research CenterUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
- Department of Pharmacology and Nutritional SciencesUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Genesee J. Martinez
- Drug & Disease Discovery D3 Research CenterUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
- Department of Pharmacology and Nutritional SciencesUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Cheavar A. Blair
- Drug & Disease Discovery D3 Research CenterUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
- Markey Cancer CenterUniversity of KentuckyLexingtonKentuckyUSA
- Department of PhysiologyUniversity of KentuckyLexingtonKentuckyUSA
| | - Terry D. Hinds
- Drug & Disease Discovery D3 Research CenterUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
- Department of Pharmacology and Nutritional SciencesUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
- Markey Cancer CenterUniversity of KentuckyLexingtonKentuckyUSA
- Barnstable Brown Diabetes CenterUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
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6
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Huschet LA, Kliem FP, Wienand P, Wunderlich CM, Ribeiro A, Bustos-Martínez I, Barco Á, Wunderlich FT, Lech M, Robles MS. FrozONE: quick cell nucleus enrichment for comprehensive proteomics analysis of frozen tissues. Life Sci Alliance 2025; 8:e202403130. [PMID: 39667914 PMCID: PMC11638322 DOI: 10.26508/lsa.202403130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 12/14/2024] Open
Abstract
Subcellular fractionation allows for the investigation of compartmentalized processes in individual cellular organelles. Nuclear enrichment methods commonly employ the use of density gradients combined with ultracentrifugation for freshly isolated tissues. Although it is broadly used in combination with proteomics, this approach poses several challenges when it comes to scalability and applicability for frozen material. To overcome these limitations, we developed FrozONE (Frozen Organ Nucleus Enrichment), a nucleus enrichment and proteomics workflow for frozen tissues. By extensively benchmarking our workflow against alternative methods, we showed that FrozONE is a faster, simpler, and more scalable alternative to conventional ultracentrifugation methods. FrozONE allowed for the study, profiling, and classification of nuclear proteomes in different tissues with complex cellular heterogeneity, ensuring optimal nucleus enrichment from different cell types and quantitative resolution for low abundant proteins. In addition to its performance in healthy mouse tissues, FrozONE proved to be very efficient for the characterization of liver nuclear proteome alterations in a pathological condition, diet-induced nonalcoholic steatohepatitis.
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Affiliation(s)
- Lukas A Huschet
- Institute of Medical Psychology and Biomedical Center (BMC), Faculty of Medicine, LMU, Munich, Germany
| | - Fabian P Kliem
- Institute of Medical Psychology and Biomedical Center (BMC), Faculty of Medicine, LMU, Munich, Germany
| | - Peter Wienand
- Max Planck Institute for Metabolism Research, Center for Molecular Medicine Cologne (CMMC) and Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
| | - Claudia M Wunderlich
- Max Planck Institute for Metabolism Research, Center for Molecular Medicine Cologne (CMMC) and Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
| | - Andrea Ribeiro
- LMU Klinikum, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Isabel Bustos-Martínez
- Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain
| | - Ángel Barco
- Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain
| | - F Thomas Wunderlich
- Max Planck Institute for Metabolism Research, Center for Molecular Medicine Cologne (CMMC) and Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
| | - Maciej Lech
- LMU Klinikum, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Maria S Robles
- Institute of Medical Psychology and Biomedical Center (BMC), Faculty of Medicine, LMU, Munich, Germany
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7
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Zhou D, Shan S, Chen L, Li C, Wang H, Lu K, Ge J, Wang N, Afshari MJ, Zhang Y, Zeng J, Gao M. Trapped in Endosome PEGylated Ultra-Small Iron Oxide Nanoparticles Enable Extraordinarily High MR Imaging Contrast for Hepatocellular Carcinomas. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2401351. [PMID: 39162181 PMCID: PMC11497028 DOI: 10.1002/advs.202401351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 06/14/2024] [Indexed: 08/21/2024]
Abstract
The early diagnosis of hepatocellular carcinomas (HCCs) remains challenging in the clinic. Primovist-enhanced magnetic resonance imaging (MRI) aids HCC diagnosis but loses sensitivity for tumors <2 cm. Therefore, developing advanced MRI contrast agents is imperative for improving the diagnostic accuracy of HCCs in very-early-stage. To address this challenge, PEGylated ultra-small iron oxide nanoparticles (PUSIONPs) are synthesized and employed as liver-specific T1 MRI contrast agents. Intravenous delivery produces simultaneous hyperintense HCC and hypointense hepatic parenchyma signals on T1 imaging, creating an extraordinarily high tumor-to-liver contrast. Systematic studies uncover PUSIONP distribution in hepatic parenchyma, HCC lesions at the organ, tissue, cellular, and subcellular levels, revealing endosomal confinement of PUSIONP without aggregation. By mimicking such situations, the dependency of relaxometric properties on local PUSIONP concentration is investigated, emphasizing the key role of different endosomal concentrations in liver and tumor cells for high tumor-to-liver contrast and clear tumor boundaries. These findings offer exceptional imaging capabilities for early HCC diagnosis, potentially benefiting real HCC patients.
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Affiliation(s)
- Dandan Zhou
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Soochow UniversityCollaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Shanshan Shan
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Soochow UniversityCollaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Lei Chen
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Soochow UniversityCollaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Cang Li
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Soochow UniversityCollaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Hongzhao Wang
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Soochow UniversityCollaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Kuan Lu
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Soochow UniversityCollaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Jianxian Ge
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Soochow UniversityCollaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Ning Wang
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Soochow UniversityCollaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Mohammad Javad Afshari
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Soochow UniversityCollaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Yaqin Zhang
- Department of RadiologyThe Fifth Affiliated Hospital of Sun Yat‐sen UniversityZhuhai519000P. R. China
| | - Jianfeng Zeng
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Soochow UniversityCollaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
| | - Mingyuan Gao
- Center for Molecular Imaging and Nuclear MedicineState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences (RAD‐X)Soochow UniversityCollaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education InstitutionsSuzhou215123P. R. China
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8
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Xu H, Yan S, Gerhard E, Xie D, Liu X, Zhang B, Shi D, Ameer GA, Yang J. Citric Acid: A Nexus Between Cellular Mechanisms and Biomaterial Innovations. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2402871. [PMID: 38801111 PMCID: PMC11309907 DOI: 10.1002/adma.202402871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 05/07/2024] [Indexed: 05/29/2024]
Abstract
Citrate-based biodegradable polymers have emerged as a distinctive biomaterial platform with tremendous potential for diverse medical applications. By harnessing their versatile chemistry, these polymers exhibit a wide range of material and bioactive properties, enabling them to regulate cell metabolism and stem cell differentiation through energy metabolism, metabonegenesis, angiogenesis, and immunomodulation. Moreover, the recent US Food and Drug Administration (FDA) clearance of the biodegradable poly(octamethylene citrate) (POC)/hydroxyapatite-based orthopedic fixation devices represents a translational research milestone for biomaterial science. POC joins a short list of biodegradable synthetic polymers that have ever been authorized by the FDA for use in humans. The clinical success of POC has sparked enthusiasm and accelerated the development of next-generation citrate-based biomaterials. This review presents a comprehensive, forward-thinking discussion on the pivotal role of citrate chemistry and metabolism in various tissue regeneration and on the development of functional citrate-based metabotissugenic biomaterials for regenerative engineering applications.
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Affiliation(s)
- Hui Xu
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Su Yan
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Ethan Gerhard
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Denghui Xie
- Department of Histology and Embryology, School of Basic Medical Sciences, Department of Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, 510515, P. R. China
- Academy of Orthopedics of Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, 510630, P. R. China
| | - Xiaodong Liu
- Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, 310030, P. R. China
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang, 310030, P. R. China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, 310030, P. R. China
- Westlake Institute for Advanced Study, Hangzhou, Zhejiang, 310030, P. R. China
| | - Bing Zhang
- Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, 310030, P. R. China
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang, 310030, P. R. China
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, 310030, P. R. China
- Westlake Institute for Advanced Study, Hangzhou, Zhejiang, 310030, P. R. China
| | - Dongquan Shi
- Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, P. R. China
| | - Guillermo A Ameer
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60208, USA
- Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, 60208, USA
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Jian Yang
- Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, 310030, P. R. China
- Biomedical Engineering Program, School of Engineering, Westlake University, Hangzhou, Zhejiang, 310030, P. R. China
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9
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Czyzynska-Cichon I, Giergiel M, Kwiatkowski G, Kurpinska A, Wojnar-Lason K, Kaczara P, Szymonski M, Lekka M, Kalvins I, Zapotoczny B, Chlopicki S. Protein disulfide isomerase A1 regulates fenestration dynamics in primary mouse liver sinusoidal endothelial cells (LSECs). Redox Biol 2024; 72:103162. [PMID: 38669864 PMCID: PMC11068635 DOI: 10.1016/j.redox.2024.103162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 04/06/2024] [Accepted: 04/15/2024] [Indexed: 04/28/2024] Open
Abstract
Protein disulfide isomerases (PDIs) are involved in many intracellular and extracellular processes, including cell adhesion and cytoskeletal reorganisation, but their contribution to the regulation of fenestrations in liver sinusoidal endothelial cells (LSECs) remains unknown. Given that fenestrations are supported on a cytoskeleton scaffold, this study aimed to investigate whether endothelial PDIs regulate fenestration dynamics in primary mouse LSECs. PDIA3 and PDIA1 were found to be the most abundant among PDI isoforms in LSECs. Taking advantage of atomic force microscopy, the effects of PDIA1 or PDIA3 inhibition on the fenestrations in LSECs were investigated using a classic PDIA1 inhibitor (bepristat) and novel aromatic N-sulfonamides of aziridine-2-carboxylic acid derivatives as PDIA1 (C-3389) or PDIA3 (C-3399) inhibitors. The effect of PDIA1 inhibition on liver perfusion was studied in vivo using dynamic contrast-enhanced magnetic resonance imaging. Additionally, PDIA1 inhibitors were examined in vitro in LSECs for effects on adhesion, cytoskeleton organisation, bioenergetics, and viability. Inhibition of PDIA1 with bepristat or C-3389 significantly reduced the number of fenestrations in LSECs, while inhibition of PDIA3 with C-3399 had no effect. Moreover, the blocking of free thiols by the cell-penetrating N-ethylmaleimide, but not by the non-cell-penetrating 4-chloromercuribenzenesulfonate, resulted in LSEC defenestration. Inhibition of PDIA1 did not affect LSEC adhesion, viability, and bioenergetics, nor did it induce a clear-cut rearrangement of the cytoskeleton. However, PDIA1-dependent defenestration was reversed by cytochalasin B, a known fenestration stimulator, pointing to the preserved ability of LSECs to form new pores. Importantly, systemic inhibition of PDIA1 in vivo affected intra-parenchymal uptake of contrast agent in mice consistent with LSEC defenestration. These results revealed the role of intracellular PDIA1 in the regulation of fenestration dynamics in LSECs, and in maintaining hepatic sinusoid homeostasis.
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Affiliation(s)
- Izabela Czyzynska-Cichon
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348, Krakow, Poland
| | - Magdalena Giergiel
- Jagiellonian University, Centre for Nanometer-Scale Science and Advanced Materials, NANOSAM, Faculty of Physics, Astronomy, and Applied Computer Science, Lojasiewicza 11, 30-348, Krakow, Poland
| | - Grzegorz Kwiatkowski
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348, Krakow, Poland
| | - Anna Kurpinska
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348, Krakow, Poland
| | - Kamila Wojnar-Lason
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348, Krakow, Poland; Jagiellonian University Medical College, Faculty of Medicine, Department of Pharmacology, Grzegorzecka 16, 31-531, Krakow, Poland
| | - Patrycja Kaczara
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348, Krakow, Poland
| | - Marek Szymonski
- Jagiellonian University, Centre for Nanometer-Scale Science and Advanced Materials, NANOSAM, Faculty of Physics, Astronomy, and Applied Computer Science, Lojasiewicza 11, 30-348, Krakow, Poland
| | - Malgorzata Lekka
- Institute of Nuclear Physics Polish Academy of Sciences, Radzikowskiego 152, 31-342, Krakow, Poland
| | - Ivars Kalvins
- Laboratory of Carbofunctional Compounds, Latvian Institute of Organic Synthesis, LV-1006, Riga, Latvia
| | - Bartlomiej Zapotoczny
- Jagiellonian University, Centre for Nanometer-Scale Science and Advanced Materials, NANOSAM, Faculty of Physics, Astronomy, and Applied Computer Science, Lojasiewicza 11, 30-348, Krakow, Poland; Institute of Nuclear Physics Polish Academy of Sciences, Radzikowskiego 152, 31-342, Krakow, Poland.
| | - Stefan Chlopicki
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348, Krakow, Poland; Jagiellonian University Medical College, Faculty of Medicine, Department of Pharmacology, Grzegorzecka 16, 31-531, Krakow, Poland.
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10
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Hauger PC, Hordijk PL. Shear Stress-Induced AMP-Activated Protein Kinase Modulation in Endothelial Cells: Its Role in Metabolic Adaptions and Cardiovascular Disease. Int J Mol Sci 2024; 25:6047. [PMID: 38892235 PMCID: PMC11173107 DOI: 10.3390/ijms25116047] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/27/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
Endothelial cells (ECs) line the inner surface of all blood vessels and form a barrier that facilitates the controlled transfer of nutrients and oxygen from the circulatory system to surrounding tissues. Exposed to both laminar and turbulent blood flow, ECs are continuously subject to differential mechanical stimulation. It has been well established that the shear stress associated with laminar flow (LF) is atheroprotective, while shear stress in areas with turbulent flow (TF) correlates with EC dysfunction. Moreover, ECs show metabolic adaptions to physiological changes, such as metabolic shifts from quiescence to a proliferative state during angiogenesis. The AMP-activated protein kinase (AMPK) is at the center of these phenomena. AMPK has a central role as a metabolic sensor in several cell types. Moreover, in ECs, AMPK is mechanosensitive, linking mechanosensation with metabolic adaptions. Finally, recent studies indicate that AMPK dysregulation is at the center of cardiovascular disease (CVD) and that pharmacological targeting of AMPK is a promising and novel strategy to treat CVDs such as atherosclerosis or ischemic injury. In this review, we summarize the current knowledge relevant to this topic, with a focus on shear stress-induced AMPK modulation and its consequences for vascular health and disease.
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Affiliation(s)
| | - Peter L. Hordijk
- Department of Physiology, Amsterdam UMC, Amsterdam Cardiovascular Sciences, Microcirculation, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands;
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11
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Chen X, Xu Y, Ju Y, Gu P. Metabolic Regulation of Endothelial Cells: A New Era for Treating Wet Age-Related Macular Degeneration. Int J Mol Sci 2024; 25:5926. [PMID: 38892113 PMCID: PMC11172501 DOI: 10.3390/ijms25115926] [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: 04/16/2024] [Revised: 05/27/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Wet age-related macular degeneration (wet AMD) is a primary contributor to visual impairment and severe vision loss globally, but the prevailing treatments are often unsatisfactory. The development of conventional treatment strategies has largely been based on the understanding that the angiogenic switch of endothelial cells (ECs) is mainly dictated by angiogenic growth factors. Even though treatments targeting vascular endothelial growth factor (VEGF), like ranibizumab, are widely administered, more than half of patients still exhibit inadequate or null responses, suggesting the involvement of other pathogenic mechanisms. With advances in research in recent years, it has become well recognized that EC metabolic regulation plays an active rather than merely passive responsive role in angiogenesis. Disturbances of these metabolic pathways may lead to excessive neovascularization in angiogenic diseases such as wet AMD, therefore targeted modulation of EC metabolism represents a promising therapeutic strategy for wet AMD. In this review, we comprehensively discuss the potential applications of EC metabolic regulation in wet AMD treatment from multiple perspectives, including the involvement of ECs in wet AMD pathogenesis, the major endothelial metabolic pathways, and novel therapeutic approaches targeting metabolism for wet AMD.
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Affiliation(s)
- Xirui Chen
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; (X.C.)
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Yang Xu
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; (X.C.)
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Yahan Ju
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; (X.C.)
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Ping Gu
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; (X.C.)
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
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12
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Szafranska K, Sørensen KK, Lalor PF, McCourt P. Sinusoidal cells and liver immunology. SINUSOIDAL CELLS IN LIVER DISEASES 2024:53-75. [DOI: 10.1016/b978-0-323-95262-0.00003-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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13
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Westwood LJ, Le Couteur DG, Hunt NJ, Cogger VC. Strategies to target and genetically modify the liver sinusoid. SINUSOIDAL CELLS IN LIVER DISEASES 2024:161-189. [DOI: 10.1016/b978-0-323-95262-0.00008-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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14
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Seternes T, Poppe TT, Bøgwald J, Lynghammar A, Dalmo RA. Anatomical distribution of scavenger endothelial cells in bony fishes (Osteichthyes). FISH & SHELLFISH IMMUNOLOGY 2024; 144:109250. [PMID: 38035950 DOI: 10.1016/j.fsi.2023.109250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 10/30/2023] [Accepted: 11/06/2023] [Indexed: 12/02/2023]
Abstract
The scavenger endothelial cells (SECs) of vertebrates are an important class of endocytic cells responsible for clearance of foreign and physiological waste macromolecules, partitioning in the immune system, functioning as a cellular powerplant by producing high energy metabolites like lactate and acetate. All animal phyla possess SECs, but the tissue localization of SECs has only been investigated in a limited number of species. By using a specific ligand for scavenger receptors (formalin treated bovine serum albumin), the study revealed that in all tetrapod species (amphibia, reptiles, birds and mammals) the SECs were found lining the sinusoids of the liver. No SECs were found in the liver of any of the bony fishes (Osteichthyes) investigated. Interestingly, we found the SECs not only to be located in the heart of marine species but also in some freshwater species such as Lota lota, Percichthys trucha and Perca fluviatilis. In some fish species, the SECs were found both in the heart and/or kidney in a number of marine and freshwater fishes, whereas in some marine, diadromous and freshwater fishes the SECs were confined only to the kidney tissue. However, from these results it can be suggested that there is neither a clear phylogenetic trend when it came to anatomical localization of SECs nor any pattern in terms of habitat (salinity preferences).
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Affiliation(s)
- Tore Seternes
- Faculty of Biosciences, Fisheries and Economics, UiT - The Arctic University of Norway, Tromsø, Norway.
| | - Trygve T Poppe
- Faculty of Biosciences, Fisheries and Economics, UiT - The Arctic University of Norway, Tromsø, Norway
| | - Jarl Bøgwald
- Faculty of Biosciences, Fisheries and Economics, UiT - The Arctic University of Norway, Tromsø, Norway
| | - Arve Lynghammar
- Faculty of Biosciences, Fisheries and Economics, UiT - The Arctic University of Norway, Tromsø, Norway
| | - Roy A Dalmo
- Faculty of Biosciences, Fisheries and Economics, UiT - The Arctic University of Norway, Tromsø, Norway
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15
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Krause GJ, Kirchner P, Stiller B, Morozova K, Diaz A, Chen KH, Krogan NJ, Agullo-Pascual E, Clement CC, Lindenau K, Swaney DL, Dilipkumar S, Bravo-Cordero JJ, Santambrogio L, Cuervo AM. Molecular determinants of the crosstalk between endosomal microautophagy and chaperone-mediated autophagy. Cell Rep 2023; 42:113529. [PMID: 38060380 PMCID: PMC10807933 DOI: 10.1016/j.celrep.2023.113529] [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: 01/11/2022] [Revised: 09/12/2023] [Accepted: 11/17/2023] [Indexed: 12/30/2023] Open
Abstract
Chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI) are pathways for selective degradation of cytosolic proteins in lysosomes and late endosomes, respectively. These autophagic processes share as a first step the recognition of the same five-amino-acid motif in substrate proteins by the Hsc70 chaperone, raising the possibility of coordinated activity of both pathways. In this work, we show the existence of a compensatory relationship between CMA and eMI and identify a role for the chaperone protein Bag6 in triage and internalization of eMI substrates into late endosomes. Association and dynamics of Bag6 at the late endosome membrane change during starvation, a stressor that, contrary to other autophagic pathways, causes a decline in eMI activity. Collectively, these results show a coordinated function of eMI with CMA, identify the interchangeable subproteome degraded by these pathways, and start to elucidate the molecular mechanisms that facilitate the switch between them.
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Affiliation(s)
- Gregory J Krause
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Philipp Kirchner
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Barbara Stiller
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Kateryna Morozova
- Department of Radiation Oncology, Weill Cornell School of Medicine, New York, NY 10021, USA
| | - Antonio Diaz
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Kuei-Ho Chen
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; The J. David Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA
| | - Nevan J Krogan
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; The J. David Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA
| | | | - Cristina C Clement
- Department of Radiation Oncology, Weill Cornell School of Medicine, New York, NY 10021, USA
| | - Kristen Lindenau
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Danielle L Swaney
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; The J. David Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA
| | - Shilpa Dilipkumar
- Microscopy CoRE, Dean's CoREs, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jose Javier Bravo-Cordero
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Laura Santambrogio
- Department of Radiation Oncology, Weill Cornell School of Medicine, New York, NY 10021, USA.
| | - Ana Maria Cuervo
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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16
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Ping D, Peng Y, Hu X, Liu C. Macrophage cytotherapy on liver cirrhosis. Front Pharmacol 2023; 14:1265935. [PMID: 38161689 PMCID: PMC10757375 DOI: 10.3389/fphar.2023.1265935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 12/04/2023] [Indexed: 01/03/2024] Open
Abstract
Macrophages, an essential cell population involved in mediating innate immunity in the host, play a crucial role on the development of hepatic cirrhosis. Extensive studies have highlighted the potential therapeutic benefits of macrophage therapy in treating hepatic cirrhosis. This review aims to provide a comprehensive overview of the various effects and underlying mechanisms associated with macrophage therapy in the context of hepatic cirrhosis.
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Affiliation(s)
- Dabing Ping
- Institute of Liver Diseases, Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuan Peng
- Institute of Liver Diseases, Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xudong Hu
- Department of Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chenghai Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai, China
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17
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Chen Z, Kelly K, Cheng H, Dong X, Hedger AK, Li L, Sontheimer EJ, Watts JK. In Vivo Prime Editing by Lipid Nanoparticle Co-delivery of Chemically Modified pegRNA and Prime Editor mRNA. GEN BIOTECHNOLOGY 2023; 2:490-502. [PMID: 39850578 PMCID: PMC11756591 DOI: 10.1089/genbio.2023.0045] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2025]
Abstract
Prime editing has gained significant attention as a next-generation gene editing technology, owing to its unique advantages. However, realizing its potential in vivo requires effective delivery strategies. While adeno-associated virus (AAV) has been employed for in vivo delivery of prime editors in research settings, it presents inherent limitations related to vector size, ongoing expression, and inability to re-dose patients. Conversely, lipid nanoparticles (LNPs) do not face these limitations and are emerging as a leading non-viral approach for the delivery of gene editors. In this study, we demonstrate successful co-delivery of chemically modified pegRNA and prime editor mRNA using LNPs for in vivo prime editing. We investigate the impact of pegRNA chemical modifications on editing efficiency and explore different re-dosing regimens. In a daily-repeat dose regimen, we saw striking liver toxicity and no increase in editing; by contrast, weekly-repeat dosing was well tolerated and enabled 1.8-fold increase in editing efficacy. Furthermore, in the NSG immunodeficient mouse model, the efficacy of LNP-delivered prime editing was enhanced by 2.8-fold. In addition, the nature of the ionizable lipids and phospholipids strongly influenced prime editing efficiency in vivo. Overall, these findings will greatly contribute to the future development of LNPs as a robust platform for delivering prime editors in vivo, fostering progress in prime editing research and therapeutic applications.
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Affiliation(s)
- Zexiang Chen
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Karen Kelly
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Haoyang Cheng
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Xiaolong Dong
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Present address: Tessera Therapeutics, Somerville, MA, USA
| | - Adam K Hedger
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Li Li
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Erik J Sontheimer
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Jonathan K Watts
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, USA
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18
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Branovets J, Soodla K, Vendelin M, Birkedal R. Rat and mouse cardiomyocytes show subtle differences in creatine kinase expression and compartmentalization. PLoS One 2023; 18:e0294718. [PMID: 38011179 PMCID: PMC10681188 DOI: 10.1371/journal.pone.0294718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 11/06/2023] [Indexed: 11/29/2023] Open
Abstract
Creatine kinase (CK) and adenylate kinase (AK) are energy transfer systems. Different studies on permeabilized cardiomyocytes suggest that ADP-channelling from mitochondrial CK alone stimulates respiration to its maximum, VO2_max, in rat but not mouse cardiomyocytes. Results are ambiguous on ADP-channelling from AK to mitochondria. This study was undertaken to directly compare the CK and AK systems in rat and mouse hearts. In homogenates, we assessed CK- and AK-activities, and the CK isoform distribution. In permeabilized cardiomyocytes, we assessed mitochondrial respiration stimulated by ADP from CK and AK, VO2_CK and VO2_AK, respectively. The ADP-channelling from CK or AK to mitochondria was assessed by adding PEP and PK to competitively inhibit the respiration rate. We found that rat compared to mouse hearts had a lower aerobic capacity, higher VO2_CK/VO2_max, and different CK-isoform distribution. Although rat hearts had a larger fraction of mitochondrial CK, less ADP was channeled from CK to the mitochondria. This suggests different intracellular compartmentalization in rat and mouse cardiomyocytes. VO2_AK/VO2_max was similar in mouse and rat cardiomyocytes, and AK did not channel ADP to the mitochondria. In the absence of intracellular compartmentalization, the AK- and CK-activities in homogenate should have been similar to the ADP-phosphorylation rates estimated from VO2_AK and VO2_CK in permeabilized cardiomyocytes. Instead, we found that the ADP-phosphorylation rates estimated from permeabilized cardiomyocytes were 2 and 9 times lower than the activities recorded in homogenate for CK and AK, respectively. Our results highlight the importance of energetic compartmentalization in cardiac metabolic regulation and signalling.
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Affiliation(s)
- Jelena Branovets
- Laboratory of Systems Biology, Department of Cybernetics, Tallinn University of Technology, Tallinn, Estonia
| | - Kärol Soodla
- Laboratory of Systems Biology, Department of Cybernetics, Tallinn University of Technology, Tallinn, Estonia
| | - Marko Vendelin
- Laboratory of Systems Biology, Department of Cybernetics, Tallinn University of Technology, Tallinn, Estonia
| | - Rikke Birkedal
- Laboratory of Systems Biology, Department of Cybernetics, Tallinn University of Technology, Tallinn, Estonia
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19
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Antwi MB, Dumitriu G, Simón-Santamaria J, Romano JS, Li R, Smedsrød B, Vik A, Eskild W, Sørensen KK. Liver sinusoidal endothelial cells show reduced scavenger function and downregulation of Fc gamma receptor IIb, yet maintain a preserved fenestration in the Glmpgt/gt mouse model of slowly progressing liver fibrosis. PLoS One 2023; 18:e0293526. [PMID: 37910485 PMCID: PMC10619817 DOI: 10.1371/journal.pone.0293526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 10/16/2023] [Indexed: 11/03/2023] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) are fenestrated endothelial cells with a unique, high endocytic clearance capacity for blood-borne waste macromolecules and colloids. This LSEC scavenger function has been insufficiently characterized in liver disease. The Glmpgt/gt mouse lacks expression of a subunit of the MFSD1/GLMP lysosomal membrane protein transporter complex, is born normal, but soon develops chronic, mild hepatocyte injury, leading to slowly progressing periportal liver fibrosis, and splenomegaly. This study examined how LSEC scavenger function and morphology are affected in the Glmpgt/gt model. FITC-labelled formaldehyde-treated serum albumin (FITC-FSA), a model ligand for LSEC scavenger receptors was administered intravenously into Glmpgt/gt mice, aged 4 months (peak of liver inflammation), 9-10 month, and age-matched Glmpwt/wt mice. Organs were harvested for light and electron microscopy, quantitative image analysis of ligand uptake, collagen accumulation, LSEC ultrastructure, and endocytosis receptor expression (also examined by qPCR and western blot). In both age groups, the Glmpgt/gt mice showed multifocal liver injury and fibrosis. The uptake of FITC-FSA in LSECs was significantly reduced in Glmpgt/gt compared to wild-type mice. Expression of LSEC receptors stabilin-1 (Stab1), and mannose receptor (Mcr1) was almost similar in liver of Glmpgt/gt mice and age-matched controls. At the same time, immunostaining revealed differences in the stabilin-1 expression pattern in sinusoids and accumulation of stabilin-1-positive macrophages in Glmpgt/gt liver. FcγRIIb (Fcgr2b), which mediates LSEC endocytosis of soluble immune complexes was widely and significantly downregulated in Glmpgt/gt liver. Despite increased collagen in space of Disse, LSECs of Glmpgt/gt mice showed well-preserved fenestrae organized in sieve plates but the frequency of holes >400 nm in diameter was increased, especially in areas with hepatocyte damage. In both genotypes, FITC-FSA also distributed to endothelial cells of spleen and bone marrow sinusoids, suggesting that these locations may function as possible compensatory sites of clearance of blood-borne scavenger receptor ligands in liver fibrosis.
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Affiliation(s)
- Milton Boaheng Antwi
- Department of Medical Biology, UiT-The Arctic University of Norway, Tromsø, Norway
- Section of Haematology, University Hospital of North Norway, Tromsø, Norway
| | - Gianina Dumitriu
- Department of Medical Biology, UiT-The Arctic University of Norway, Tromsø, Norway
| | | | | | - Ruomei Li
- Department of Medical Biology, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Bård Smedsrød
- Department of Medical Biology, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Anders Vik
- Section of Haematology, University Hospital of North Norway, Tromsø, Norway
- Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Winnie Eskild
- Department of Biosciences, University of Oslo, Oslo, Norway
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20
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Heya MS, García-Ponce R, Soto BAM, Verde-Star MJ, Soto-Domínguez A, García-Hernandez DG, Saucedo-Cárdenas O, Hernández-Salazar M, Guillén-Meléndez GA. Green Alternatives in Treatment of Liver Diseases: the Challenges of Traditional Medicine and Green Nanomedicine. Chem Biodivers 2023; 20:e202300463. [PMID: 37531499 DOI: 10.1002/cbdv.202300463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 07/21/2023] [Accepted: 08/01/2023] [Indexed: 08/04/2023]
Abstract
Over the last decade, liver diseases have become a global problem, with approximately two million deaths per year. The high increase in the mortality rate of these diseases is mostly related to the limitations in the understanding of the evolutionary clinical cases of liver diseases, the low delivery of drugs in the liver, the non-specific administration of drugs, and the side effects generated at the systemic level by conventional therapeutic agents. Today it is common knowledge that phytochemicals have a high curative potential, even in the prevention and/or reversibility of liver disorders; however, even using these green molecules, researchers continue to deal with the same challenges implemented with conventional therapeutic agents, which limits the pharmacological potential of these friendly molecules. On the other hand, the latest advances in nanotechnology have proven that the use of nanocarriers as a delivery system for green active ingredients, as well as conventional ones, increases the pharmacological potential of these active ingredients due to their physicochemical characteristics (size, Zeta potential, etc.,) moldable depending on the therapeutic objective; in addition to the above, it should be noted that in recent years, nanoparticles have been developed for the specific delivery of drugs towards a specific target (stellar cells, hepatocytes, Kupffer cells), depending on the clinical state of the disease in the patient. The present review addresses the challenges of traditional medicine and green nanomedicine as alternatives in the treatment of liver diseases.
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Affiliation(s)
- Michel Stephane Heya
- Faculty of Public Health and Nutrition, Universidad Autónoma de Nuevo León, Ave. Pedro de Alba S/N & Ave. Manuel L. Barragán, San Nicolas de los Garza, 66451, Nuevo León, México
| | - Romario García-Ponce
- Biological Science School, Universidad Autónoma de Nuevo León, Ave., Pedro de Alba S/N & Ave. Manuel L. Barragán, San Nicolás de los Garza, 66451, Nuevo León, México
| | - Beatriz Amari Medina Soto
- Department of Microbiology, Faculty of Veterinary Medicine and Zootechnics., Universidad Autónoma de Nuevo León, Francisco Villa S/N, Ex Hacienda El Canadá, Gral. Escobedo, Nuevo León, México
| | - María Julia Verde-Star
- Biological Science School, Universidad Autónoma de Nuevo León, Ave., Pedro de Alba S/N & Ave. Manuel L. Barragán, San Nicolás de los Garza, 66451, Nuevo León, México
| | - Adolfo Soto-Domínguez
- Department of Histology, Faculty of Medicine, Universidad Autónoma de Nuevo León, Madero y Aguirre Pequeño S/N, Mitras Centro, 64460, Monterrey, Nuevo León, México
| | - David Gilberto García-Hernandez
- Biological Science School, Universidad Autónoma de Nuevo León, Ave., Pedro de Alba S/N & Ave. Manuel L. Barragán, San Nicolás de los Garza, 66451, Nuevo León, México
| | - Odila Saucedo-Cárdenas
- Department of Histology, Faculty of Medicine, Universidad Autónoma de Nuevo León, Madero y Aguirre Pequeño S/N, Mitras Centro, 64460, Monterrey, Nuevo León, México
| | - Marcelo Hernández-Salazar
- Faculty of Public Health and Nutrition, Universidad Autónoma de Nuevo León, Ave. Pedro de Alba S/N & Ave. Manuel L. Barragán, San Nicolas de los Garza, 66451, Nuevo León, México
| | - Gloria Arely Guillén-Meléndez
- Department of Histology, Faculty of Medicine, Universidad Autónoma de Nuevo León, Madero y Aguirre Pequeño S/N, Mitras Centro, 64460, Monterrey, Nuevo León, México
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21
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Unterweger IA, Klepstad J, Hannezo E, Lundegaard PR, Trusina A, Ober EA. Lineage tracing identifies heterogeneous hepatoblast contribution to cell lineages and postembryonic organ growth dynamics. PLoS Biol 2023; 21:e3002315. [PMID: 37792696 PMCID: PMC10550115 DOI: 10.1371/journal.pbio.3002315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 08/29/2023] [Indexed: 10/06/2023] Open
Abstract
To meet the physiological demands of the body, organs need to establish a functional tissue architecture and adequate size as the embryo develops to adulthood. In the liver, uni- and bipotent progenitor differentiation into hepatocytes and biliary epithelial cells (BECs), and their relative proportions, comprise the functional architecture. Yet, the contribution of individual liver progenitors at the organ level to both fates, and their specific proportion, is unresolved. Combining mathematical modelling with organ-wide, multispectral FRaeppli-NLS lineage tracing in zebrafish, we demonstrate that a precise BEC-to-hepatocyte ratio is established (i) fast, (ii) solely by heterogeneous lineage decisions from uni- and bipotent progenitors, and (iii) independent of subsequent cell type-specific proliferation. Extending lineage tracing to adulthood determined that embryonic cells undergo spatially heterogeneous three-dimensional growth associated with distinct environments. Strikingly, giant clusters comprising almost half a ventral lobe suggest lobe-specific dominant-like growth behaviours. We show substantial hepatocyte polyploidy in juveniles representing another hallmark of postembryonic liver growth. Our findings uncover heterogeneous progenitor contributions to tissue architecture-defining cell type proportions and postembryonic organ growth as key mechanisms forming the adult liver.
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Affiliation(s)
- Iris. A. Unterweger
- University of Copenhagen, NNF Center for Stem Cell Biology (DanStem), Copenhagen N, Denmark
- University of Copenhagen, Department of Biomedical Sciences, Copenhagen N, Denmark
| | - Julie Klepstad
- Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark
- Andalusian Center for Developmental Biology, CSIC, University Pablo de Olavide, Seville, Spain
| | - Edouard Hannezo
- Institute of Science and Technology, Klosterneuburg, Austria
| | - Pia R. Lundegaard
- University of Copenhagen, Department of Biomedical Sciences, Copenhagen N, Denmark
| | - Ala Trusina
- Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark
| | - Elke A. Ober
- University of Copenhagen, NNF Center for Stem Cell Biology (DanStem), Copenhagen N, Denmark
- University of Copenhagen, Department of Biomedical Sciences, Copenhagen N, Denmark
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22
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Patil NY, Rus I, Joshi AD. Role of ERK1/2 Signaling in Cinnabarinic Acid-Driven Stanniocalcin 2-Mediated Protection against Alcohol-Induced Apoptosis. J Pharmacol Exp Ther 2023; 387:111-120. [PMID: 37562971 PMCID: PMC10519581 DOI: 10.1124/jpet.123.001670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/07/2023] [Accepted: 07/13/2023] [Indexed: 08/12/2023] Open
Abstract
We have previously shown that a bona fide aryl hydrocarbon receptor (AhR) agonist, cinnabarinic acid (CA), protects against alcohol-induced hepatocyte apoptosis via activation of a novel AhR target gene, stanniocalcin 2 (Stc2). Stc2 translates to a secreted disulfide-linked hormone, STC2, known to function in cell development, calcium and phosphate regulation, angiogenesis, and antiapoptosis-albeit the comprehensive mechanism by which the CA-AhR-STC2 axis confers antiapoptosis is yet to be characterized. In this study, using RNA interference library screening, downstream antiapoptotic molecular signaling components involved in CA-induced STC2-mediated protection against ethanol-induced apoptosis were investigated. RNA interference library screening of kinases and phosphatases in Hepa1 cells and subsequent pathway analysis identified mitogen-activated protein kinase (MAPK) signaling as a critical molecular pathway involved in CA-mediated protection. Specifically, phosphorylation of ERK1/2 was induced in response to CA treatment without alterations in p38 and JNK signaling pathways. Silencing Stc2 in Hepa1 cells and in vivo experiments performed in Stc2-/- (Stc2 knockout) mice, which failed to confer CA-mediated protection against ethanol-induced apoptosis, showed abrogation of ERK1/2 activation, underlining the significance of ERK1/2 signaling in CA-STC2-mediated protection. In conclusion, activation of ERK1/2 signaling in CA-driven AhR-dependent Stc2-mediated protection represents a novel mechanism of protection against acute alcohol-induced apoptosis. SIGNIFICANCE STATEMENT: Previous studies have shown the role of stanniocalcin 2 (Stc2) in cinnabarinic acid (CA)-mediated protection against alcohol-induced apoptosis. Here, using RNA interference library screening and subsequent in vivo studies, the functional significance of ERK1/2 activation in CA-induced Stc2-mediated protection against acute ethanol-induced apoptosis was identified. This study is thus significant as it illustrates a comprehensive downstream mechanism by which CA-induced Stc2 protects against alcoholic liver disease.
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Affiliation(s)
- Nikhil Y Patil
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Iulia Rus
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Aditya D Joshi
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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23
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Dawson LW, Cronin NM, DeMali KA. Mechanotransduction: Forcing a change in metabolism. Curr Opin Cell Biol 2023; 84:102219. [PMID: 37651955 PMCID: PMC10523412 DOI: 10.1016/j.ceb.2023.102219] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/24/2023] [Accepted: 07/25/2023] [Indexed: 09/02/2023]
Abstract
Epithelial and endothelial cells experience numerous mechanical cues throughout their lifetimes. Cells resist these forces by fortifying their cytoskeletal networks and adhesions. This reinforcement is energetically costly. Here we describe how these energetic demands are met. We focus on the response of epithelial and endothelial cells to mechanical cues, describe the energetic needs of epithelia and endothelia, and identify the mechanisms these cells employ to increase glycolysis, oxidative phosphorylation, and fatty acid metabolism. We discuss the similarities and differences in the responses of the two cell types.
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Affiliation(s)
- Logan W Dawson
- Department of Biochemistry and Molecular Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Nicholas M Cronin
- Department of Biochemistry and Molecular Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Kris A DeMali
- Department of Biochemistry and Molecular Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
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24
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Lee WH, Najjar SM, Kahn CR, Hinds TD. Hepatic insulin receptor: new views on the mechanisms of liver disease. Metabolism 2023; 145:155607. [PMID: 37271372 PMCID: PMC10330768 DOI: 10.1016/j.metabol.2023.155607] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 05/26/2023] [Accepted: 05/28/2023] [Indexed: 06/06/2023]
Abstract
Over 65 % of people with obesity display the metabolic-associated fatty liver disease (MAFLD), which can manifest as steatohepatitis, fibrosis, cirrhosis, or liver cancer. The development and progression of MAFLD involve hepatic insulin resistance and reduced insulin clearance. This review discusses the relationships between altered insulin signaling, hepatic insulin resistance, and reduced insulin clearance in the development of MAFLD and how this provides the impetus for exploring the use of insulin sensitizers to curb this disease. The review also explores the role of the insulin receptor in hepatocytes and hepatic stellate cells and how it signals in metabolic and end-stage liver diseases. Finally, we discuss new research findings that indicate that advanced hepatic diseases may be an insulin-sensitive state in the liver and deliberate whether insulin sensitizers should be used to manage late-stage liver diseases.
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Affiliation(s)
- Wang-Hsin Lee
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Sonia M Najjar
- Department of Biomedical Sciences and the Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - C Ronald Kahn
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Terry D Hinds
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA; Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
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25
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Deshmukh K, Apte U. The Role of Endoplasmic Reticulum Stress Response in Liver Regeneration. Semin Liver Dis 2023; 43:279-292. [PMID: 37451282 PMCID: PMC10942737 DOI: 10.1055/a-2129-8977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Exposure to hepatotoxic chemicals is involved in liver disease-related morbidity and mortality worldwide. The liver responds to damage by triggering compensatory hepatic regeneration. Physical agent or chemical-induced liver damage disrupts hepatocyte proteostasis, including endoplasmic reticulum (ER) homeostasis. Post-liver injury ER experiences a homeostatic imbalance, followed by active ER stress response signaling. Activated ER stress response causes selective upregulation of stress response genes and downregulation of many hepatocyte genes. Acetaminophen overdose, carbon tetrachloride, acute and chronic alcohol exposure, and physical injury activate the ER stress response, but details about the cellular consequences of the ER stress response on liver regeneration remain unclear. The current data indicate that inhibiting the ER stress response after partial hepatectomy-induced liver damage promotes liver regeneration, whereas inhibiting the ER stress response after chemical-induced hepatotoxicity impairs liver regeneration. This review summarizes key findings and emphasizes the knowledge gaps in the role of ER stress in injury and regeneration.
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Affiliation(s)
- Kshitij Deshmukh
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, Iowa
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
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26
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Yadav S. Advanced therapeutics avenues in hepatocellular carcinoma: a novel paradigm. Med Oncol 2023; 40:239. [PMID: 37442842 DOI: 10.1007/s12032-023-02104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and it poses a significant risk to patients health and longevity due to its high morbidity and fatality rates. Surgical ablation, radiotherapy, chemotherapy, and, most recently, immunotherapy have all been investigated for HCC, but none have yielded the desired outcomes. Several unique nanocarrier drug delivery techniques have been studied for their potential therapeutic implications in the treatment of HCC. Nanoparticle-based imaging could be effective for more accurate HCC diagnosis. Since its inception, nanomedicine has significantly transformed the approach to both the treatment and diagnostics of liver cancer. Nanoparticles (NPs) are being studied as a potential treatment for liver cancer because of their ability to carry small substances, such as treatment with chemotherapy, microRNA, and therapeutic genes. The primary focus of this study is on the most current discoveries and practical uses of nanomedicine-based diagnostic and therapeutic techniques for liver cancer. In this section, we had gone over what we know about metabolic dysfunction in HCC and the treatment options that attempt to fix it by targeting metabolic pathways. Furthermore, we propose a multi-target metabolic strategy as a viable HCC treatment option. Based on the findings given here, the scientists believe that smart nanomaterials have great promise for improving cancer theranostics and opening up new avenues for tumor diagnosis and treatment.
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Affiliation(s)
- Shikha Yadav
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Plot No.2, Sector 17-A, Yamuna Expressway, Gautam Buddhnagar, Greater Noida, Uttar Pradesh, 201310, India.
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27
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Ma B, Ju A, Zhang S, An Q, Xu S, Liu J, Yu L, Fu Y, Luo Y. Albumosomes formed by cytoplasmic pre-folding albumin maintain mitochondrial homeostasis and inhibit nonalcoholic fatty liver disease. Signal Transduct Target Ther 2023; 8:229. [PMID: 37321990 PMCID: PMC10272166 DOI: 10.1038/s41392-023-01437-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 03/01/2023] [Accepted: 04/06/2023] [Indexed: 06/17/2023] Open
Abstract
Hepatic mitochondrial dysfunction contributes to the progression of nonalcoholic fatty liver disease (NAFLD). However, the factors that maintain mitochondrial homeostasis, especially in hepatocytes, are largely unknown. Hepatocytes synthesize various high-level plasma proteins, among which albumin is most abundant. In this study, we found that pre-folding albumin in the cytoplasm is completely different from folded albumin in the serum. Mechanistically, endogenous pre-folding albumin undergoes phase transition in the cytoplasm to form a shell-like spherical structure, which we call the "albumosome". Albumosomes interact with and trap pre-folding carnitine palmitoyltransferase 2 (CPT2) in the cytoplasm. Albumosomes control the excessive sorting of CPT2 to the mitochondria under high-fat-diet-induced stress conditions; in this way, albumosomes maintain mitochondrial homeostasis from exhaustion. Physiologically, albumosomes accumulate in hepatocytes during murine aging and protect the livers of aged mice from mitochondrial damage and fat deposition. Morphologically, mature albumosomes have a mean diameter of 4μm and are surrounded by heat shock protein Hsp90 and Hsp70 family proteins, forming a larger shell. The Hsp90 inhibitor 17-AAG promotes hepatic albumosomal accumulation in vitro and in vivo, through which suppressing the progression of NAFLD in mice.
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Affiliation(s)
- Boyuan Ma
- School of Life Sciences, Tsinghua University, 100084, Beijing, China
- The National Engineering Research Center for Protein Technology, Tsinghua University, 100084, Beijing, China
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, 100084, Beijing, China
| | - Anji Ju
- School of Life Sciences, Tsinghua University, 100084, Beijing, China
- The National Engineering Research Center for Protein Technology, Tsinghua University, 100084, Beijing, China
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, 100084, Beijing, China
| | - Shaosen Zhang
- School of Life Sciences, Tsinghua University, 100084, Beijing, China
- The National Engineering Research Center for Protein Technology, Tsinghua University, 100084, Beijing, China
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, 100084, Beijing, China
- Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Qi An
- School of Life Sciences, Tsinghua University, 100084, Beijing, China
- The National Engineering Research Center for Protein Technology, Tsinghua University, 100084, Beijing, China
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, 100084, Beijing, China
| | - Siran Xu
- School of Life Sciences, Tsinghua University, 100084, Beijing, China
- The National Engineering Research Center for Protein Technology, Tsinghua University, 100084, Beijing, China
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, 100084, Beijing, China
| | - Jie Liu
- School of Life Sciences, Tsinghua University, 100084, Beijing, China
- The National Engineering Research Center for Protein Technology, Tsinghua University, 100084, Beijing, China
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, 100084, Beijing, China
- Immunogenetics Laboratory, Shenzhen Blood Center, 518025, Shenzhen, Guangdong, China
| | - Li Yu
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Centre for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, 100084, Beijing, China
| | - Yan Fu
- School of Life Sciences, Tsinghua University, 100084, Beijing, China.
- The National Engineering Research Center for Protein Technology, Tsinghua University, 100084, Beijing, China.
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, 100084, Beijing, China.
| | - Yongzhang Luo
- School of Life Sciences, Tsinghua University, 100084, Beijing, China.
- The National Engineering Research Center for Protein Technology, Tsinghua University, 100084, Beijing, China.
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, 100084, Beijing, China.
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28
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Ferreira MJ, Rodrigues TA, Pedrosa AG, Gales L, Salvador A, Francisco T, Azevedo JE. The mammalian peroxisomal membrane is permeable to both GSH and GSSG - Implications for intraperoxisomal redox homeostasis. Redox Biol 2023; 63:102764. [PMID: 37257275 DOI: 10.1016/j.redox.2023.102764] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/14/2023] [Accepted: 05/24/2023] [Indexed: 06/02/2023] Open
Abstract
Despite the large amounts of H2O2 generated in mammalian peroxisomes, cysteine residues of intraperoxisomal proteins are maintained in a reduced state. The biochemistry behind this phenomenon remains unexplored, and simple questions such as "is the peroxisomal membrane permeable to glutathione?" or "is there a thiol-disulfide oxidoreductase in the organelle matrix?" still have no answer. We used a cell-free in vitro system to equip rat liver peroxisomes with a glutathione redox sensor. The organelles were then incubated with glutathione solutions of different redox potentials and the oxidation/reduction kinetics of the redox sensor was monitored. The data suggest that the mammalian peroxisomal membrane is promptly permeable to both reduced and oxidized glutathione. No evidence for the presence of a robust thiol-disulfide oxidoreductase in the peroxisomal matrix could be found. Also, prolonged incubation of organelle suspensions with glutaredoxin 1 did not result in the internalization of the enzyme. To explore a potential role of glutathione in intraperoxisomal redox homeostasis we performed kinetic simulations. The results suggest that even in the absence of a glutaredoxin, glutathione is more important in protecting cysteine residues of matrix proteins from oxidation by H2O2 than peroxisomal catalase itself.
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Affiliation(s)
- Maria J Ferreira
- Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
| | - Tony A Rodrigues
- Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
| | - Ana G Pedrosa
- Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
| | - Luís Gales
- Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
| | - Armindo Salvador
- Coimbra Chemistry Center-Institute of Molecular Sciences (CQC-IMS), University of Coimbra, 3004-535, Coimbra, Portugal; CNC-Center for Neuroscience and Cell Biology, 3004-504, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal
| | - Tânia Francisco
- Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
| | - Jorge E Azevedo
- Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
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29
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Lee SM, Muratalla J, Sierra-Cruz M, Cordoba-Chacon J. Role of hepatic peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease. J Endocrinol 2023; 257:e220155. [PMID: 36688873 PMCID: PMC10048618 DOI: 10.1530/joe-22-0155] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 01/23/2023] [Indexed: 01/24/2023]
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target of a group of insulin sensitizers called thiazolidinediones (TZDs) which regulate the expression of genes involved in glucose and lipid metabolism as well as adipokines that regulate metabolic function in other tissues. Non-alcoholic fatty liver disease (NAFLD) has a high prevalence worldwide and is even higher in patients with obesity and insulin resistance. TZD-mediated activation of PPARγ could serve as a good treatment for NAFLD because TZDs have shown anti-fibrogenic and anti-inflammatory effectsin vitro and increase insulin sensitivity in peripheral tissues which improves liver pathology. However, mechanistic studies in mouse models suggest that the activation of PPARγ in hepatocytes might reduce or limit the therapeutic potential of TZD against NAFLD. In this review, we briefly describe the short history of PPAR isoforms, the relevance of their expression in different tissues, as well as the pathogenesis and potential therapeutics for NAFLD. We also discuss some evidence derived from mouse models that could be useful for endocrinologists to assess tissue-specific roles of PPARs, complement reverse endocrinology approaches, and understand the direct role that PPARγ has in hepatocytes and non-parenchymal cells.
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Affiliation(s)
- Samuel M. Lee
- Department of Medicine. Division of Endocrinology, Diabetes and Metabolism. University of Illinois at Chicago, Chicago. IL
| | - Jose Muratalla
- Department of Medicine. Division of Endocrinology, Diabetes and Metabolism. University of Illinois at Chicago, Chicago. IL
| | - Marta Sierra-Cruz
- Department of Medicine. Division of Endocrinology, Diabetes and Metabolism. University of Illinois at Chicago, Chicago. IL
| | - Jose Cordoba-Chacon
- Department of Medicine. Division of Endocrinology, Diabetes and Metabolism. University of Illinois at Chicago, Chicago. IL
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30
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Cao L, Wu D, Qin L, Tan D, Fan Q, Jia X, Yang M, Zhou T, Feng C, Lu Y, He Y. Single-Cell RNA Transcriptome Profiling of Liver Cells of Short-Term Alcoholic Liver Injury in Mice. Int J Mol Sci 2023; 24:ijms24054344. [PMID: 36901774 PMCID: PMC10002329 DOI: 10.3390/ijms24054344] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/23/2023] [Accepted: 02/20/2023] [Indexed: 02/24/2023] Open
Abstract
Alcoholic liver disease (ALD) is currently considered a global healthcare problem with limited pharmacological treatment options. There are abundant cell types in the liver, such as hepatocytes, endothelial cells, Kupffer cells and so on, but little is known about which kind of liver cells play the most important role in the process of ALD. To obtain a cellular resolution of alcoholic liver injury pathogenesis, 51,619 liver single-cell transcriptomes (scRNA-seq) with different alcohol consumption durations were investigated, 12 liver cell types were identified, and the cellular and molecular mechanisms of the alcoholic liver injury were revealed. We found that more aberrantly differential expressed genes (DEGs) were present in hepatocytes, endothelial cells, and Kupffer cells than in other cell types in alcoholic treatment mice. Alcohol promoted the pathological processes of liver injury; the specific mechanisms involved: lipid metabolism, oxidative stress, hypoxia, complementation and anticoagulation, and hepatocyte energy metabolism on hepatocytes; NO production, immune regulation, epithelial and cell migration on endothelial cells; antigen presentation and energy metabolism on Kupffer cells, based on the GO analysis. In addition, our results showed that some transcription factors (TFs) are activated in alcohol-treated mice. In conclusion, our study improves the understanding of liver cell heterogeneity in alcohol-fed mice at the single-cell level. It has potential value for understanding key molecular mechanisms and improving current prevention and treatment strategies for short-term alcoholic liver injury.
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Affiliation(s)
- Ligang Cao
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Di Wu
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Lin Qin
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Daopeng Tan
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Qingjie Fan
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Xiaohuan Jia
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Mengting Yang
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Tingting Zhou
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Chengcheng Feng
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Yanliu Lu
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Yuqi He
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
- Correspondence:
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31
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Zhang S, Bacon W, Peppelenbosch MP, van Kemenade F, Stubbs AP. Deciphering Tumour Microenvironment of Liver Cancer through Deconvolution of Bulk RNA-Seq Data with Single-Cell Atlas. Cancers (Basel) 2022; 15:153. [PMID: 36612149 PMCID: PMC9818189 DOI: 10.3390/cancers15010153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/21/2022] [Accepted: 12/24/2022] [Indexed: 12/29/2022] Open
Abstract
Liver cancers give rise to a heavy burden on healthcare worldwide. Understanding the tumour microenvironment (TME) underpins the development of precision therapy. Single-cell RNA sequencing (scRNA-seq) technology has generated high-quality cell atlases of the TME, but its wider application faces enormous costs for various clinical circumstances. Fortunately, a variety of deconvolution algorithms can instead repurpose bulk RNA-seq data, alleviating the need for generating scRNA-seq datasets. In this study, we reviewed major public omics databases for relevance in this study and utilised eight RNA-seqs and one microarray dataset from clinical studies. To decipher the TME of liver cancer, we estimated the fractions of liver cell components by deconvoluting the samples with Cibersortx using three reference scRNA-seq atlases. We also confirmed that Cibersortx can accurately deconvolute cell types/subtypes of interest. Compared with non-tumorous liver, liver cancers showed multiple decreased cell types forming normal liver microarchitecture, as well as elevated cell types involved in fibrogenesis, abnormal angiogenesis, and disturbed immune responses. Survival analysis shows that the fractions of five cell types/subtypes significantly correlated with patient outcomes, indicating potential therapeutic targets. Therefore, deconvolution of bulk RNA-seq data with scRNA-seq atlas references can be a useful tool to help understand the TME.
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Affiliation(s)
- Shaoshi Zhang
- Department of Pathology and Clinical Bioinformatics, Erasmus University Medical Centre, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
| | - Wendi Bacon
- School of Life, Health & Chemical Sciences, Faculty of Science, Technology, Engineering & Mathematics, The Open University, Milton Keynes MK7 6AA, UK
| | - Maikel P. Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
| | - Folkert van Kemenade
- School of Life, Health & Chemical Sciences, Faculty of Science, Technology, Engineering & Mathematics, The Open University, Milton Keynes MK7 6AA, UK
| | - Andrew Peter Stubbs
- Department of Pathology and Clinical Bioinformatics, Erasmus University Medical Centre, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
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32
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Wilson C, Lee MD, Buckley C, Zhang X, McCarron JG. Mitochondrial ATP Production is Required for Endothelial Cell Control of Vascular Tone. FUNCTION 2022; 4:zqac063. [PMID: 36778749 PMCID: PMC9909368 DOI: 10.1093/function/zqac063] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/06/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Arteries and veins are lined by nonproliferating endothelial cells that play a critical role in regulating blood flow. Endothelial cells also regulate tissue perfusion, metabolite exchange, and thrombosis. It is thought that endothelial cells rely on ATP generated via glycolysis, rather than mitochondrial oxidative phosphorylation, to fuel each of these energy-demanding processes. However, endothelial metabolism has mainly been studied in the context of proliferative cells, and little is known about energy production in endothelial cells within the fully formed vascular wall. Using intact arteries isolated from rats and mice, we show that inhibiting mitochondrial respiration disrupts endothelial control of vascular tone. Basal, mechanically activated, and agonist-evoked calcium activity in intact artery endothelial cells are each prevented by inhibiting mitochondrial ATP synthesis. Agonist-evoked calcium activity was also inhibited by blocking the transport of pyruvate, the master fuel for mitochondrial energy production, through the mitochondrial pyruvate carrier. The role for mitochondria in endothelial cell energy production is independent of species, sex, or vascular bed. These data show that a mitochondrial ATP supply is necessary for calcium-dependent, nitric oxide-mediated endothelial control of vascular tone, and identifies the critical role of endothelial mitochondrial energy production in fueling perfused blood vessel function.
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Affiliation(s)
| | - Matthew D Lee
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Charlotte Buckley
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
| | - Xun Zhang
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
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Yoon JS, Lee CW. Protein phosphatases regulate the liver microenvironment in the development of hepatocellular carcinoma. Exp Mol Med 2022; 54:1799-1813. [PMID: 36380016 PMCID: PMC9722691 DOI: 10.1038/s12276-022-00883-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
The liver is a complicated heterogeneous organ composed of different cells. Parenchymal cells called hepatocytes and various nonparenchymal cells, including immune cells and stromal cells, are distributed in liver lobules with hepatic architecture. They interact with each other to compose the liver microenvironment and determine its characteristics. Although the liver microenvironment maintains liver homeostasis and function under healthy conditions, it also shows proinflammatory and profibrogenic characteristics that can induce the progression of hepatitis and hepatic fibrosis, eventually changing to a protumoral microenvironment that contributes to the development of hepatocellular carcinoma (HCC). According to recent studies, phosphatases are involved in liver diseases and HCC development by regulating protein phosphorylation in intracellular signaling pathways and changing the activities and characteristics of liver cells. Therefore, this review aims to highlight the importance of protein phosphatases in HCC development and in the regulation of the cellular components in the liver microenvironment and to show their significance as therapeutic targets.
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Affiliation(s)
- Joon-Sup Yoon
- grid.264381.a0000 0001 2181 989XDepartment of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, 16419 Republic of Korea
| | - Chang-Woo Lee
- grid.264381.a0000 0001 2181 989XDepartment of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, 16419 Republic of Korea ,grid.264381.a0000 0001 2181 989XDepartment of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351 Republic of Korea
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34
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Mao L, Yuan X, Su J, Ma Y, Li C, Chen H, Zhang F. Human Umbilical Vein Endothelial Cells Survive on the Ischemic TCA Cycle under Lethal Ischemic Conditions. J Proteome Res 2022; 21:2385-2396. [PMID: 36074008 PMCID: PMC9552233 DOI: 10.1021/acs.jproteome.2c00255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
![]()
It is generally believed that vascular endothelial cells
(VECs)
rely on glycolysis instead of the tricarboxylic acid (TCA) cycle under
both normoxic and hypoxic conditions. However, the metabolic pattern
of human umbilical vein endothelial cells (HUVECs) under extreme ischemia
(hypoxia and nutrient deprivation) needs to be elucidated. We initiated
a lethal ischemic model of HUVECs, performed proteomics and bioinformatics,
and verified the metabolic pattern shift of HUVECs. Ischemic HUVECs
displayed extensive aerobic respiration, including upregulation of
the TCA cycle and mitochondrial respiratory chain in mitochondria
and downregulation of glycolysis in cytoplasm. The TCA cycle was enhanced
while the cell viability was decreased through the citrate synthase
pathway when substrates of the TCA cycle (acetate and/or pyruvate)
were added and vice versa when inhibitors of the TCA cycle (palmitoyl-CoA
and/or avidin) were applied. The inconsistency of the TCA cycle level
and cell viability suggested that the extensive TCA cycle can keep
cells alive yet generate toxic substances that reduce cell viability.
The data revealed that HUVECs depend on “ischemic TCA cycle”
instead of glycolysis to keep cells alive under lethal ischemic conditions,
but consideration must be given to relieve cell injury.
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Affiliation(s)
- Lisha Mao
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Medical University, Chongqing 401147, China
| | - Xiaoqi Yuan
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Medical University, Chongqing 401147, China
| | - Junlei Su
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Medical University, Chongqing 401147, China
| | - Yaping Ma
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Chaofan Li
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Hongying Chen
- Department of Oral and Maxillofacial Surgery, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Fugui Zhang
- Department of Oral and Maxillofacial Surgery, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
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Unraveling the effect of intra- and intercellular processes on acetaminophen-induced liver injury. NPJ Syst Biol Appl 2022; 8:27. [PMID: 35933513 PMCID: PMC9357019 DOI: 10.1038/s41540-022-00238-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 07/20/2022] [Indexed: 11/09/2022] Open
Abstract
In high dosages, acetaminophen (APAP) can cause severe liver damage, but susceptibility to liver failure varies across individuals and is influenced by factors such as health status. Because APAP-induced liver injury and recovery is regulated by an intricate system of intra- and extracellular molecular signaling, we here aim to quantify the importance of specific modules in determining the outcome after an APAP insult and of potential targets for therapies that mitigate adversity. For this purpose, we integrated hepatocellular acetaminophen metabolism, DNA damage response induction and cell fate into a multiscale mechanistic liver lobule model which involves various cell types, such as hepatocytes, residential Kupffer cells and macrophages. Our model simulations show that zonal differences in metabolism and detoxification efficiency are essential determinants of necrotic damage. Moreover, the extent of senescence, which is regulated by intracellular processes and triggered by extracellular signaling, influences the potential to recover. In silico therapies at early and late time points after APAP insult indicated that prevention of necrotic damage is most beneficial for recovery, whereas interference with regulation of senescence promotes regeneration in a less pronounced way.
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36
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Liver Regeneration: Changes in Oxidative Stress, Immune System, Cytokines, and Epigenetic Modifications Associated with Aging. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9018811. [PMID: 35936214 PMCID: PMC9352489 DOI: 10.1155/2022/9018811] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/25/2022] [Accepted: 06/29/2022] [Indexed: 01/10/2023]
Abstract
The regenerative capacity of the liver decreases with increase in age. In recent years, studies in mice have found that the regenerative capacity of the liver is associated with changes in the immune system of the liver, cytokines in the body, aging-related epigenetic modifications in the cell, and intracellular signaling pathways. In the immune system of the aging liver, monocytes and macrophages play an important role in tissue repair. During tissue repair, monocytes and macrophages undergo a series of functional and phenotypic changes to initiate and maintain tissue repair. Studies have discovered that knocking out macrophages in the liver during the repair phase results in significant impairment of liver regeneration. Furthermore, as the body ages, the secretion and function of cytokines undergo a series of changes. For example, the levels of interleukin-6, transforming growth factor-alpha, hepatocyte growth factor, and vascular endothelial growth factor undergo changes that alter hepatocyte regulation, thereby affecting its proliferation. In addition, body aging is accompanied by cellular aging, which leads to changes in gene expression and epigenetic modifications. Additionally, this in turn causes alterations in cell function, morphology, and division and affects the regenerative capacity of the liver. As the body ages, the activity of associated functional proteins, such as CCAAT-enhancer-binding proteins, p53, and switch/sucrose nonfermentable complex, changes in the liver, leading to alterations in several signaling pathways, such as the Hippo, PI3K-Akt, mTOR, and STAT3 pathways. Therefore, in recent years, research on aging and liver regeneration has primarily focused on the immune system, signaling pathways, epigenetic changes of senescent cells, and cytokine secretion in the liver. Hence, this review details the roles of these influencing factors in liver regeneration and impact of aging-related factors.
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Monocrotaline Toxicity Alters the Function of Hepatocyte Membrane Transporters in Rats. Int J Mol Sci 2022; 23:ijms23147928. [PMID: 35887275 PMCID: PMC9323134 DOI: 10.3390/ijms23147928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/13/2022] [Accepted: 07/16/2022] [Indexed: 12/10/2022] Open
Abstract
Pyrrolizidine alkaloid monocrotaline (MCT) induces sinusoidal obstruction syndrome (SOS) in rats characterised by a sinusoidal congestive obstruction. Additionally, MCT administration decreases the biliary excretion of gadobenate dimeglumine (BOPTA), a hepatobiliary substrate used in clinical imaging. BOPTA crosses hepatocyte membranes through organic anion transporting polypeptides, multidrug-resistance-associated protein 2, and Mrp3/4 transporters, and a modified function of these transporters is likely to explain the decreased biliary excretion. This study compared BOPTA transport across hepatocytes in livers isolated from normal (Nl) rats and rats with intragastric administration of MCT. BOPTA hepatocyte influx clearance was similar in both groups, while biliary clearance and bile concentrations were much lower in MCT than in Nl livers. BOPTA efflux clearance back to the sinusoids compensated for the low biliary excretion, and hepatocyte concentrations remained similar in both groups. This SOS-associated changes of transporter functions might impact the pharmacokinetics of numerous drugs that use similar transporters to cross hepatocytes.
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38
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NAFLD: Mechanisms, Treatments, and Biomarkers. Biomolecules 2022; 12:biom12060824. [PMID: 35740949 PMCID: PMC9221336 DOI: 10.3390/biom12060824] [Citation(s) in RCA: 205] [Impact Index Per Article: 68.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is one of the most common causes of liver diseases worldwide. NAFLD is growing in parallel with the obesity epidemic. No pharmacological treatment is available to treat NAFLD, specifically. The reason might be that NAFLD is a multi-factorial disease with an incomplete understanding of the mechanisms involved, an absence of accurate and inexpensive imaging tools, and lack of adequate non-invasive biomarkers. NAFLD consists of the accumulation of excess lipids in the liver, causing lipotoxicity that might progress to metabolic-associated steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma. The mechanisms for the pathogenesis of NAFLD, current interventions in the management of the disease, and the role of sirtuins as potential targets for treatment are discussed here. In addition, the current diagnostic tools, and the role of non-coding RNAs as emerging diagnostic biomarkers are summarized. The availability of non-invasive biomarkers, and accurate and inexpensive non-invasive diagnosis tools are crucial in the detection of the early signs in the progression of NAFLD. This will expedite clinical trials and the validation of the emerging therapeutic treatments.
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Chehaitly A, Guihot AL, Proux C, Grimaud L, Aurrière J, Legouriellec B, Rivron J, Vessieres E, Tétaud C, Zorzano A, Procaccio V, Joubaud F, Reynier P, Lenaers G, Loufrani L, Henrion D. Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis. Antioxidants (Basel) 2022; 11:antiox11061078. [PMID: 35739974 PMCID: PMC9219969 DOI: 10.3390/antiox11061078] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 12/22/2022] Open
Abstract
Flow (shear stress)-mediated dilation (FMD) of resistance arteries is a rapid endothelial response involved in tissue perfusion. FMD is reduced early in cardiovascular diseases, generating a major risk factor for atherosclerosis. As alteration of mitochondrial fusion reduces endothelial cells’ (ECs) sprouting and angiogenesis, we investigated its role in ECs responses to flow. Opa1 silencing reduced ECs (HUVECs) migration and flow-mediated elongation. In isolated perfused resistance arteries, FMD was reduced in Opa1+/− mice, a model of the human disease due to Opa1 haplo-insufficiency, and in mice with an EC specific Opa1 knock-out (EC-Opa1). Reducing mitochondrial oxidative stress restored FMD in EC-Opa1 mice. In isolated perfused kidneys from EC-Opa1 mice, flow induced a greater pressure, less ATP, and more H2O2 production, compared to control mice. Opa1 expression and mitochondrial length were reduced in ECs submitted in vitro to disturbed flow and in vivo in the atheroprone zone of the mouse aortic cross. Aortic lipid deposition was greater in Ldlr−/--Opa1+/- and in Ldlr−/--EC-Opa1 mice than in control mice fed with a high-fat diet. In conclusion, we found that reduction in mitochondrial fusion in mouse ECs altered the dilator response to shear stress due to excessive superoxide production and induced greater atherosclerosis development.
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Affiliation(s)
- Ahmad Chehaitly
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
| | - Anne-Laure Guihot
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
| | - Coralyne Proux
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
| | - Linda Grimaud
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
| | - Jade Aurrière
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
| | - Benoit Legouriellec
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
| | - Jordan Rivron
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
| | - Emilie Vessieres
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
| | - Clément Tétaud
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
| | - Antonio Zorzano
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10–12, 08028 Barcelona, Spain;
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biologie, University of Barcelona, 08028 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, C/ de Monforte de Lemos, 5, 28029 Madrid, Spain
| | - Vincent Procaccio
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
- University Hospital (CHU) of Angers, 4 rue Larrey, F-49933 Angers, France;
| | - Françoise Joubaud
- University Hospital (CHU) of Angers, 4 rue Larrey, F-49933 Angers, France;
| | - Pascal Reynier
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
- University Hospital (CHU) of Angers, 4 rue Larrey, F-49933 Angers, France;
| | - Guy Lenaers
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
- University Hospital (CHU) of Angers, 4 rue Larrey, F-49933 Angers, France;
| | - Laurent Loufrani
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
| | - Daniel Henrion
- MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, France; (A.C.); (A.-L.G.); (C.P.); (L.G.); (J.A.); (B.L.); (J.R.); (E.V.); (C.T.); (V.P.); (P.R.); (G.L.); (L.L.)
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, 3 rue Roger Amsler, F-49500 Angers, France
- Centre National de la Recherche Scientifique (CNRS) UMR 6015, 3 rue Roger Amsler, F-49500 Angers, France
- University Hospital (CHU) of Angers, 4 rue Larrey, F-49933 Angers, France;
- Correspondence: ; Tel.: +33-2-41-73-58-45
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Zeng ZL, Yuan Q, Zu X, Liu J. Insights Into the Role of Mitochondria in Vascular Calcification. Front Cardiovasc Med 2022; 9:879752. [PMID: 35571215 PMCID: PMC9099050 DOI: 10.3389/fcvm.2022.879752] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 03/14/2022] [Indexed: 12/22/2022] Open
Abstract
Vascular calcification (VC) is a growing burden in aging societies worldwide, and with a significant increase in all-cause mortality and atherosclerotic plaque rupture, it is frequently found in patients with aging, diabetes, atherosclerosis, or chronic kidney disease. However, the mechanism of VC is still not yet fully understood, and there are still no effective therapies for VC. Regarding energy metabolism factories, mitochondria play a crucial role in maintaining vascular physiology. Discoveries in past decades signifying the role of mitochondrial homeostasis in normal physiology and pathological conditions led to tremendous advances in the field of VC. Therapies targeting basic mitochondrial processes, such as energy metabolism, damage in mitochondrial DNA, or free-radical generation, hold great promise. The remarkably unexplored field of the mitochondrial process has the potential to shed light on several VC-related diseases. This review focuses on current knowledge of mitochondrial dysfunction, dynamics anomalies, oxidative stress, and how it may relate to VC onset and progression and discusses the main challenges and prerequisites for their therapeutic applications.
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Affiliation(s)
- ZL Zeng
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Department of Clinical Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Key Laboratory for Arteriosclerology of Hunan Province, Department of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, China
| | - Qing Yuan
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Department of Clinical Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Xuyu Zu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Department of Clinical Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
- *Correspondence: Xuyu Zu
| | - Jianghua Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Department of Clinical Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Jianghua Liu
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Ochi M, Kinoshita K, Yamaguchi JI, Endo H. Bottom-up physiologically based pharmacokinetic modeling for predicting the human pharmacokinetic profiles of the ester prodrug MGS0274 and its active metabolite MGS0008, a metabotropic glutamate 2/3 receptor agonist. Xenobiotica 2022; 52:119-128. [PMID: 35296225 DOI: 10.1080/00498254.2022.2053894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
1. For ester prodrugs that are used to improve the gastrointestinal absorption of highly hydrophilic, pharmacologically active substances, it is challenging to predict the human pharmacokinetics (PK) of the prodrugs and their parent compounds using only preclinical data.2. This research was aimed at constructing a PBPK model for predicting the human PK of the ester prodrug MGS0274 and its parent compound MGS0008 after a single oral administration of MGS0274 besylate.3. First, we identified carboxylesterase 1 (CES1) as the major enzyme involved in the hydrolysis of MGS0274. Second, we constructed a new compartment model to estimate the passive diffusion clearance (CLpd) of MGS0008, a critical parameter for predicting the PK of highly hydrophilic compounds, based on in vivo monkey PK data. Finally, we constructed a permeability-limited liver PBPK model incorporating the CLpd assumed to be the same in humans.4. We confirmed that our method reliably predicted the human PK and that the estimated CLpd was comparable to that calculated retrospectively using the PBPK model, suggesting that the methodology for estimating the CLpd was valid.5. Our proposed methodology is expected to be helpful for human PK prediction of ester prodrugs hydrolyzed by CES1 and their hydrophilic parent compounds even during the preclinical phase.
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Affiliation(s)
- Motoki Ochi
- Drug Metabolism and Pharmacokinetics, Drug Safety and Pharmacokinetics Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Kohnosuke Kinoshita
- Drug Metabolism and Pharmacokinetics, Drug Safety and Pharmacokinetics Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Jun-Ichi Yamaguchi
- Drug Metabolism and Pharmacokinetics, Drug Safety and Pharmacokinetics Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Hiromi Endo
- Drug Metabolism and Pharmacokinetics, Drug Safety and Pharmacokinetics Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan
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Werner M, Schefczyk S, Trippler M, Treckmann JW, Baba HA, Gerken G, Schlaak JF, Broering R. Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3. Viruses 2022; 14:218. [PMID: 35215812 PMCID: PMC8874605 DOI: 10.3390/v14020218] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 02/06/2023] Open
Abstract
The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1-9 ligands for 6-24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.
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Affiliation(s)
- Melanie Werner
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| | - Stefan Schefczyk
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| | - Martin Trippler
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| | - Juergen W. Treckmann
- Department of General-, Visceral- and Transplantation-Surgery, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany;
| | - Hideo A. Baba
- Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany;
| | - Guido Gerken
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
- Helios Hospital, Gastroenterology, Hepatology and Palliative Medicine, Robert-Koch-Straße 2, 42549 Velbert, Germany
| | - Joerg F. Schlaak
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
- AMEOS Hospital, St. Clemens, Internal Medicine—Hepatology, Gastroenterology, Infectiology and Diabetology, Wilhelmstr. 34, 46145 Oberhausen, Germany
| | - Ruth Broering
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
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Pastor CM, Brouwer KLR. New Pharmacokinetic Parameters of Imaging Substrates Quantified from Rat Liver Compartments. Drug Metab Dispos 2022; 50:58-64. [PMID: 34670777 DOI: 10.1124/dmd.121.000546] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 10/18/2021] [Indexed: 11/22/2022] Open
Abstract
Hepatobiliary imaging is increasingly used by pharmacologists to quantify liver concentrations of transporter-dependent drugs. However, liver imaging does not quantify concentrations in extracellular space, hepatocytes, and bile canaliculi. Our study compared the compartmental distribution of two hepatobiliary substrates gadobenate dimeglumine [BOPTA; 0.08 liver extraction ratio (ER)] and mebrofenin (MEB; 0.93 ER) in a model of perfused rat liver. A gamma counter placed over livers measured liver concentrations. Livers were preperfused with gadopentetate dimeglumine to measure extracellular concentrations. Concentrations coming from bile canaliculi and hepatocytes were calculated. Transporter activities were assessed by concentration ratios between compartments and pharmacokinetic parameters that describe the accumulation and decay profiles of hepatocyte concentrations. The high liver concentrations of MEB relied mainly on hepatocyte and bile canaliculi concentrations. In contrast, the three compartments contributed to the low liver concentrations obtained during BOPTA perfusion. Nonlinear regression analysis of substrate accumulation in hepatocytes revealed that cellular efflux is measurable ∼4 minutes after the start of perfusion. The hepatocyte-to-extracellular concentration ratio measured at this time point was much higher during MEB perfusion. BOPTA transport by multidrug resistance associated protein 2 induced an aquaporin-mediated water transport, whereas MEB transport did not. BOPTA clearance from hepatocytes to bile canaliculi was higher than MEB clearance. MEB did not efflux back to sinusoids, whereas BOPTA basolateral efflux contributed to the decrease in hepatocyte concentrations. In conclusion, our ex vivo model quantifies substrate compartmental distribution and transport across hepatocyte membranes and provides an additional understanding of substrate distribution in the liver. SIGNIFICANCE STATEMENT: When transporter-dependent drugs target hepatocytes, cellular concentrations are important to investigate. Low concentrations on cellular targets impair drug therapeutic effects, whereas excessive hepatocyte concentrations may induce cellular toxicity. With a gamma counter placed over rat perfused livers, we measured substrate concentrations in the extracellular space, hepatocytes, and bile canaliculi. Transport across hepatocyte membranes was calculated. The study provides an additional understanding of substrate distribution in the liver.
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Affiliation(s)
- Catherine M Pastor
- Department of Radiology, University Hospital of Geneva, Switzerland (C.M.P.); Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75006 Paris, France (C.M.P.); and Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (K.L.R.B.)
| | - Kim L R Brouwer
- Department of Radiology, University Hospital of Geneva, Switzerland (C.M.P.); Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75006 Paris, France (C.M.P.); and Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (K.L.R.B.)
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Hull SM, Brunel LG, Heilshorn SC. 3D Bioprinting of Cell-Laden Hydrogels for Improved Biological Functionality. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2103691. [PMID: 34672027 PMCID: PMC8988886 DOI: 10.1002/adma.202103691] [Citation(s) in RCA: 115] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 09/15/2021] [Indexed: 05/03/2023]
Abstract
The encapsulation of cells within gel-phase materials to form bioinks offers distinct advantages for next-generation 3D bioprinting. 3D bioprinting has emerged as a promising tool for patterning cells, but the technology remains limited in its ability to produce biofunctional, tissue-like constructs due to a dearth of materials suitable for bioinks. While early demonstrations commonly used viscous polymers optimized for printability, these materials often lacked cell compatibility and biological functionality. In response, advanced materials that exist in the gel phase during the entire printing process are being developed, since hydrogels are uniquely positioned to both protect cells during extrusion and provide biological signals to embedded cells as the construct matures during culture. Here, an overview of the design considerations for gel-phase materials as bioinks is presented, with a focus on their mechanical, biochemical, and dynamic gel properties. Current challenges and opportunities that arise due to the fact that bioprinted constructs are active, living hydrogels composed of both acellular and cellular components are also evaluated. Engineering hydrogels with consideration of cells as an intrinsic component of the printed bioink will enable control over the evolution of the living construct after printing to achieve greater biofunctionality.
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Affiliation(s)
- Sarah M Hull
- Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA
| | - Lucia G Brunel
- Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA
| | - Sarah C Heilshorn
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA
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Deng X, Wu Y, Xu H, Yan J, Liu H, Zhang B. Recent research progress in galactose-based fluorescent probes for detection of biomarkers of liver diseases. Chem Commun (Camb) 2022; 58:12518-12527. [DOI: 10.1039/d2cc04180d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
This highlight illustrates the challenges and latest progress in galactose-based fluorescent probes for early diagnosis of liver diseases.
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Affiliation(s)
- Xiaojing Deng
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China
| | - Yingxu Wu
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China
| | - Hu Xu
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 16044, China
| | - Jiawei Yan
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China
| | - Huanying Liu
- School of Mechanical and Power Engineering, Dalian Ocean University, Dalian 116023, China
| | - Boyu Zhang
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China
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Kumar N, Saraber P, Ding Z, Kusumbe AP. Diversity of Vascular Niches in Bones and Joints During Homeostasis, Ageing, and Diseases. Front Immunol 2021; 12:798211. [PMID: 34975909 PMCID: PMC8718446 DOI: 10.3389/fimmu.2021.798211] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 11/19/2021] [Indexed: 12/29/2022] Open
Abstract
The bones and joints in the skeletal system are composed of diverse cell types, including vascular niches, bone cells, connective tissue cells and mineral deposits and regulate whole-body homeostasis. The capacity of maintaining strength and generation of blood lineages lies within the skeletal system. Bone harbours blood and immune cells and their progenitors, and vascular cells provide several immune cell type niches. Blood vessels in bone are phenotypically and functionally diverse, with distinct capillary subtypes exhibiting striking changes with age. The bone vasculature has a special impact on osteogenesis and haematopoiesis, and dysregulation of the vasculature is associated with diverse blood and bone diseases. Ageing is associated with perturbed haematopoiesis, loss of osteogenesis, increased adipogenesis and diminished immune response and immune cell production. Endothelial and perivascular cells impact immune cell production and play a crucial role during inflammation. Here, we discuss normal and maladapted vascular niches in bone during development, homeostasis, ageing and bone diseases such as rheumatoid arthritis and osteoarthritis. Further, we discuss the role of vascular niches during bone malignancy.
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Affiliation(s)
| | | | | | - Anjali P. Kusumbe
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Tissue and Tumor Microenvironments Group, University of Oxford, Oxford, United Kingdom
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47
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Bhandari S, Larsen AK, McCourt P, Smedsrød B, Sørensen KK. The Scavenger Function of Liver Sinusoidal Endothelial Cells in Health and Disease. Front Physiol 2021; 12:757469. [PMID: 34707514 PMCID: PMC8542980 DOI: 10.3389/fphys.2021.757469] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
The aim of this review is to give an outline of the blood clearance function of the liver sinusoidal endothelial cells (LSECs) in health and disease. Lining the hundreds of millions of hepatic sinusoids in the human liver the LSECs are perfectly located to survey the constituents of the blood. These cells are equipped with high-affinity receptors and an intracellular vesicle transport apparatus, enabling a remarkably efficient machinery for removal of large molecules and nanoparticles from the blood, thus contributing importantly to maintain blood and tissue homeostasis. We describe here central aspects of LSEC signature receptors that enable the cells to recognize and internalize blood-borne waste macromolecules at great speed and high capacity. Notably, this blood clearance system is a silent process, in the sense that it usually neither requires or elicits cell activation or immune responses. Most of our knowledge about LSECs arises from studies in animals, of which mouse and rat make up the great majority, and some species differences relevant for extrapolating from animal models to human are discussed. In the last part of the review, we discuss comparative aspects of the LSEC scavenger functions and specialized scavenger endothelial cells (SECs) in other vascular beds and in different vertebrate classes. In conclusion, the activity of LSECs and other SECs prevent exposure of a great number of waste products to the immune system, and molecules with noxious biological activities are effectively “silenced” by the rapid clearance in LSECs. An undesired consequence of this avid scavenging system is unwanted uptake of nanomedicines and biologics in the cells. As the development of this new generation of therapeutics evolves, there will be a sharp increase in the need to understand the clearance function of LSECs in health and disease. There is still a significant knowledge gap in how the LSEC clearance function is affected in liver disease.
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Affiliation(s)
- Sabin Bhandari
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
| | - Anett Kristin Larsen
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
| | - Peter McCourt
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
| | - Bård Smedsrød
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
| | - Karen Kristine Sørensen
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
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Steatosis Alters the Activity of Hepatocyte Membrane Transporters in Obese Rats. Cells 2021; 10:cells10102733. [PMID: 34685713 PMCID: PMC8534847 DOI: 10.3390/cells10102733] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 02/06/2023] Open
Abstract
Fat accumulation (steatosis) in ballooned hepatocytes alters the expression of membrane transporters in Zucker fatty (fa/fa) rats. The aim of the study was to quantify the functions of these transporters and their impact on hepatocyte concentrations using a clinical hepatobiliary contrast agent (Gadobenate dimeglumine, BOPTA) for liver imaging. In isolated and perfused rat livers, we quantified BOPTA accumulation and decay profiles in fa/+ (normal) and fa/fa hepatocytes by placing a gamma counter over livers. Profiles of BOPTA accumulation and decay in hepatocytes were analysed with nonlinear regressions to characterise BOPTA influx and efflux across hepatocyte transporters. At the end of the accumulation period, BOPTA hepatocyte concentrations and influx clearances were not significantly different in fa/+ and fa/fa livers. In contrast, bile clearance was significantly lower in fatty hepatocytes while efflux clearance back to sinusoids compensated the low efflux into canaliculi. The time when BOPTA cellular efflux impacts the accumulation profile of hepatocyte concentrations was slightly delayed (2 min) by steatosis, anticipating a delayed emptying of hepatocytes. The experimental model is useful for quantifying the functions of hepatocyte transporters in liver diseases.
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Cunningham RP, Porat-Shliom N. Liver Zonation - Revisiting Old Questions With New Technologies. Front Physiol 2021; 12:732929. [PMID: 34566696 PMCID: PMC8458816 DOI: 10.3389/fphys.2021.732929] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/10/2021] [Indexed: 12/12/2022] Open
Abstract
Despite the ever-increasing prevalence of non-alcoholic fatty liver disease (NAFLD), the etiology and pathogenesis remain poorly understood. This is due, in part, to the liver's complex physiology and architecture. The liver maintains glucose and lipid homeostasis by coordinating numerous metabolic processes with great efficiency. This is made possible by the spatial compartmentalization of metabolic pathways a phenomenon known as liver zonation. Despite the importance of zonation to normal liver function, it is unresolved if and how perturbations to liver zonation can drive hepatic pathophysiology and NAFLD development. While hepatocyte heterogeneity has been identified over a century ago, its examination had been severely hindered due to technological limitations. Recent advances in single cell analysis and imaging technologies now permit further characterization of cells across the liver lobule. This review summarizes the advances in examining liver zonation and elucidating its regulatory role in liver physiology and pathology. Understanding the spatial organization of metabolism is vital to further our knowledge of liver disease and to provide targeted therapeutic avenues.
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Affiliation(s)
- Rory P Cunningham
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Natalie Porat-Shliom
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
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50
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Pastor CM, Joly F, Vilgrain V, Millet P. Concentrations and pharmacokinetic parameters of MRI and SPECT hepatobiliary agents in rat liver compartments. Eur Radiol Exp 2021; 5:42. [PMID: 34545428 PMCID: PMC8452805 DOI: 10.1186/s41747-021-00236-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/28/2021] [Indexed: 11/10/2022] Open
Abstract
Background In hepatobiliary imaging, systems detect the total amount of agents originating from extracellular space, bile canaliculi, and hepatocytes. They add in situ concentration of each compartment corrected by its respective volume ratio to provide liver concentrations. In vivo contribution of each compartment to liver concentration is inaccessible. Our aim was to quantify the compartmental distribution of two hepatobiliary agents in an ex vivo model and determine how their liver extraction ratios and cholestasis (livers lacking canalicular transporters) might modify it. Methods We perfused labelled gadobenate dimeglumine (Bopta, 200 μM, 7% liver extraction ratio) and mebrofenin (Meb, 64 μM, 94% liver extraction ratio) in normal (n = 18) and cholestatic (n = 6) rat livers. We quantified liver concentrations with a gamma counter placed over livers. Concentrations in hepatocytes and bile canaliculi were calculated. Mann-Whitney and Kruskal-Wallis tests were used. Results Hepatocyte concentrations were 2,043 ± 333 μM (Meb) versus 360 ± 69 μM (Bopta, p < 0.001). Meb extracellular concentrations did not contribute to liver concentrations (1.3 ± 0.3%). The contribution of Bopta extracellular concentration was 12.4 ± 1.9% (p < 0.001 versus Meb). Contribution of canaliculi was similar for both agents (16%). Cholestatic livers had no Bopta in canaliculi but their hepatocyte concentrations increased in comparison to normal livers. Conclusion Hepatocyte concentrations are correlated to liver extraction ratios of hepatobiliary agents. When Bopta is not present in canaliculi of cholestatic livers, hepatocyte concentrations increase in comparison to normal livers. This new understanding extends the interpretation of clinical liver images.
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Affiliation(s)
- Catherine M Pastor
- Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, Université de Paris, F-75006, Paris, France. .,Department of Radiology, University Hospital of Geneva, Rue Gabrielle-Perret-Gentil, 4, 1205, Geneva, Switzerland.
| | - Florian Joly
- Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, Université de Paris, F-75006, Paris, France
| | - Valérie Vilgrain
- Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, Université de Paris, F-75006, Paris, France.,Department of Radiology, Hôpital Beaujon, Hôpitaux Paris Nord Val de Seine (AP-HP), 92110, Clichy, France
| | - Philippe Millet
- Department of Psychiatry, University Hospital of Geneva, Geneva, Switzerland.,Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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