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1
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Ou LL, Jiang JL, Guo ML, Wu JH, Zhong WW, He YH. Research progress on the roles of complement in liver injury. World J Hepatol 2025; 17:103839. [DOI: 10.4254/wjh.v17.i3.103839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/29/2025] [Accepted: 02/27/2025] [Indexed: 03/26/2025] Open
Abstract
The complement system is crucial for maintaining immunological homeostasis in the liver, playing a significant role in both innate and adaptive immune responses. Dysregulation of this system is closely linked to the pathogenesis of various liver diseases. Modulating the complement system can affect the progression of these conditions. To provide insights into treating liver injury by targeting the regulation of the complement system, we conducted a comprehensive search of major biomedical databases, including MEDLINE, PubMed, EMBASE, and Web of Science, to identify articles on complement and liver injury and reviewed the functions and mechanisms of the complement system in liver injury.
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Affiliation(s)
- Li-Li Ou
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Jin-Lian Jiang
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Man-Lu Guo
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Jin-Hua Wu
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Wei-Wei Zhong
- Department of Infectious Diseases, Jingmen Central Hospital, Jingmen Central Hospital Affiliated to Jingchu University of Technology, Jingmen 448000, Hubei Province, China
| | - Yi-Huai He
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
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Raya Tonetti F, Eguileor A, Mrdjen M, Pathak V, Travers J, Nagy LE, Llorente C. Gut-liver axis: Recent concepts in pathophysiology in alcohol-associated liver disease. Hepatology 2024; 80:1342-1371. [PMID: 38691396 PMCID: PMC11801230 DOI: 10.1097/hep.0000000000000924] [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] [Received: 02/13/2024] [Accepted: 04/20/2024] [Indexed: 05/03/2024]
Abstract
The growing recognition of the role of the gut microbiome's impact on alcohol-associated diseases, especially in alcohol-associated liver disease, emphasizes the need to understand molecular mechanisms involved in governing organ-organ communication to identify novel avenues to combat alcohol-associated diseases. The gut-liver axis refers to the bidirectional communication and interaction between the gut and the liver. Intestinal microbiota plays a pivotal role in maintaining homeostasis within the gut-liver axis, and this axis plays a significant role in alcohol-associated liver disease. The intricate communication between intestine and liver involves communication between multiple cellular components in each organ that enable them to carry out their physiological functions. In this review, we focus on novel approaches to understanding how chronic alcohol exposure impacts the microbiome and individual cells within the liver and intestine, as well as the impact of ethanol on the molecular machinery required for intraorgan and interorgan communication.
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Affiliation(s)
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Marko Mrdjen
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | - Vai Pathak
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jared Travers
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Department of Gastroenterology and Hepatology, University Hospital, Cleveland OH
| | - Laura E Nagy
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland OH
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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3
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Li Y, Horst K, Greven J, Mert Ü, Lupu L, Palmer A, Doerfer L, Zhao Q, Zhang X, Halbgebauer R, Ignatius A, Marzi I, van Griensven M, Balmayor E, Hildebrand F, Mollnes TE, Huber-Lang M. Modulation of the hepatic RANK-RANKL-OPG axis by combined C5 and CD14 inhibition in a long-term polytrauma model. Front Immunol 2024; 15:1434274. [PMID: 39640261 PMCID: PMC11617561 DOI: 10.3389/fimmu.2024.1434274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 10/30/2024] [Indexed: 12/07/2024] Open
Abstract
Background Polytrauma and hemorrhagic shock can lead to direct and indirect liver damage involving intricate pathophysiologic mechanisms. While hepatic function has been frequently highlighted, there is minimal research on how the receptor activator of the NF-κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system is regulated in the liver following trauma. Furthermore, cross-talking complement and toll-like-receptor (TLR) systems can contribute to the posttraumatic response. Therefore, we investigated the hepatic consequences of polytrauma focusing on the RANK-RANKL-OPG axis, and evaluated the effects of a dual blockade of complement factor C5 and TLR-cofactor CD14 on hepatic features. Methods The established pig model of polytrauma (PT) and hemorrhagic shock included pulmonary contusion, hepatic dissection, and bilateral femur fractures, surgically addressed either by external fixation (Fix ex) or intramedullary nailing (Nail). Four groups were investigated: 1) sham animals; 2) PT treated by Fix ex (Fix ex); 3) PT by Nail (Nail); or 4) PT by Nail plus combined C5/CD14 inhibition (Nail+Therapy). Serum samples were obtained between 0 - 72 h, and liver samples at 72 h after PT. Liver tissues were histologically scored and subjected to RT-qPCR-analyses, immunohistochemistry and ELISAs to evaluate the posttraumatic hepatic response with a focus on the RANK-RANKL-OPG system. Results Following PT, the liver injury score of the Nail+Therapy group was significantly lower than in the Fix ex or Nail group without immunomodulation (p<0.05). Similarly, the degree of necrosis, lobular stasis, and inflammation were significantly reduced when treated with C5/CD14-inhibitors. Compared to the Nail group, AST serum concentrations were significantly decreased in the Nail+Therapy group after 72 h (p<0.05). PCR analyses indicated that RANK, RANKL, and OPG levels in the liver were increased after PT in the Nail group compared to lower levels in the Nail+Therapy group. Furthermore, liver tissue analyses revealed increased RANK protein levels and cellular immunostaining for RANK in the Nail group, both of which were significantly reduced in the case of C5/CD14-inhibition (p<0.05). Conclusion Following experimental PT, dual inhibition of C5/CD14 resulted in altered, mainly reduced hepatic synthesis of proteins relevant to bone repair. However, a comprehensive investigation of the subsequent effects on the liver-bone axis are needed.
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Affiliation(s)
- Yang Li
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Klemens Horst
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Johannes Greven
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Ümit Mert
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Ludmila Lupu
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Annette Palmer
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Lena Doerfer
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Qun Zhao
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Xing Zhang
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Rebecca Halbgebauer
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Anita Ignatius
- Institute of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Ingo Marzi
- Department of Trauma, Hand, and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany
| | - Martijn van Griensven
- The Department of Cell Biology-Inspired Tissue Engineering (cBITE), MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, Netherlands
| | - Elizabeth Balmayor
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Frank Hildebrand
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Tom Eirik Mollnes
- Department of Immunology, Oslo University Hospital, University of Oslo, Oslo, Norway
- Research Laboratory, Nordland Hospital Bodø, Bodø, Norway
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
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4
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Prado LG, Nagy LE. Role of Complement in Liver Diseases. Semin Liver Dis 2024; 44:510-522. [PMID: 39608405 DOI: 10.1055/s-0044-1795143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Abstract
This review aims to summarize recent research using animal models, cell models, and human data regarding the role of complement in liver disease. Complement is part of the innate immune system and was initially characterized for its role in control of pathogens. However, evidence now indicates that complement also plays an important role in the response to cellular injury that is independent of pathogens. The liver is the main organ responsible for producing circulating complement. In response to liver injury, complement is activated and likely plays a dual role, both contributing to and protecting from injury. In uncontrolled complement activation, cell injury and liver inflammation occur, contributing to progression of liver disease. Complement activation is implicated in the pathogenesis of multiple liver diseases, including alcohol-associated liver disease, metabolic dysfunction-associated steatotic liver disease, fibrosis and cirrhosis, hepatocellular carcinoma, and autoimmune hepatitis. However, the mechanisms by which complement is overactivated in liver diseases are still being unraveled.
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Affiliation(s)
- Luan G Prado
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
| | - Laura E Nagy
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
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Jiang H, Guo Y, Wang Q, Wang Y, Peng D, Fang Y, Yan L, Ruan Z, Zhang S, Zhao Y, Zhang W, Shang W, Feng Z. The dysfunction of complement and coagulation in diseases: the implications for the therapeutic interventions. MedComm (Beijing) 2024; 5:e785. [PMID: 39445002 PMCID: PMC11496570 DOI: 10.1002/mco2.785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 09/16/2024] [Accepted: 09/18/2024] [Indexed: 10/25/2024] Open
Abstract
The complement system, comprising over 30 proteins, is integral to the immune system, and the coagulation system is critical for vascular homeostasis. The activation of the complement and coagulation systems involves an organized proteolytic cascade, and the overactivation of these systems is a central pathogenic mechanism in several diseases. This review describes the role of complement and coagulation system activation in critical illness, particularly sepsis. The complexities of sepsis reveal significant knowledge gaps that can be compared to a profound abyss, highlighting the urgent need for further investigation and exploration. It is well recognized that the inflammatory network, coagulation, and complement systems are integral mechanisms through which multiple factors contribute to increased susceptibility to infection and may result in a disordered immune response during septic events in patients. Given the overlapping pathogenic mechanisms in sepsis, immunomodulatory therapies currently under development may be particularly beneficial for patients with sepsis who have concurrent infections. Herein, we present recent findings regarding the molecular relationships between the coagulation and complement pathways in the advancement of sepsis, and propose potential intervention targets related to the crosstalk between coagulation and complement, aiming to provide more valuable treatment of sepsis.
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Affiliation(s)
- Honghong Jiang
- Faculty of Pediatrics, the Seventh Medical Center of Chinese PLA General HospitalNational Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing Key Laboratory of Pediatric Organ FailureBeijingChina
| | - Yiming Guo
- Department of Biological Science, The Dietrich School of Arts and SciencesUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Qihang Wang
- Department of Obstetrics and GynecologyThe Seventh Medical Center of Chinese PLA General HospitalBeijingChina
| | - Yiran Wang
- Department of Obstetrics and GynecologyThe sixth Medical Center of Chinese PLA General HospitalBeijingChina
| | - Dingchuan Peng
- School of MedicineSouth China University of TechnologyGuangzhouChina
| | - Yigong Fang
- Institute of Acupuncture and MoxibustionChina Academy of Chinese Medical SciencesBeijingChina
| | - Lei Yan
- Faculty of Pediatrics, the Seventh Medical Center of Chinese PLA General HospitalNational Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing Key Laboratory of Pediatric Organ FailureBeijingChina
| | - Zhuolin Ruan
- Department of Obstetrics and Gynecology，Chinese PLA General HospitalBeijingChina
| | - Sheng Zhang
- Faculty of Pediatrics, the Seventh Medical Center of Chinese PLA General HospitalNational Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing Key Laboratory of Pediatric Organ FailureBeijingChina
| | - Yong Zhao
- Department of Obstetrics and GynecologyThe Seventh Medical Center of Chinese PLA General HospitalBeijingChina
| | - Wendan Zhang
- Faculty of Pediatrics, the Seventh Medical Center of Chinese PLA General HospitalNational Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing Key Laboratory of Pediatric Organ FailureBeijingChina
| | - Wei Shang
- Faculty of Pediatrics, the Seventh Medical Center of Chinese PLA General HospitalNational Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing Key Laboratory of Pediatric Organ FailureBeijingChina
- Department of Obstetrics and GynecologyThe Seventh Medical Center of Chinese PLA General HospitalBeijingChina
| | - Zhichun Feng
- Faculty of Pediatrics, the Seventh Medical Center of Chinese PLA General HospitalNational Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing Key Laboratory of Pediatric Organ FailureBeijingChina
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Zheng Y, Wang Y, Xiong X, Zhang L, Zhu J, Huang B, Liu X, Liu J, Zhu Z, Yang G, Qu H, Zheng H. CD9 Counteracts Liver Steatosis and Mediates GCGR Agonist Hepatic Effects. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400819. [PMID: 38837628 PMCID: PMC11304330 DOI: 10.1002/advs.202400819] [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: 01/23/2024] [Revised: 05/04/2024] [Indexed: 06/07/2024]
Abstract
Glucagon receptor (GCGR) agonism offers potentially greater effects on the mitigation of hepatic steatosis. However, its underlying mechanism is not fully understood. Here, it screened tetraspanin CD9 might medicate hepatic effects of GCGR agonist. CD9 is decreased in the fatty livers of patients and upregulated upon GCGR activation. Deficiency of CD9 in the liver exacerbated diet-induced hepatic steatosis via complement factor D (CFD) regulated fatty acid metabolism. Specifically, CD9 modulated hepatic fatty acid synthesis and oxidation genes through regulating CFD expression via the ubiquitination-proteasomal degradation of FLI1. In addition, CD9 influenced body weight by modulating lipogenesis and thermogenesis of adipose tissue through CFD. Moreover, CD9 reinforcement in the liver alleviated hepatic steatosis, and blockage of CD9 abolished the remission of hepatic steatosis induced by cotadutide treatment. Thus, CD9 medicates the hepatic beneficial effects of GCGR signaling, and may server as a promising therapeutic target for hepatic steatosis.
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Affiliation(s)
- Yi Zheng
- Department of EndocrinologyTranslational Research of Diabetes Key Laboratory of Chongqing Education Commission of Chinathe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Yuren Wang
- Department of EndocrinologyTranslational Research of Diabetes Key Laboratory of Chongqing Education Commission of Chinathe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Xin Xiong
- Department of EndocrinologyTranslational Research of Diabetes Key Laboratory of Chongqing Education Commission of Chinathe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Linlin Zhang
- Department of EndocrinologyTranslational Research of Diabetes Key Laboratory of Chongqing Education Commission of Chinathe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Jiaran Zhu
- Department of EndocrinologyTranslational Research of Diabetes Key Laboratory of Chongqing Education Commission of Chinathe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Bangliang Huang
- Department of EndocrinologyTranslational Research of Diabetes Key Laboratory of Chongqing Education Commission of Chinathe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Xiufei Liu
- Department of EndocrinologyTranslational Research of Diabetes Key Laboratory of Chongqing Education Commission of Chinathe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Jinbo Liu
- Department of EndocrinologyQilu Hospital of Shandong UniversityJinan250012China
| | - Zhiming Zhu
- Department of Hypertension and Endocrinologythe Third Affiliated Hospital of Army Medical UniversityChongqing400042China
| | - Gangyi Yang
- Department of Endocrinologythe Second Affiliated Hospital of Chongqing Medical UniversityChongqing400010China
| | - Hua Qu
- Department of EndocrinologyTranslational Research of Diabetes Key Laboratory of Chongqing Education Commission of Chinathe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Hongting Zheng
- Department of EndocrinologyTranslational Research of Diabetes Key Laboratory of Chongqing Education Commission of Chinathe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
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Peng J, Liang G, Li Y, Mao S, Zhang C, Wang Y, Li Z. Identification of a novel FOXO3 agonist that protects against alcohol induced liver injury. Biochem Biophys Res Commun 2024; 704:149690. [PMID: 38387326 DOI: 10.1016/j.bbrc.2024.149690] [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: 11/08/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 02/24/2024]
Abstract
Alcohol-related liver disease (ALD) is a global healthcare concern which caused by excessive alcohol consumption with limited treatment options. The pathogenesis of ALD is complex and involves in hepatocyte damage, hepatic inflammation, increased gut permeability and microbiome dysbiosis. FOXO3 is a well-recognized transcription factor which associated with longevity via promoting antioxidant stress response, preventing senescence and cell death, and inhibiting inflammation. We and many others have reported that FOXO3-/- mice develop more severe liver injury in response to alcohol. In the present study, we aimed to develop compounds that activate FOXO3 and further investigate their effects in alcohol induced liver injury. Through virtual screening, we discovered series of small molecular compounds that showed high affinity to FOXO3. We confirmed effects of compounds on FOXO3 target gene expression, as well as antioxidant and anti-apoptotic effects in vitro. Subsequently we evaluated the protective efficacy of compounds in alcohol induced liver injury in vivo. As a result, the leading compound we identified, 214991, activated downstream target genes expression of FOXO3, inhibited intracellular ROS accumulation and cell apoptosis induced by H2O2 and sorafenib. By using Lieber-DeCarli alcohol feeding mouse model, 214991 showed protective effects against alcohol-induced liver inflammation, macrophage and neutrophil infiltration, and steatosis. These findings not only reinforce the potential of FOXO3 as a valuable target for therapeutic intervention of ALD, but also suggested that compound 214991 as a promising candidate for the development of innovative therapeutic strategies of ALD.
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Affiliation(s)
- Jinying Peng
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
| | - Gaoshuang Liang
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
| | - Yaqi Li
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Hunan, 410081, China; Institute of Interdisciplinary Studies, Hunan Normal University, Hunan, 410081, China; Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Hunan, 410081, China
| | - Siyu Mao
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
| | - Chen Zhang
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
| | - Ying Wang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Hunan, 410081, China; Institute of Interdisciplinary Studies, Hunan Normal University, Hunan, 410081, China; Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Hunan, 410081, China.
| | - Zhuan Li
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China.
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Taiwo M, Huang E, Pathak V, Bellar A, Welch N, Dasarathy J, Streem D, McClain CJ, Mitchell MC, Barton BA, Szabo G, Dasarathy S, Schaefer EA, Luther J, Z. Day L, Ouyang X, Suyavaran A, Mehal WZ, Jacobs JM, Goodman RP, Rotroff DM, Nagy LE. Proteomics identifies complement protein signatures in patients with alcohol-associated hepatitis. JCI Insight 2024; 9:e174127. [PMID: 38573776 PMCID: PMC11141929 DOI: 10.1172/jci.insight.174127] [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: 07/24/2023] [Accepted: 03/27/2024] [Indexed: 04/06/2024] Open
Abstract
Diagnostic challenges continue to impede development of effective therapies for successful management of alcohol-associated hepatitis (AH), creating an unmet need to identify noninvasive biomarkers for AH. In murine models, complement contributes to ethanol-induced liver injury. Therefore, we hypothesized that complement proteins could be rational diagnostic/prognostic biomarkers in AH. Here, we performed a comparative analysis of data derived from human hepatic and serum proteome to identify and characterize complement protein signatures in severe AH (sAH). The quantity of multiple complement proteins was perturbed in liver and serum proteome of patients with sAH. Multiple complement proteins differentiated patients with sAH from those with alcohol cirrhosis (AC) or alcohol use disorder (AUD) and healthy controls (HCs). Serum collectin 11 and C1q binding protein were strongly associated with sAH and exhibited good discriminatory performance among patients with sAH, AC, or AUD and HCs. Furthermore, complement component receptor 1-like protein was negatively associated with pro-inflammatory cytokines. Additionally, lower serum MBL associated serine protease 1 and coagulation factor II independently predicted 90-day mortality. In summary, meta-analysis of proteomic profiles from liver and circulation revealed complement protein signatures of sAH, highlighting a complex perturbation of complement and identifying potential diagnostic and prognostic biomarkers for patients with sAH.
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Affiliation(s)
| | | | - Vai Pathak
- Department of Quantitative Health Sciences, and
| | | | - Nicole Welch
- Department of Inflammation and Immunity
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jaividhya Dasarathy
- Department of Family Medicine, Metro Health Medical Center, Cleveland, Ohio, USA
| | - David Streem
- Department of Psychiatry and Psychology, Cleveland Clinic Lutheran Hospital, Cleveland, Ohio, USA
| | - Craig J. McClain
- Department of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Mack C. Mitchell
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Bruce A. Barton
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Srinivasan Dasarathy
- Department of Inflammation and Immunity
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | | | - Esperance A. Schaefer
- Alcohol Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jay Luther
- Alcohol Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Le Z. Day
- Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington, USA
| | - Xinshou Ouyang
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Arumugam Suyavaran
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Wajahat Z. Mehal
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
- West Haven VA Medical Center, West Haven, Connecticut, USA
| | - Jon M. Jacobs
- Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington, USA
| | - Russell P. Goodman
- Alcohol Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Endocrine Unit, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Daniel M. Rotroff
- Department of Quantitative Health Sciences, and
- Endocrine and Metabolism Institute and
- Center for Quantitative Metabolic Research, Cleveland Clinic, Cleveland, Ohio, USA
| | - Laura E. Nagy
- Department of Inflammation and Immunity
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
- See Supplemental Acknowledgments for information on the AlcHepNet Consortium
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9
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Rezaee-Zavareh MS, Kim N, Yang JD. Starting the journey: Understanding the roles of complement proteins in liver diseases through mendelian randomization. Clin Mol Hepatol 2024; 30:150-153. [PMID: 38385196 PMCID: PMC11016470 DOI: 10.3350/cmh.2024.0116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 02/19/2024] [Accepted: 02/20/2024] [Indexed: 02/23/2024] Open
Affiliation(s)
| | - Naomy Kim
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Shi Y, Dong H, Sun S, Wu X, Fang J, Zhao J, Han J, Li Z, Wu H, Liu L, Wu W, Tian Y, Yuan G, Fan X, Xu C. Protein-centric omics analysis reveals circulating complements linked to non-viral liver diseases as potential therapeutic targets. Clin Mol Hepatol 2024; 30:80-97. [PMID: 38061333 PMCID: PMC10776287 DOI: 10.3350/cmh.2023.0343] [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] [Received: 09/03/2023] [Revised: 12/04/2023] [Accepted: 12/07/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND/AIMS To evaluate the causal correlation between complement components and non-viral liver diseases and their potential use as druggable targets. METHODS We conducted Mendelian randomization (MR) to assess the causal role of circulating complements in the risk of non-viral liver diseases. A complement-centric protein interaction network was constructed to explore biological functions and identify potential therapeutic options. RESULTS In the MR analysis, genetically predicted levels of complement C1q C chain (C1QC) were positively associated with the risk of autoimmune hepatitis (odds ratio 1.125, 95% confidence interval 1.018-1.244), while complement factor H-related protein 5 (CFHR5) was positively associated with the risk of primary sclerosing cholangitis (PSC;1.193, 1.048- 1.357). On the other hand, CFHR1 (0.621, 0.497-0.776) and CFHR2 (0.824, 0.703-0.965) were inversely associated with the risk of alcohol-related cirrhosis. There were also significant inverse associations between C8 gamma chain (C8G) and PSC (0.832, 0.707-0.979), as well as the risk of metabolic dysfunction-associated steatotic liver disease (1.167, 1.036-1.314). Additionally, C1S (0.111, 0.018-0.672), C7 (1.631, 1.190-2.236), and CFHR2 (1.279, 1.059-1.546) were significantly associated with the risk of hepatocellular carcinoma. Proteins from the complement regulatory networks and various liver diseaserelated proteins share common biological processes. Furthermore, potential therapeutic drugs for various liver diseases were identified through drug repurposing based on the complement regulatory network. CONCLUSION Our study suggests that certain complement components, including C1S, C1QC, CFHR1, CFHR2, CFHR5, C7, and C8G, might play a role in non-viral liver diseases and could be potential targets for drug development.
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Affiliation(s)
- Yingzhou Shi
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Hang Dong
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Shiwei Sun
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Xiaoqin Wu
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Jiansong Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Jianbo Zhao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Junming Han
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Zongyue Li
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Huixiao Wu
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Luna Liu
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Wanhong Wu
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Yang Tian
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Guandou Yuan
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiude Fan
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Chao Xu
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
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Niu X, Zhu L, Xu Y, Zhang M, Hao Y, Ma L, Li Y, Xing H. Global prevalence, incidence, and outcomes of alcohol related liver diseases: a systematic review and meta-analysis. BMC Public Health 2023; 23:859. [PMID: 37170239 PMCID: PMC10173666 DOI: 10.1186/s12889-023-15749-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 04/25/2023] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND Alcohol related liver disease (ARLD) is one of the major chronic liver diseases worldwide. This review aimed to describe the global prevalence, incidence, and outcomes of ARLD. METHODS Medline, Embase, The Cochrane Library, and China National Knowledge Infrastructure (CNKI) were searched from inception to May 31, 2022. The language was restricted to English or Chinese. According to the criteria, articles describing the basic characteristics of the population were selected. Two reviewers extracted the data independently. RESULTS A total of 372 studies were identified: 353 were used for prevalence analysis, 7 were used for incidence analysis, and 114 were used to for outcome analysis. The prevalence of ARLD worldwide was 4.8%. The prevalence in males was 2.9%, which was higher than female (0.5%). Among the ethnic groups, the percentage was highest in Caucasians (68.9%). Alcoholic liver cirrhosis comprised the highest proportion in the disease spectrum of ARLD at 32.9%. The prevalence of ascites in ARLD population was highest (25.1%). The ARLD population who drinking for > 20 years accounted for 54.8%, and the average daily alcohol intake was 146.6 g/d. About 59.5% of ARLD patients were current or former smokers, and 18.7% were complicated with hepatitis virus infection. The incidence was 0.208/1000 person-years. The overall mortality was 23.9%, and the liver-related mortality was 21.6%. CONCLUSION The global prevalence of ARLD was 4.8% and was affected by sex, region, drinking years, and other factors. Therefore, removing the factors causing a high disease prevalence is an urgent requisite. TRIAL REGISTRATION PROSPERO Nr: CRD42021286192.
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Affiliation(s)
- Xuanxuan Niu
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Lin Zhu
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Yifan Xu
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Menghan Zhang
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Yanxu Hao
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Lei Ma
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Yan Li
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Huichun Xing
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
- Peking University Ditan Teaching Hospital, Beijing, 100015 China
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Anton PE, Rutt LN, Capper C, Orlicky DJ, McCullough RL. Profiling the oxylipidome in aged mice after chronic ethanol feeding: Identifying lipid metabolites as drivers of hepatocyte stress. Alcohol 2023; 107:119-135. [PMID: 36150611 DOI: 10.1016/j.alcohol.2022.08.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 08/10/2022] [Accepted: 08/25/2022] [Indexed: 02/08/2023]
Abstract
The global population of people over the age of 65 is increasing and expected to reach 1.5 billion by 2050. While aging is associated with a number of chronic illnesses including dementia, the underlying contribution of alcohol misuse in the elderly is understudied. Long-term chronic alcohol misuse can lead to alcohol-associated liver disease, consisting of a spectrum of pathologies, including steatosis and cirrhosis; liver disease can be rapidly accelerated by non-resolving inflammation. Despite this knowledge, the mechanistic underpinnings of dysregulated host immunity and accelerated liver disease progression in the aged by alcohol is unknown. Alcohol misuse in the elderly is on the rise and aging is associated with progressive increases in pro-inflammatory cytokine production. The goals of the current study are to characterize bioactive lipid mediators of inflammation by making use of a murine model of ethanol-induced liver disease in 3-month-old and 20-month-old mice by quantitatively profiling selected oxylipins in liver, brain and plasma. Following chronic ethanol exposure, liver injury, steatosis, and senescence markers were robustly increased in aged mice compared to young adult mice. Expression of proinflammatory cytokines and lipid metabolizing enzymes were increased in liver by both age and ethanol feeding. Lipoxygenase-derived lipid metabolites 9- and 13-hydroxy-octadecadienoic acid and 15-hydroxyeicosatetraenoic acid were increased in liver and plasma in ethanol-fed aged mice and positively correlated with liver injury. In plasma, 9,10-dihydroxy-octadecenoic acid/epoxy-octadecenoic acid plasma ratios correlated with liver injury in ethanol-fed aged mice. Finally, 15-hydroxyeicosatetraenoic acid and 9,10-dihydroxy-octadecenoic acid positively correlated between liver and plasma. Importantly, leukotriene E4, 9,10-dihydroxy-octadecenoic acid and 15-hydroxyeicosatetraenoic acid increased lipid accumulation and ER stress in cultured AML12 hepatocytes. These data highlight the complexity of lipid metabolite networks but identify key mediators that may be used for diagnostic and prognostic markers in early stages of alcohol-related liver disease in patients of all ages.
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Affiliation(s)
- Paige E Anton
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Lauren N Rutt
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Courtney Capper
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - David J Orlicky
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Rebecca L McCullough
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States; Colorado University Alcohol Research Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States; GI and Liver Innate Immune Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
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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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Wu X, Fan X, Miyata T, Kim A, Cajigas-Du Ross CK, Ray S, Huang E, Taiwo M, Arya R, Wu J, Nagy LE. Recent Advances in Understanding of Pathogenesis of Alcohol-Associated Liver Disease. ANNUAL REVIEW OF PATHOLOGY 2023; 18:411-438. [PMID: 36270295 PMCID: PMC10060166 DOI: 10.1146/annurev-pathmechdis-031521-030435] [Citation(s) in RCA: 99] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Alcohol-associated liver disease (ALD) is one of the major diseases arising from chronic alcohol consumption and is one of the most common causes of liver-related morbidity and mortality. ALD includes asymptomatic liver steatosis, fibrosis, cirrhosis, and alcohol-associated hepatitis and its complications. The progression of ALD involves complex cell-cell and organ-organ interactions. We focus on the impact of alcohol on dysregulation of homeostatic mechanisms and regulation of injury and repair in the liver. In particular, we discuss recent advances in understanding the disruption of balance between programmed cell death and prosurvival pathways, such as autophagy and membrane trafficking, in the pathogenesis of ALD. We also summarize current understanding of innate immune responses, liver sinusoidal endothelial cell dysfunction and hepatic stellate cell activation, and gut-liver and adipose-liver cross talk in response to ethanol. In addition,we describe the current potential therapeutic targets and clinical trials aimed at alleviating hepatocyte injury, reducing inflammatory responses, and targeting gut microbiota, for the treatment of ALD.
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Affiliation(s)
- Xiaoqin Wu
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Xiude Fan
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Tatsunori Miyata
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Adam Kim
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Christina K Cajigas-Du Ross
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Semanti Ray
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Emily Huang
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Moyinoluwa Taiwo
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Rakesh Arya
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Jianguo Wu
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Laura E Nagy
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA
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Duryee MJ, Aripova N, Hunter CD, Ruskamp RJ, Tessin MR, Works DR, Mikuls TR, Thiele GM. A novel reactive aldehyde species inhibitor prevents the deleterious effects of ethanol in an animal model of alcoholic liver disease. Int Immunopharmacol 2022; 113:109400. [DOI: 10.1016/j.intimp.2022.109400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/27/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
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Bajaj JS, Nagy LE. Natural History of Alcohol-Associated Liver Disease: Understanding the Changing Landscape of Pathophysiology and Patient Care. Gastroenterology 2022; 163:840-851. [PMID: 35598629 PMCID: PMC9509416 DOI: 10.1053/j.gastro.2022.05.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 05/12/2022] [Accepted: 05/14/2022] [Indexed: 12/02/2022]
Abstract
Alcohol use and consequent liver disease are major burdens that have worsened during the COVID-19 pandemic. There are several facets to the pathophysiology and clinical consequences of alcohol-use disorder (AUD) and progression to alcohol-associated liver disease (ALD) that require a concerted effort by clinicians and translational and basic science investigators. Several recent advances from bedside to bench and bench to bedside have been made in ALD. We focused this review on a case-based approach that provides a human context to these important advances across the spectrum of ALD.
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Affiliation(s)
- Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia; Central Virginia Veterans Healthcare System, Richmond, Virginia.
| | - Laura E Nagy
- Center for Liver Disease Research, Departments of Inflammation and Immunity and Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio; Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
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Hardesty J, Day L, Warner J, Warner D, Gritsenko M, Asghar A, Stolz A, Morgan T, McClain C, Jacobs J, Kirpich I. Hepatic Protein and Phosphoprotein Signatures of Alcohol-Associated Cirrhosis and Hepatitis. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:1066-1082. [PMID: 35490715 PMCID: PMC9253914 DOI: 10.1016/j.ajpath.2022.04.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/08/2022] [Accepted: 04/14/2022] [Indexed: 12/12/2022]
Abstract
Alcohol-associated liver disease is a global health care burden, with alcohol-associated cirrhosis (AC) and alcohol-associated hepatitis (AH) being two clinical manifestations with poor prognosis. The limited efficacy of standard of care for AC and AH highlights a need for therapeutic targets and strategies. The current study aimed to address this need through the identification of hepatic proteome and phosphoproteome signatures of AC and AH. Proteomic and phosphoproteomic analyses were conducted on explant liver tissue (test cohort) and liver biopsies (validation cohort) from patients with AH. Changes in protein expression across AH severity and similarities and differences in AH and AC hepatic proteome were analyzed. Significant alterations in multiple proteins involved in various biological processes were observed in both AC and AH, including elevated expression of transcription factors involved in fibrogenesis (eg, Yes1-associated transcriptional regulator). Another finding was elevated levels of hepatic albumin (ALBU) concomitant with diminished ALBU phosphorylation, which may prevent ALBU release, leading to hypoalbuminemia. Furthermore, altered expression of proteins related to neutrophil function and chemotaxis, including elevated myeloperoxidase, cathelicidin antimicrobial peptide, complement C3, and complement C5 were observed in early AH, which declined at later stages. Finally, a loss in expression of mitochondria proteins, including enzymes responsible for the synthesis of cardiolipin was observed. The current study identified hepatic protein signatures of AC and AH as well as AH severity, which may facilitate the development of therapeutic strategies.
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Affiliation(s)
- Josiah Hardesty
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville Alcohol Center, Louisville, Kentucky
| | - Le Day
- Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington
| | - Jeffrey Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville Alcohol Center, Louisville, Kentucky
| | - Dennis Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Marina Gritsenko
- Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington
| | - Aliya Asghar
- Gastroenterology, VA Long Beach Healthcare, VA Long Beach Healthcare System, Long Beach, California
| | - Andrew Stolz
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Timothy Morgan
- Gastroenterology, VA Long Beach Healthcare, VA Long Beach Healthcare System, Long Beach, California
| | - Craig McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville Alcohol Center, Louisville, Kentucky; Robley Rex Veterans Medical Center, Louisville, Kentucky; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, Kentucky; University of Louisville Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, Kentucky
| | - Jon Jacobs
- Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington
| | - Irina Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville Alcohol Center, Louisville, Kentucky; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, Kentucky; University of Louisville Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, Kentucky.
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18
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Santiesteban-Lores LE, Carneiro MC, Isaac L, Bavia L. Complement System in Alcohol-Associated Liver Disease. Immunol Lett 2021; 236:37-50. [PMID: 34111475 DOI: 10.1016/j.imlet.2021.05.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/20/2021] [Accepted: 05/25/2021] [Indexed: 12/19/2022]
Abstract
Innate immunity contributes effectively to the development of Alcohol-Associated liver disease (ALD). Particularly, human studies and murine models of ALD have shown that Complement activation plays an important role during the initial and later stages of ALD. The Complement System may contribute to the pathogenesis of this disease since it has been shown that ethanol-derived metabolic products activate the Complement cascade on liver membranes, leading to hepatocellular damage. However, studies evaluating the plasma levels of Complement proteins in ALD patients present contradictory results in some cases, and do not establish a well-marked role for each Complement component. The impairment of leukocyte chemoattractant activity observed in these patients may contribute to the susceptibility to bacterial infections in the latter stages of the disease. On the other hand, murine models of ALD have provided more detailed insights into the mechanisms that link the Complement System to the pathogenesis of the disease. It has been observed that Classical pathway can be activated via C1q binding to apoptotic cells in the liver and contributes to the development of hepatic inflammation. C3 contributes to the accumulation of triglycerides in the liver and in adipose tissue, while C5 seems to be involved with inflammation and liver injury after chronic ethanol consumption. In this review, we present a compendium of studies evaluating the role of Complement in human and murine models of ALD. We also discuss potential therapies to human ALD, highlighting the use of Complement inhibitors.
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Affiliation(s)
| | | | - Lourdes Isaac
- Institute of Biomedical Sciences, University of São Paulo, Brazil
| | - Lorena Bavia
- Institute of Biomedical Sciences, University of São Paulo, Brazil.
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19
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Ma L, Sahu SK, Cano M, Kuppuswamy V, Bajwa J, McPhatter J, Pine A, Meizlish ML, Goshua G, Chang CH, Zhang H, Price C, Bahel P, Rinder H, Lei T, Day A, Reynolds D, Wu X, Schriefer R, Rauseo AM, Goss CW, O’Halloran JA, Presti RM, Kim AH, Gelman AE, Dela Cruz CS, Lee AI, Mudd PA, Chun HJ, Atkinson JP, Kulkarni HS. Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci Immunol 2021; 6:eabh2259. [PMID: 34446527 PMCID: PMC8158979 DOI: 10.1126/sciimmunol.abh2259] [Citation(s) in RCA: 141] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 05/11/2021] [Indexed: 12/13/2022]
Abstract
Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers: Washington University School of Medicine (n=134) and Yale School of Medicine (n=49). We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza (n=54), and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). We demonstrate that circulating markers of complement activation are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., angiopoietin-2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.
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Affiliation(s)
- Lina Ma
- Division of Pulmonary and Critical Care Medicine, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
| | - Sanjaya K. Sahu
- Division of Pulmonary and Critical Care Medicine, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
| | - Marlene Cano
- Division of Pulmonary and Critical Care Medicine, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
| | - Vasanthan Kuppuswamy
- Division of Hospital Medicine, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
| | - Jamal Bajwa
- Division of Pulmonary and Critical Care Medicine, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
- Marian University; Indianapolis, USA
| | - Ja’Nia McPhatter
- Division of Pulmonary and Critical Care Medicine, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
- University of Pittsburgh; Pittsburgh, USA
| | - Alexander Pine
- Section of Hematology, Department of Internal Medicine, Yale School of Medicine; New Haven, USA
| | | | - George Goshua
- Section of Hematology, Department of Internal Medicine, Yale School of Medicine; New Haven, USA
| | - C-Hong Chang
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine; New Haven, USA
| | - Hanming Zhang
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine; New Haven, USA
| | - Christina Price
- Section of Immunology, Department of Internal Medicine, Yale School of Medicine; New Haven, USA
| | | | | | - Tingting Lei
- Department of Pathology and Immunology, Washington University School of Medicine; St. Louis, USA
| | - Aaron Day
- Department of Emergency Medicine, Washington University School of Medicine; St. Louis, USA
| | - Daniel Reynolds
- Division of Pulmonary and Critical Care Medicine, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
| | - Xiaobo Wu
- Division of Rheumatology, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
| | - Rebecca Schriefer
- Division of Rheumatology, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
| | - Adriana M. Rauseo
- Division of Infectious Diseases, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
| | - Charles W. Goss
- Division of Biostatistics, Washington University School of Medicine; St. Louis, USA
| | - Jane A. O’Halloran
- Division of Infectious Diseases, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
| | - Rachel M. Presti
- Division of Infectious Diseases, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
| | - Alfred H. Kim
- Division of Rheumatology, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
| | - Andrew E. Gelman
- Department of Pathology and Immunology, Washington University School of Medicine; St. Louis, USA
- Division of Biostatistics, Washington University School of Medicine; St. Louis, USA
| | - Charles S. Dela Cruz
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine; New Haven, USA
| | - Alfred I. Lee
- Section of Hematology, Department of Internal Medicine, Yale School of Medicine; New Haven, USA
| | - Philip A. Mudd
- Department of Emergency Medicine, Washington University School of Medicine; St. Louis, USA
| | - Hyung J. Chun
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine; New Haven, USA
| | - John P. Atkinson
- Division of Rheumatology, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
| | - Hrishikesh S. Kulkarni
- Division of Pulmonary and Critical Care Medicine, John T. Milliken Department of Medicine, Washington University School of Medicine; St. Louis, USA
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20
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Schonfeld M, Villar MT, Artigues A, Weinman SA, Tikhanovich I. Arginine Methylation of Hepatic hnRNPH Suppresses Complement Activation and Systemic Inflammation in Alcohol-Fed Mice. Hepatol Commun 2021; 5:812-829. [PMID: 34027271 PMCID: PMC8122385 DOI: 10.1002/hep4.1674] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/29/2020] [Accepted: 12/17/2020] [Indexed: 01/16/2023] Open
Abstract
Protein arginine methyl transferase 1 (PRMT1) is the main enzyme for cellular arginine methylation. It regulates many aspects of liver biology including inflammation, lipid metabolism, and proliferation. Previously we identified that PRMT1 is necessary for protection from alcohol-induced liver injury. However, many PRMT1 targets in the liver after alcohol exposure are not yet identified. We studied the changes in the PRMT1-dependent arginine methylated proteome after alcohol feeding in mouse liver using mass spectrometry. We found that arginine methylation of the RNA-binding protein (heterogeneous nuclear ribonucleoprotein [hnRNP]) H1 is mediated by PRMT1 and is altered in alcohol-fed mice. PRMT1-dependent methylation suppressed hnRNP H1 binding to several messenger RNAs of complement pathway including complement component C3. We found that PRMT1-dependent hnRNP H methylation suppressed complement component expression in vitro, and phosphorylation is required for this function of PRMT1. In agreement with that finding, hepatocyte-specific PRMT1 knockout mice had an increase in complement component expression in the liver. Excessive complement expression in alcohol-fed PRMT1 knockout mice resulted in further complement activation and an increase in serum C3a and C5a levels, which correlated with inflammation in multiple organs including lung and adipose tissue. Using specific inhibitors to block C3aR and C5aR receptors, we were able to prevent lung and adipose tissue inflammation without affecting inflammation in the liver or liver injury. Conclusion: Taken together, these data suggest that PRMT1-dependent suppression of complement production in the liver is necessary for prevention of systemic inflammation in alcohol-fed mice. C3a and C5a play a role in this liver-lung and liver-adipose interaction in alcohol-fed mice deficient in liver arginine methylation.
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Affiliation(s)
- Michael Schonfeld
- Department of Internal MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Maria T Villar
- Department of BiochemistryUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Antonio Artigues
- Department of BiochemistryUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Steven A Weinman
- Department of Internal MedicineUniversity of Kansas Medical CenterKansas CityKSUSA.,Liver CenterUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Irina Tikhanovich
- Department of Internal MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
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21
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Immunological mechanisms and therapeutic targets of fatty liver diseases. Cell Mol Immunol 2020; 18:73-91. [PMID: 33268887 PMCID: PMC7852578 DOI: 10.1038/s41423-020-00579-3] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the two major types of chronic liver disease worldwide. Inflammatory processes play key roles in the pathogeneses of fatty liver diseases, and continuous inflammation promotes the progression of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). Although both ALD and NAFLD are closely related to inflammation, their respective developmental mechanisms differ to some extent. Here, we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and NASH. Multiple cell types in the liver, including macrophages, neutrophils, other immune cell types and hepatocytes, are involved in fatty liver disease inflammation. In addition, microRNAs (miRNAs), extracellular vesicles (EVs), and complement also contribute to the inflammatory process, as does intertissue crosstalk between the liver and the intestine, adipose tissue, and the nervous system. We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections. Understanding the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.
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22
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Zhou Y, Yuan G, Zhong F, He S. Roles of the complement system in alcohol-induced liver disease. Clin Mol Hepatol 2020; 26:677-685. [PMID: 33053939 PMCID: PMC7641541 DOI: 10.3350/cmh.2020.0094] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 08/25/2020] [Indexed: 12/19/2022] Open
Abstract
Alcohol-induced liver disease (ALD) is a complex disorder, with a disease spectrum ranging from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Although the pathogenesis of ALD is incompletely understood and currently no effective drugs are available for ALD, several lines of evidence suggest that complement activation and oxidative stress play crucial roles in the pathogenesis of ALD. Complement activation can regulate the production of ROS and influence oxidative stress in ALD. Precise regulation of the complement system in ALD may be a rational and novel avenue to postpone and even reverse the progression of disease and simultaneously promote the repair of liver injury. In this mini-review, we briefly summarize the recent research progress, especially focusing on the role of complement and oxidative stress-induced transfer RNA-derived fragments, which might help us to better understand the pathogenesis of ALD and provide aid in the development of novel therapeutic strategies for ALD.
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Affiliation(s)
- Yi Zhou
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Guandou Yuan
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Fudi Zhong
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Songqing He
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
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