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Liu Z, Wei S, Jiang Y, Su W, Ma F, Cai G, Liu Y, Sun X, Lu L, Fu W, Xu Y, Huang R, Li J, Lin X, Cui A, Zang M, Xu A, Li Y. Protein phosphatase 6 regulates metabolic dysfunction-associated steatohepatitis via the mTORC1 pathway. J Hepatol 2025:S0168-8278(25)00079-0. [PMID: 39947331 DOI: 10.1016/j.jhep.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 02/04/2025] [Accepted: 02/04/2025] [Indexed: 04/22/2025]
Abstract
BACKGROUND & AIMS Metabolic dysfunction-associated steatohepatitis (MASH) is a serious chronic liver disease for which therapeutic options are limited. Although fibroblast growth factor 21 (FGF21) analogs have shown therapeutic promise for MASH in multiple preclinical and clinical studies, their underlying mechanisms of action remain elusive. METHODS Liver-specific PPP6C and βKlotho knockout mice and their wild-type littermates were fed an AMLN (Amylin liver NASH) diet for 16 weeks or a CDA-HFD (choline-deficient, L-amino acid-defined, high-fat diet) for 8 weeks, followed by daily subcutaneous injection of recombinant FGF21 (0.5 mg/kg) or vehicle for 4 weeks. A mass spectrometry assay identified PPP6C as a βKlotho-binding protein. An in vitro phosphatase assay was used to evaluate the effects of FGF21 on PPP6C activity. PPP6C expression was also analyzed in human samples from patients with MASH. RESULTS We identified serine and threonine phosphatase PPP6C as a direct target of FGF21. Hepatic PPP6C deficiency accelerates MASH progression in mice fed an AMLN diet or CDA-HFD, which blocks the effect of FGF21 on MASH. Mechanistically, PPP6C is sufficient to interact with the coreceptor βKlotho upon FGF21 treatment and directly dephosphorylates tuberous sclerosis complex 2 (TSC2) at Ser939 and Thr1462, thereby inhibiting mTORC1 and promoting nuclear entry of TFE3 and Lipin1. In the livers of patients with MASH, expression levels of PPP6C are decreased whereas TSC2 phosphorylation is elevated. CONCLUSIONS PPP6C acts as a fundamental downstream mediator essential for FGF21 signaling in hepatocytes and targeting PPP6C by FGF21 may offer therapeutic potential for treating MASH in humans. IMPACT AND IMPLICATIONS Metabolic dysfunction-associated steatohepatitis (MASH) is a severe chronic liver disease that increases susceptibility to more severe cirrhosis and hepatocellular carcinoma. Effective therapeutic strategies for MASH remain an unmet need. Herein, we have identified serine and threonine protein phosphatase PPP6C as a negative regulator of MASH progression in mice and humans. PPP6C activity is increased by FGF21 via an autocrine effect mediated by FGFRs/βKlotho in hepatocytes. Pharmacological administration of FGF21 protects against MASH pathology at least in large through the interaction between βKlotho and PPP6C and PPP6C-mediated dephosphorylation of TSC2 in hepatocytes. This study implies that pharmacological approaches targeting PPP6C activity may offer attractive prospects for treating liver fibrosis and MASH.
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Affiliation(s)
- Zhengshuai Liu
- CAS Key Laboratory of Nutrition and Metabolism, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Shuang Wei
- CAS Key Laboratory of Nutrition and Metabolism, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yang Jiang
- CAS Key Laboratory of Nutrition and Metabolism, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China
| | - Weitong Su
- CAS Key Laboratory of Nutrition and Metabolism, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Fengguang Ma
- CAS Key Laboratory of Nutrition and Metabolism, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Genxiang Cai
- CAS Key Laboratory of Nutrition and Metabolism, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yuxiao Liu
- CAS Key Laboratory of Nutrition and Metabolism, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xiaoyang Sun
- Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ling Lu
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Wenguang Fu
- Department of General Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Yong Xu
- Department of Endocrinology and Metabolism, Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Ruijing Huang
- Tasly Pharmaceutical Group CO., LTD., Tianjin 300410, China
| | - Jian Li
- Tasly Pharmaceutical Group CO., LTD., Tianjin 300410, China
| | - Xu Lin
- CAS Key Laboratory of Nutrition and Metabolism, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Aoyuan Cui
- CAS Key Laboratory of Nutrition and Metabolism, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Mengwei Zang
- Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, Department of Molecular Medicine, University of Texas Health San Antonio, Texas, USA; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas, USA
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, The University of Hong Kong, Hong Kong, China
| | - Yu Li
- CAS Key Laboratory of Nutrition and Metabolism, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
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Gonzalez-Sanchez E, Vaquero J, Caballero-Diaz D, Grzelak J, Fusté NP, Bertran E, Amengual J, Garcia-Saez J, Martín-Mur B, Gut M, Esteve-Codina A, Alay A, Coulouarn C, Calero-Perez S, Valdecantos P, Valverde AM, Sánchez A, Herrera B, Fabregat I. The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche. J Pathol 2024; 263:482-495. [PMID: 38872438 DOI: 10.1002/path.6299] [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: 01/10/2024] [Revised: 03/19/2024] [Accepted: 04/25/2024] [Indexed: 06/15/2024]
Abstract
Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro-fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with carbon tetrachloride (CCl4), which induces a pro-inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated ΔEGFR mice when compared with CCl4-treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from in vitro experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-fibrotic and pro-inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase-dependent actions in hepatocytes that reveal its key role in chronic liver damage. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Grants
- EHDG1703 CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases
- CERCA Programme/Generalitat de Catalunya
- CIVP20A6593 Fundacion Ramon Areces
- PID2019-108651RJ-I00 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- PID2021-122551OB-100 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- PID-2021-122766OB-100 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- RTC2019-007125-1 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- RTI2018-094052-B-100 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- RTI2018-094079-B-100 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- RTI2018-099098-B-100 Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- RYC2021-034121-I Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain
- European Regional Development Fund
- Instituto de Salud Carlos III
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Affiliation(s)
- Ester Gonzalez-Sanchez
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Department of Physiology and Pharmacology, Faculty of Pharmacy, University of Salamanca, Salamanca, Spain
| | - Javier Vaquero
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
- Centro de Investigación del Cancer and Instituto de Biología Molecular y Celular del Cancer, CSIC-Universidad de Salamanca, Salamanca, Spain
| | - Daniel Caballero-Diaz
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
| | - Jan Grzelak
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
| | - Noel P Fusté
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
| | - Esther Bertran
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
| | - Josep Amengual
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
| | - Juan Garcia-Saez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
- Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Beatriz Martín-Mur
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Marta Gut
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
| | - Anna Esteve-Codina
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Ania Alay
- Unit of Bioinformatics for Precision Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain
- Preclinical and Experimental Research in Thoracic Tumors (PReTT), Oncobell Program, IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Cedric Coulouarn
- Inserm, Univ Rennes, OSS (Oncogenesis, Stress, Signaling) UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | - Silvia Calero-Perez
- Biomedical Research Institute Sols-Morreale, Spanish National Research Council and Autonomous University of Madrid (IIBM, CSIC-UAM), Madrid, Spain
- Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders (CIBERDEM); ISCIII, Madrid, Spain
| | - Pilar Valdecantos
- Biomedical Research Institute Sols-Morreale, Spanish National Research Council and Autonomous University of Madrid (IIBM, CSIC-UAM), Madrid, Spain
- Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders (CIBERDEM); ISCIII, Madrid, Spain
| | - Angela M Valverde
- Biomedical Research Institute Sols-Morreale, Spanish National Research Council and Autonomous University of Madrid (IIBM, CSIC-UAM), Madrid, Spain
- Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders (CIBERDEM); ISCIII, Madrid, Spain
| | - Aránzazu Sánchez
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
- Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Blanca Herrera
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
- Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Isabel Fabregat
- Oncobell Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet, Barcelona, Spain
- Biomedical Research Networking Center in CIBER in Hepatic and Digestive Diseases (CIBEREHD), ISCIII, Madrid, Spain
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Li YM, He HW, Zhang N. Targeting Protein Phosphatases for the Treatment of Chronic Liver Disease. Curr Drug Targets 2024; 25:171-189. [PMID: 38213163 DOI: 10.2174/0113894501278886231221092522] [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: 10/12/2023] [Revised: 11/27/2023] [Accepted: 11/29/2023] [Indexed: 01/13/2024]
Abstract
There exists a huge number of patients suffering from chronic liver disease worldwide. As a disease with high incidence and mortality worldwide, strengthening the research on the pathogenesis of chronic liver disease and the development of novel drugs is an important issue related to the health of all human beings. Phosphorylation modification of proteins plays a crucial role in cellular signal transduction, and phosphatases are involved in the development of liver diseases. Therefore, this article summarized the important role of protein phosphatases in chronic liver disease with the aim of facilitating the development of drugs targeting protein phosphatases for the treatment of chronic liver disease.
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Affiliation(s)
- Yi-Ming Li
- NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Hong-Wei He
- NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Na Zhang
- NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
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4
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Li W, Tan M, Wang H, Wang Z, Pang Y, Yang R, Zhong S, Pan X, Chen S, Wang Q, Li D, Xiao Y, Chen W, Chen L. METTL3-mediated m6A mRNA modification was involved in cadmium-induced liver injury. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 331:121887. [PMID: 37236586 DOI: 10.1016/j.envpol.2023.121887] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 05/12/2023] [Accepted: 05/23/2023] [Indexed: 05/28/2023]
Abstract
Cadmium is an environmental pollutant that has extensive deleterious effects. However, the mechanisms underlying the hepatotoxicity induced by long-term exposure to cadmium remained undefined. In the present study, we explored the role of m6A methylation in the development of cadmium-induced liver disease. We showed a dynamic change of RNA methylation in liver tissue from mice administrated with cadmium chloride (CdCl2) for 3, 6 and 9 months, respectively. Particularly, the METTL3 expression was declined in a time-dependent manner, associated with the degree of liver injury, indicating the involvement of METTL3 in hepatotoxicity induced by CdCl2. Moreover, we established a mouse model with liver-specific over-expression of Mettl3 and administrated these mice with CdCl2 for 6 months. Notably, METTL3 highly expressed in hepatocytes attenuated CdCl2-induced steatosis and liver fibrosis in mice. In vitro assay also showed METTL3 overexpression ameliorated the CdCl2-induced cytotoxicity and activation of primary hepatic stellate cells. Furthermore, transcriptome analysis identified 268 differentially expressed genes both in mice liver tissue treated with CdCl2 for 3 months and 9 months. Among them, 115 genes were predicted to be regulated by METTL3 determined by m6A2Target database. Further analysis revealed the perturbation of metabolic pathway, glycerophospholipid metabolism, ErbB signaling pathway, Hippo signaling pathway, and choline metabolism in cancer, and circadian rhythm, led to hepatotoxicity induced by CdCl2. Collectively, our findings reveal new insight into the crucial role of epigenetic modifications in hepatic diseases caused by long-term exposure to cadmium.
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Affiliation(s)
- Wenxue Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China; Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, 510440, China
| | - Mingxue Tan
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Huiqi Wang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Ziwei Wang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yaqin Pang
- Faculty of Toxicology, School of Public Health, Youjiang Medical College for Nationalities, Guangxi, 533000, China
| | - Rongfang Yang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Shiyuan Zhong
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xinhong Pan
- Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, 510440, China
| | - Shen Chen
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Qing Wang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Daochuan Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yongmei Xiao
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Wen Chen
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Liping Chen
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China.
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El Husseini K, Poté N, Jaillet M, Mordant P, Mal H, Frija-Masson J, Borie R, Cazes A, Crestani B, Mailleux A. [Adipocytes, adipokines and metabolic alterations in pulmonary fibrosis]. Rev Mal Respir 2023; 40:225-229. [PMID: 36740493 DOI: 10.1016/j.rmr.2023.01.016] [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: 01/05/2023] [Accepted: 01/06/2023] [Indexed: 02/07/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by severe remodeling of the lung parenchyma, with an accumulation of activated myofibroblasts and extracellular matrix, along with aberrant cellular differentiation. Within the subpleural fibrous zones, ectopic adipocyte deposits often appear. In addition, alterations in lipid homeostasis have been associated with IPF pathophysiology. In this mini-review, we will discuss the potential involvement of the adipocyte secretome and its paracrine or endocrine-based contribution to the pathophysiology of IPF, via protein or lipid mediators in particular.
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Affiliation(s)
- K El Husseini
- Service de pneumologie A, Hôpital Bichat, AP-HP ; Inserm Unit 1152, Université de Paris, Paris, France; Inserm Unité 1152 - PHERE, Université de Paris, Paris, France.
| | - N Poté
- Service d'anatomopathologie, Hôpital Bichat, AP-HP ; Inserm Unité 1152 - PHERE, Université de Paris, Paris, France
| | - M Jaillet
- Inserm Unité 1152 - PHERE, Université de Paris, Paris, France
| | - P Mordant
- Service de chirurgie vasculaire et thoracique, Hôpital Bichat, AP-HP, Paris, France
| | - H Mal
- Service de pneumologie B, Hôpital Bichat, AP-HP ; Inserm Unité 1152 - PHERE, Université de Paris, Paris, France
| | - J Frija-Masson
- Service de physiologie-explorations fonctionnelles respiratoires, Hôpital Bichat, AP-HP, Paris, France
| | - R Borie
- Service de pneumologie A, Hôpital Bichat, AP-HP ; Inserm Unit 1152, Université de Paris, Paris, France
| | - A Cazes
- Service d'anatomopathologie, Hôpital Bichat, AP-HP ; Inserm Unité 1152 - PHERE, Université de Paris, Paris, France
| | - B Crestani
- Service de pneumologie A, Hôpital Bichat, AP-HP ; Inserm Unit 1152, Université de Paris, Paris, France; Inserm Unité 1152 - PHERE, Université de Paris, Paris, France
| | - A Mailleux
- Inserm Unité 1152 - PHERE, Université de Paris, Paris, France
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Manipulating PP2Acα-ASK-JNK signaling to favor apoptotic over necroptotic hepatocyte fate reduces the extent of necrosis and fibrosis upon acute liver injury. Cell Death Dis 2022; 13:985. [PMID: 36418313 PMCID: PMC9684557 DOI: 10.1038/s41419-022-05353-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 10/13/2022] [Accepted: 10/17/2022] [Indexed: 11/24/2022]
Abstract
In the widely used Carbon tetrachloride (CCl4)-induced acute liver injury (ALI) mouse model, hepatocytes are known to die from programmed cell death (PCD) processes including apoptosis and necroptosis. Both in vivo and in vitro experiments showed that CCl4 treatment could induce both apoptosis and necroptosis. Treatment of mice with the apoptosis inducer SMAC mimetic reduced necroptosis, led to less pronounced liver damage, and improved overall liver function. By LC-MS/MS, we found that PP2Acα expression was increased in ALI mice liver, and we confirmed its high expression in subacute hepatitis patients. We observed that ALI severity (including aggravated fibrogenesis) was significantly alleviated in hepatocyte-specific PP2Acα conditional knockout (PP2Acα cKO) mice. Furthermore, the relative extent of apoptosis over necroptosis was increased in the PP2Acα cKO ALI mice. Pursuing the idea that biasing the type of PCD towards apoptosis may reduce liver damage, we found that treatment of PP2Acα cKO ALI mice with the apoptosis inhibitor z-Vad-fmk increased the extent of necroptosis and caused severer damage. Mechanistically, disruption of PP2Acα prevents the dephosphorylation of pASK1(Ser967), thereby preventing the sustained activation of JNK. Inhibition of PP2Acα prevents CCl4-induced liver injury and fibrogenesis by disrupting ASK/JNK pathway mediated PCD signaling, ultimately improving liver function by biasing hepatocytes towards an apoptotic rather than necroptotic cell fate. Thus, targeting PP2A and/or ASK1 to favor apoptotic over necroptotic hepatocyte fate may represent an attractive therapeutic strategy for treating ALI.
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You Y, Gao C, Wu J, Qu H, Xiao Y, Kang Z, Li J, Hong J. Enhanced Expression of ARK5 in Hepatic Stellate Cell and Hepatocyte Synergistically Promote Liver Fibrosis. Int J Mol Sci 2022; 23:ijms232113084. [PMID: 36361872 PMCID: PMC9655442 DOI: 10.3390/ijms232113084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/18/2022] [Accepted: 10/22/2022] [Indexed: 11/22/2022] Open
Abstract
AMPK-related protein kinase 5 (ARK5) is involved in a broad spectrum of physiological and cell events, and aberrant expression of ARK5 has been observed in a wide variety of solid tumors, including liver cancer. However, the role of ARK5 in liver fibrosis remains largely unexplored. We found that ARK5 expression was elevated in mouse fibrotic livers, and showed a positive correlation with the progression of liver fibrosis. ARK5 was highly expressed not only in activated hepatic stellate cells (HSCs), but also in hepatocytes. In HSCs, ARK5 prevents the degradation of transforming growth factor β type I receptor (TβRI) and mothers against decapentaplegic homolog 4 (Smad4) proteins by inhibiting the expression of Smad ubiquitin regulatory factor 2 (Smurf2), thus maintaining the continuous transduction of the transforming growth factor β (TGF-β) signaling pathway, which is essential for cell activation, proliferation and survival. In hepatocytes, ARK5 induces the occurrence of epithelial-mesenchymal transition (EMT), and also promotes the secretion of inflammatory factors. Inflammatory factors, in turn, further enhance the activation of HSCs and deepen the degree of liver fibrosis. Notably, we demonstrated in a mouse model that targeting ARK5 with the selective inhibitor HTH-01-015 attenuates CCl4-induced liver fibrosis in mice. Taken together, the results indicate that ARK5 is a critical driver of liver fibrosis, and promotes liver fibrosis by synergy between HSCs and hepatocytes.
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Affiliation(s)
- Yang You
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China
| | - Chongqing Gao
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China
| | - Junru Wu
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China
| | - Hengdong Qu
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China
| | - Yang Xiao
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China
- Department of Hepatological Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China
| | - Ziwei Kang
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China
| | - Jinying Li
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China
| | - Jian Hong
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China
- Department of Hepatological Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China
- Correspondence: ; Tel.: +86-20-8522-0253
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Shi X, Wang J, Zhang X, Yang S, Luo W, Wang S, Huang J, Chen M, Cheng Y, Chao J. GREM1/PPP2R3A expression in heterogeneous fibroblasts initiates pulmonary fibrosis. Cell Biosci 2022; 12:123. [PMID: 35933397 PMCID: PMC9356444 DOI: 10.1186/s13578-022-00860-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 07/22/2022] [Indexed: 11/22/2022] Open
Abstract
Background Fibroblasts have important roles in the synthesis and remodeling of extracellular matrix (ECM) proteins during pulmonary fibrosis. However, the spatiotemporal distribution of heterogeneous fibroblasts during disease progression remains unknown. Results In the current study, silica was used to generate a mouse model of pathological changes in the lung, and single-cell sequencing, spatial transcriptome sequencing and an analysis of markers of cell subtypes were performed to identify fibroblast subtypes. A group of heterogeneous fibroblasts that play an important role at the early pathological stage were identified, characterized based on the expression of inflammatory and proliferation genes (termed inflammatory-proliferative fibroblasts) and found to be concentrated in the lesion area. The expression of GREM1/protein phosphatase 2 regulatory subunit B''alpha (PPP2R3A) in inflammatory-proliferative fibroblasts was found to initiate early pulmonary pathological changes by increasing the viability, proliferation and migration of cells. Conclusions Inflammatory-proliferative fibroblasts play a key role in the early pathological changes that occur in silicosis, and during this process, GREM1 is the driving factor that targets PPP2R3A and initiates the inflammatory response, which is followed by irreversible fibrosis induced by SiO2. The GREM1/PPP2R3A pathway may be a potential target in the early treatment of silicosis. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00860-0.
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Luo N, Zhong W, Li J, Zhai Z, Lu J, Dong R. Targeted activation of HNF4α/HGF1/FOXA2 reverses hepatic fibrosis via exosome-mediated delivery of CRISPR/dCas9-SAM system. Nanomedicine (Lond) 2022; 17:1411-1427. [PMID: 36326013 DOI: 10.2217/nnm-2022-0083] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Aim: Hepatic fibrosis is one of the most common conditions worldwide, and yet no effective antifibrotic therapy is available. This study aimed to reverse hepatic fibrosis via exosome-mediated delivery of the CRISPR/dCas9-SAM system. Materials & methods: The authors constructed a modified-exosome delivery system targeting hepatic stellate cells (HSCs), and constructed the CRISPR/dCas9-SAM system inducing HSCs convert into hepatocyte-like cells in vitro and in vivo. Results: RBP4-modified exosomes could efficiently load and deliver the CRISPR/dCas9 system to HSCs. The in vitro CRISPR/dCas9 system induced the conversion from HSCs to hepatocyte-like cells via targeted activation of HNF4α/HGF1/FOXA2 genes. Importantly, in vivo targeted delivery of this system significantly attenuated CCl4-induced hepatic fibrosis. Conclusion: Targeted activation of HNF4α/HGF1/FOXA2 reverses hepatic fibrosis via exosome-mediated delivery of the CRISPR/dCas9-SAM system, which provides a feasible antifibrotic strategy.
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Affiliation(s)
- Nianan Luo
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.,Department of General Surgery, 943 Hospital of PLA, Wuwei, 733000, China
| | - Wenjun Zhong
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.,School of Clinical Medicine, Xi'an Medical University, Xi'an, 710032, China
| | - Jiangbin Li
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Zhongjie Zhai
- Department of Military Preventive Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Jianguo Lu
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Rui Dong
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
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10
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Deletion of p38γ attenuates ethanol consumption- and acetaminophen-induced liver injury in mice through promoting Dlg1. Acta Pharmacol Sin 2022; 43:1733-1748. [PMID: 34789918 PMCID: PMC9253030 DOI: 10.1038/s41401-021-00795-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 10/12/2021] [Indexed: 12/13/2022]
Abstract
Acetaminophen (APAP) is one of the major causes of drug-induced acute liver injury, and ethanol may aggravate APAP-induced liver injury. The problem of ethanol- and APAP-induced liver injury becomes increasingly prominent, but the mechanism of ethanol- and APAP-induced liver injury remains ambiguous. p38γ is one of the four isoforms of P38 mitogen activated protein kinases, that contributes to inflammation in different diseases. In this study we investigated the role of p38γ in ethanol- and APAP-induced liver injury. Liver injury was induced in male C57BL/6 J mice by giving liquid diet containing 5% ethanol (v/v) for 10 days, followed by gavage of ethanol (25% (v/v), 6 g/kg) once or injecting APAP (200 mg/kg, ip), or combined the both treatments. We showed that ethanol significantly aggravated APAP-induced liver injury in C57BL/6 J mice. Moreover, the expression level of p38γ was up-regulated in the liver of ethanol-, APAP- and ethanol+APAP-treated mice. Knockdown of p38γ markedly attenuated liver injury, inflammation, and steatosis in ethanol+APAP-treated mice. Liver sections of p38γ-knockdown mice displayed lower levels of Oil Red O stained dots and small leaky shapes. AML-12 cells were exposed to APAP (5 mM), ethanol (100 mM) or combined treatments. We showed that P38γ was markedly increased in ethanol+APAP-treated AML-12 cells, whereas knockdown of p38γ significantly inhibited inflammation, lipid accumulation and oxidative stress in ethanol+APAP-treated AML-12 cells. Furthermore, we revealed that p38γ could combine with Dlg1, a member of membrane-associated guanylate kinase family. Deletion of p38γ up-regulated the expression level of Dlg1 in ethanol+APAP-treated AML-12 cells. In summary, our results suggest that p38γ functions as an important regulator in ethanol- and APAP-induced liver injury through modulation of Dlg1.
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11
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Maitiabula G, Tian F, Wang P, Zhang L, Gao X, Wan S, Sun H, Yang J, Zhang Y, Gao T, Xue B, Li C, Li J, Wang X. Liver PP2A-Cα Protects From Parenteral Nutrition-associated Hepatic Steatosis. Cell Mol Gastroenterol Hepatol 2022; 14:669-692. [PMID: 35643235 PMCID: PMC9421584 DOI: 10.1016/j.jcmgh.2022.05.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 05/18/2022] [Accepted: 05/18/2022] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Parenteral nutrition (PN) is a lifesaving therapy for patients with intestinal failure. Hepatic steatosis is a potentially fatal complication of long-term PN, but the involved pathological mechanisms are incompletely unclarified. Herein, we identify the role of protein phosphatase 2A (PP2A) in the pathogenesis of parenteral nutrition-associated hepatic steatosis (PNAHS). METHODS Proteomic/phosphoproteomic analyses of liver samples from patients with PNAHS were applied to identify the mechanism of PNAHS. Total parenteral nutrition (TPN) mice model, in vivo, and in vitro experiments were used to assess the effect of PP2A-Cα on liver fatty acid metabolism. RESULTS Reduced expression of PP2A-Cα (catalytic subunit) enhanced activation of serine/threonine kinase Akt2 and decreased activation of adenosine monophosphate-activated protein kinase (AMPK) were associated with hepatic steatosis in patients with PNAHS. Mice given PN for 14 days developed hepatic steatosis, down-regulation of PP2A-Cα, activation of Akt2, and inhibition of AMPK. Hepatocyte-specific deletion of PP2A-Cα in mice given PN exacerbated Akt2 activation, AMPK inhibition, and hepatic steatosis through an effect on fatty acid degradation, whereas hepatocyte-specific PP2A-Cα overexpression significantly ameliorated hepatic steatosis accompanied with Akt2 suppression and AMPK activation. Additionally, pharmacological activation of Akt2 in mice overexpressing PP2A-Cα led to the aggravation of hepatic steatosis. CONCLUSIONS Our findings demonstrate that hepatic PP2A-Cα serves as a protective factor of PNAHS due to ameliorating hepatic steatosis and improving liver function. Our study provides a strong rationale that PP2A-Cα may be involved in the pathogenesis of PNAHS.
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Affiliation(s)
- Gulisudumu Maitiabula
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Feng Tian
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Peng Wang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Li Zhang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xuejin Gao
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Songlin Wan
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Haifeng Sun
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jianbo Yang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yupeng Zhang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Tingting Gao
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Bin Xue
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of the Medical School of Nanjing University, Nanjing, China,Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China,Bin Xue, PhD, LongMian Avenue, Nanjing 211166, China. tel: +86-25-87115542
| | - Chaojun Li
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of the Medical School of Nanjing University, Nanjing, China,Chaojun Li, PhD, Hankou Road, Nanjing, 210093, China. tel: +86-25-83596289.
| | - Jieshou Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xinying Wang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China,Correspondence Address correspondence to: Xinying Wang, MD, PhD, Department of General Surgery, Jinling Hospital, Medical School of Nanjing University. 305 East Zhongshan Road, Nanjing, 210002, China. tel: +86-25-80861429
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12
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Erratum for Chen et al. Perturbation of specific signaling pathways is involved in initiation of mouse liver fibrosis. Hepatology 2022; 75:1360-1361. [PMID: 35318702 DOI: 10.1002/hep.32377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 01/27/2022] [Indexed: 12/08/2022]
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13
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Chen L, Guo P, Li W, Jiang X, Zhao Q, Li D, Wang Q, Xiao Y, Xing X, Pang Y, Aschner M, Zhang L, Chen W. Protein phosphatase 2A regulates cytotoxicity and drug resistance by dephosphorylating xenobiotic metabolism enzymes AHR and MDR1. J Biol Chem 2022; 298:101918. [PMID: 35405096 PMCID: PMC9118923 DOI: 10.1016/j.jbc.2022.101918] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/26/2022] [Accepted: 03/28/2022] [Indexed: 11/20/2022] Open
Abstract
Protein phosphatase 2A (PP2A) is a serine/threonine dephosphorylating enzyme complex that plays numerous roles in biological processes, including cell growth and metabolism. However, its specific actions in many of these critical pathways are unclear. To explore mechanisms underlying metabolic enzyme regulation in the liver, we investigated the key pathways involved in regulation of xenobiotic-metabolizing enzymes in a mouse model with hepatocyte-specific deletion of Ppp2r1a, encoding the Aα subunit of PP2A. We performed transcriptome and phosphoproteome analysis in mouse livers at the age of 3 months and identified 2695 differentially expressed genes and 549 upregulated phosphoproteins in homozygous knockout mouse livers compared with WT littermates. In particular, the expression of metabolic enzymes Cyp2e1, Cyp1a1, Cyp1a2, Mdr1a, and Abcg2 was dramatically altered in homozygous knockout mouse livers. We also demonstrated that activation of PP2A reversed the decline of metabolic enzyme expression in primary mouse hepatocytes. We found that specific PP2A holoenzymes were involved in metabolic enzyme induction through dephosphorylation of transcription factors, nuclear receptors, or the target enzymes themselves, leading to dysregulation of xenobiotic metabolism or drug-induced hepatotoxicity. Notably, we confirmed that a regulatory axis, PP2A B56α–aryl hydrocarbon receptor–Cyp1a1, was involved in benzo(a)pyrene-induced cytotoxicity through dephosphorylation of the metabolic nuclear receptor, aryl hydrocarbon receptor, at serine 36. In addition, we showed that PP2A B56δ complexes directly dephosphorylated the multidrug efflux pump MDR1 (encoded by multi-drug resistance gene 1), contributing to drug resistance against the chemotherapeutic 5-fluorouracil. Taken together, these novel findings demonstrate the involvement of PP2A in the regulation of liver metabolism.
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Affiliation(s)
- Liping Chen
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Ping Guo
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Wenxue Li
- Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou 510440, China
| | - Xinhang Jiang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Qun Zhao
- Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Science, National Chromatographic Research and Analysis Center, Dalian 116023, China
| | - Daochuan Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Qing Wang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Yongmei Xiao
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Xiumei Xing
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Yaqin Pang
- Faculty of Toxicology, School of Public Health, Youjiang Medical College for Nationalities, Guangxi 533000, China
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer 209, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Lihua Zhang
- Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Science, National Chromatographic Research and Analysis Center, Dalian 116023, China.
| | - Wen Chen
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
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Liu Y, Li Y, Liang J, Sun Z, Wu Q, Liu Y, Sun C. Leptin: an entry point for the treatment of peripheral tissue fibrosis and related diseases. Int Immunopharmacol 2022; 106:108608. [PMID: 35180626 DOI: 10.1016/j.intimp.2022.108608] [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: 11/25/2021] [Revised: 01/24/2022] [Accepted: 02/02/2022] [Indexed: 11/26/2022]
Abstract
Leptin is a small peptide mainly secreted by adipocyte, which acts on the central nervous system of the hypothalamus to regulate the body's energy balance by inhibiting food intake, it also can directly act on specific cells through leptin receptors (for example, ObRa, which exists in the blood-brain barrier or kidneys), thereby affect cell metabolism. Excessive deposition of extracellular matrix (ECM) causes damage to normal tissues or destruction of organ structure, which will eventually lead to tissue or organ fibrosis. The sustainable development of fibrosis can lead to structural damage and functional decline of organs, and even exhaustion, which seriously threatens human health and life. In recent years, studies have found that leptin directly alleviates the fibrosis process of various tissues and organs in mammals. Therefore, we speculate that leptin may become a significant treatment for fibrosis of various tissues and organs in the future. So, the main purpose of this review is to explore the specific mechanism of leptin in the process of fibrosis in multiple tissues and organs, and to provide a theoretical basis for the treatment of various tissues and organs fibrosis and related diseases caused by it, which is of great significance in the future.
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Affiliation(s)
- Yuexia Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Yizhou Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Juntong Liang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Zhuwen Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Qiong Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China; Medical College, Qinghai University, Xining, 810000, China.
| | - Yongnian Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China; Medical College, Qinghai University, Xining, 810000, China.
| | - Chao Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
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Feng NN, Du XY, Zhang YS, Jiao ZK, Wu XH, Yang BM. Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma. Front Endocrinol (Lausanne) 2022; 13:1061091. [PMID: 36714595 PMCID: PMC9877416 DOI: 10.3389/fendo.2022.1061091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 12/13/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUNDS The pandemic of overweight and obesity (quantified by body mass index (BMI) ≥ 25) has rapidly raised the patient number of non-alcoholic fatty hepatocellular carcinoma (HCC), and several clinical trials have shown that BMI is associated with the prognosis of HCC. However, whether overweight/obesity is an independent prognostic factor is arguable, and the role of overweight/obesity-related metabolisms in the progression of HCC is scarcely known. MATERIALS AND METHODS In the present study, clinical information, mRNA expression profile, and genomic data were downloaded from The Cancer Genome Atlas (TCGA) as a training cohort (TCGA-HCC) for the identification of overweight/obesity-related transcriptome. Machine learning and the Cox regression analysis were conducted for the construction of the overweight/obesity-associated gene (OAG) signature. The Kaplan-Meier curve, receiver operating characteristic (ROC) curve, and the Cox regression analysis were performed to assess the prognostic value of the OAG signature, which was further validated in two independent retrospective cohorts from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). Subsequently, functional enrichment, genomic profiling, and tumor microenvironment (TME) evaluation were utilized to characterize biological activities associated with the OAG signature. GSE109211 and GSE104580 were retrieved to evaluate the underlying response of sorafenib and transcatheter arterial chemoembolization (TACE) treatment, respectively. The Genomics of Drug Sensitivity in Cancer (GDSC) database was employed for the evaluation of chemotherapeutic response. RESULTS Overweight/obesity-associated transcriptome was mainly involved in metabolic processes and noticeably and markedly correlated with prognosis and TME of HCC. Afterward, a novel established OAG signature (including 17 genes, namely, GAGE2D, PDE6A, GABRR1, DCAF8L1, DPYSL4, SLC6A3, MMP3, RIBC2, KCNH2, HTRA3, PDX1, ATHL1, PRTG, SHC4, C21orf29, SMIM32, and C1orf133) divided patients into high and low OAG score groups with distinct prognosis (median overall survival (OS): 24.87 vs. 83.51 months, p < 0.0001), and the values of area under ROC curve (AUC) in predicting 1-, 2-, 3-, and 4-year OS were 0.81, 0.80, 0.83, and 0.85, respectively. Moreover, the OAG score was independent of clinical features and also exhibited a good ability for prognosis prediction in the ICGC-LIHC-JP cohort and GSE54236 dataset. Expectedly, the OAG score was also highly correlated with metabolic processes, especially oxidative-related signaling pathways. Furthermore, abundant enrichment of chemokines, receptors, MHC molecules, and other immunomodulators as well as PD-L1/PD-1 expression among patients with high OAG scores indicated that they might have better responses to immunotherapy. However, probably exclusion of T cells from infiltrating tumors resulting in lower infiltration of effective T cells would restrict immunotherapeutic effects. In addition, the OAG score was significantly associated with the response of sorafenib and TACE treatment. CONCLUSIONS Overall, this study comprehensively disclosed the relationship between BMI-guided transcriptome and HCC. Moreover, the OAG signature had the potential clinical applications in the future to promote clinical management and precision medicine of HCC.
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Affiliation(s)
- Ning-Ning Feng
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xi-Yue Du
- Department of Radiotherapy, Hengshui People’s Hospital, Hengshui, Hebei, China
| | - Yue-Shan Zhang
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhi-Kai Jiao
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiao-Hui Wu
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Bao-Ming Yang
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- *Correspondence: Bao-Ming Yang, ;
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The Mechanism of Leptin on Inhibiting Fibrosis and Promoting Browning of White Fat by Reducing ITGA5 in Mice. Int J Mol Sci 2021; 22:ijms222212353. [PMID: 34830238 PMCID: PMC8618604 DOI: 10.3390/ijms222212353] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/10/2021] [Accepted: 11/13/2021] [Indexed: 12/15/2022] Open
Abstract
Leptin is a small molecule protein secreted by adipocytes, which can promote white fat browning through activating the hypothalamic nervous system and inhibiting downstream signaling pathways. Moreover, white fat browning has been proven to alleviate fat tissue fibrosis. This study explores the mechanism of leptin in regulating adipose tissue fibrosis and white fat browning. After treating mice with leptin, we screened out the recombinant integrin alpha 5 (ITGA5) through proteomics sequencing, which may play a role in adipose tissue fibrosis. Through real-time quantitative PCR (qPCR), western blotting (WB), hematoxylin-eosin (HE) staining, Masson’s trichrome, immunofluorescence, immunohistochemistry, etc., the results showed that after leptin treated adipocytes, the expression of fibrosis-related genes and ITGA5 was significantly down-regulated in adipocytes. We constructed fibrosis model through transforming growth factor-β (TGF-β) and a high-fat diet (HFD), and treated with ITGA5 overexpression vector and interference fragments. The results indicated the expression of fibrosis-related genes were significantly down-regulated after interfering with ITGA5. After treating adipocytes with wortmannin, fibrosis-related gene expression was inhibited after overexpression of ITGA5. Moreover, after injecting mice with leptin, we also found that leptin significantly up-regulated the expression of adipose tissue browning-related genes. Overall, our research shows that leptin can inhibit the activation of phosphatidylinositol 3 kinase (PI3K)-protein kinase B (AKT) signaling pathway by reducing the expression of ITGA5, which could alleviate adipose tissue fibrosis, and further promote white fat browning. Our research provides a theoretical basis for further research on the effect of leptin in fibrosis-related adipose tissue metabolism.
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