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Yang H, Wei A, Zhou X, Chen Z, Wang Y. SUCNR1 Deficiency Alleviates Liver Ischemia-Reperfusion Injury by Regulating Kupffer Cell Activation and Polarization Through the ERK/NF-κB Pathway in Mice. Inflammation 2025:10.1007/s10753-025-02290-9. [PMID: 40106070 DOI: 10.1007/s10753-025-02290-9] [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: 08/13/2024] [Revised: 03/05/2025] [Accepted: 03/06/2025] [Indexed: 03/22/2025]
Abstract
Succinate regulates inflammation through its receptor, succinate receptor 1 (SUCNR1). However, the effects of this interaction on Kupffer cell (KC)-driven inflammation during liver ischemia-reperfusion injury (IRI) remain unclear. Herein, we investigated the succinate/SUCNR1 axis in the progression of liver IRI. In this study, succinate levels and SUCNR1 expression were analyzed in mice underwent segmental liver IRI. Sucnr1 deficiency (Sucnr1-/-) and Wild-type mice were treated with or without clodronate before liver IRI modeling, and a co-culture system was established to assess the impact of Sucnr1 deficiency in KCs on hepatocyte viability and apoptosis. KC activation status and polarization were determined, in vivo and in vitro. Furthermore, the downstream pathways in regulating KC polarization were investigated. We observed a significant increase in succinate levels in the serum and liver, and SUCNR1 expression in KCs after IRI. Sucnr1 deletion alleviated liver IRI and hepatocyte apoptosis either in vivo or in vitro. However, the aforementioned hepatoprotective effects were abolished by the depletion of KCs with clodronate. Sucnr1 deletion inhibited KC activation and M1 polarization, and dampened proinflammatory cytokine release after liver IRI. In addition, Sucnr1 knockout reversed the increasing phosphorylation of ERK and NF-κB p65 in KCs following liver IRI. The phosphorylation of ERK/NF-κB p65 and M1 polarization in KCs were also inhibited by the SUCNR1 antagonist Compound 4C or ERK inhibitor SCH772984. Together, these findings suggest that SUCNR1 deficiency protects against liver IRI by modulating KC activation and polarization probably through the ERK/NF-κB pathway.
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Affiliation(s)
- Huan Yang
- Department of Anesthesiology, the First Affiliated Hospital, Hengyang Medical School, University of South China, 69 Chuanshan Road, Shigu District, Hengyang, 421001, Hunan Province, China
| | - An Wei
- Department of Anesthesiology, the First Affiliated Hospital, Hengyang Medical School, University of South China, 69 Chuanshan Road, Shigu District, Hengyang, 421001, Hunan Province, China
| | - Xinting Zhou
- Department of Anesthesiology, the First Affiliated Hospital, Hengyang Medical School, University of South China, 69 Chuanshan Road, Shigu District, Hengyang, 421001, Hunan Province, China
| | - Zhiwei Chen
- Department of Anesthesiology, the First Affiliated Hospital, Hengyang Medical School, University of South China, 69 Chuanshan Road, Shigu District, Hengyang, 421001, Hunan Province, China
| | - Yiheng Wang
- Department of Anesthesiology, the First Affiliated Hospital, Hengyang Medical School, University of South China, 69 Chuanshan Road, Shigu District, Hengyang, 421001, Hunan Province, China.
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Zhang J, Lou K, Chi J, Wu J, Fan X, Cui Y. Research progress on intratumoral microorganisms in renal cancer. World J Urol 2025; 43:72. [PMID: 39812826 DOI: 10.1007/s00345-024-05403-5] [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: 08/23/2024] [Accepted: 11/27/2024] [Indexed: 01/16/2025] Open
Abstract
The human body harbors a vast array of microorganisms. Changes in the microbial ecosystem can potentially lead to diseases, including cancer. Traditionally, research has focused more on the gut microbiota and its influence on cancer. However, with the advancement of sequencing technologies, scholars have discovered that microorganisms within kidney tissues are significant components of tumor tissues. Intratumoral microorganisms may affect tumor growth and development through certain mechanisms, influence the function of immune cells, or impact the effectiveness of chemotherapy or immunotherapy in patients. This paper reviews the latest progress in the research on intratumoral microorganisms in renal cancer (RCa). It summarizes the types and distribution characteristics of these microorganisms, discusses the close association between specific viral infections (such as HPV and EBV) and RCa, and highlights the role of microorganisms in the pathogenesis of RCa. This review provides new perspectives for understanding the pathogenic mechanisms of RCa, thereby offering potential clinical applications.
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Affiliation(s)
- Jiankun Zhang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Keyuan Lou
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Junpeng Chi
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Jitao Wu
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Xinying Fan
- Department of Blood Purification, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China.
| | - Yuanshan Cui
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China.
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Gilgenkrantz H, Paradis V, Lotersztajn S. Cell metabolism-based therapy for liver fibrosis, repair, and hepatocellular carcinoma. Hepatology 2025; 81:269-287. [PMID: 37212145 PMCID: PMC11643143 DOI: 10.1097/hep.0000000000000479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 04/21/2023] [Indexed: 05/23/2023]
Abstract
Progression of chronic liver injury to fibrosis, abnormal liver regeneration, and HCC is driven by a dysregulated dialog between epithelial cells and their microenvironment, in particular immune, fibroblasts, and endothelial cells. There is currently no antifibrogenic therapy, and drug treatment of HCC is limited to tyrosine kinase inhibitors and immunotherapy targeting the tumor microenvironment. Metabolic reprogramming of epithelial and nonparenchymal cells is critical at each stage of disease progression, suggesting that targeting specific metabolic pathways could constitute an interesting therapeutic approach. In this review, we discuss how modulating intrinsic metabolism of key effector liver cells might disrupt the pathogenic sequence from chronic liver injury to fibrosis/cirrhosis, regeneration, and HCC.
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Affiliation(s)
- Hélène Gilgenkrantz
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
| | - Valérie Paradis
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
- Pathology Department, Beaujon Hospital APHP, Paris-Cité University, Clichy, France
| | - Sophie Lotersztajn
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
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Cai Y, Chen Z, Chen E, Zhang D, Wei T, Sun M, Lian Y. Succinic Acid Ameliorates Concanavalin A-Induced Hepatitis by Altering the Inflammatory Microenvironment and Expression of BCL-2 Family Proteins. Inflammation 2024; 47:2000-2012. [PMID: 38613638 DOI: 10.1007/s10753-024-02021-6] [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: 02/03/2024] [Revised: 03/25/2024] [Accepted: 04/03/2024] [Indexed: 04/15/2024]
Abstract
Autoimmune hepatitis (AIH) is a severe immune-mediated inflammatory liver disease that currently lacks feasible drug treatment methods. Our study aimed to evaluate the protective effect of succinic acid against AIH and provide a reliable method for the clinical treatment of AIH. We performed an in vivo study of the effects of succinic acid on concanavalin A (ConA)-induced liver injury in mice. We examined liver transaminase levels, performed hematoxylin and eosin (HE) staining, and observed apoptotic phenotypes in mice. We performed flow cytometry to detect changes in the number of neutrophils and monocytes, and used liposomes to eliminate the liver Kupffer cells and evaluate their role. We performed bioinformatics analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting to detect mitochondrial apoptosis-induced changes in proteins from the B-cell lymphoma 2(Bcl-2) family. Succinic acid ameliorated ConA-induced AIH in a concentration-dependent manner, as reflected in the survival curve. HE and TUNEL staining and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed decreased alanine transaminase and aspartate aminotransferase levels, and reduced liver inflammation and apoptosis. RT-qPCR and enzyme-linked immunosorbent assay revealed that succinic acid significantly reduced liver pro-inflammatory cytokine levels. Flow cytometry revealed significantly decreased levels of liver neutrophils. Moreover, the protective effect of succinic acid disappeared after the Kupffer cells were eliminated, confirming their important role in the effect. Bioinformatics analysis, RT-qPCR, and western blotting showed that succinic acid-induced changes in proteins from the Bcl-2 family involved mitochondrial apoptosis, indicating the molecular mechanism underlying the protective effect of succinic acid. Succinic acid ameliorated ConA-induced liver injury by regulating immune balance, inhibiting pro-inflammatory factors, and promoting anti-apoptotic proteins in the liver. This study provides novel insights into the biological functions and therapeutic potential of succinic acid in the treatment of autoimmune liver injury.
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Affiliation(s)
- Ying Cai
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Zhiyuan Chen
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Ermei Chen
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Dongdong Zhang
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Tao Wei
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Mingyang Sun
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Yifan Lian
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China.
- Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China.
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Li X, Wang S, Zhang D, Feng Y, Liu Y, Yu W, Cui L, Harkany T, Verkhratsky A, Xia M, Li B. The periaxonal space as a conduit for cerebrospinal fluid flow to peripheral organs. Proc Natl Acad Sci U S A 2024; 121:e2400024121. [PMID: 39485799 PMCID: PMC11551422 DOI: 10.1073/pnas.2400024121] [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: 01/12/2024] [Accepted: 09/20/2024] [Indexed: 11/03/2024] Open
Abstract
Mechanisms controlling the movement of the cerebrospinal fluid (CSF) toward peripheral nerves are poorly characterized. We found that, in addition to the foramina Magendie and Luschka for CSF flow toward the subarachnoid space and glymphatic system, CSF outflow could also occur along periaxonal spaces (termed "PAS pathway") from the spinal cord to peripheral organs, such as the liver and pancreas. When interrogating the latter route, we found that serotonin, acting through 5-HT2B receptors expressed in ependymocytes that line the central canal, triggered Ca2+ signals to induce polymerization of F-actin, a cytoskeletal protein, to reduce the volume of ependymal cells. This paralleled an increased rate of PAS-mediated CSF redistribution toward peripheral organs. In the liver, CSF was received by hepatic stellate cells. CSF efflux toward peripheral organs through the PAS pathway represents a mechanism dynamically connecting the nervous system with the periphery. Our findings are compatible with the traditional theory of CSF efflux into the glymphatic system to clear metabolic waste from the cerebral parenchyma. Thus, we extend the knowledge of CSF flow and expand the understanding of connectivity between the CNS and peripheral organs.
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Affiliation(s)
- Xinyu Li
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Siman Wang
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Dianjun Zhang
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Yuliang Feng
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Yingyu Liu
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Weiyang Yu
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Lulu Cui
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
| | - Tibor Harkany
- Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna1090, Austria
- Department of Neuroscience, Biomedicum, Karolinska Institutet, Solna17165, Sweden
| | - Alexei Verkhratsky
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Faculty of Biology, Medicine and Health, The University of Manchester, ManchesterM13 9PL, United Kingdom
- Department of Neurosciences, University of the Basque Country, Leioa48940, Bizkaia, Spain
- Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, VilniusLT-01102, Lithuania
| | - Maosheng Xia
- Department of Orthopaedics, The First Hospital, China Medical University, Shenyang110002, China
| | - Baoman Li
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang110122, China
- Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, China Medical University, Shenyang110122, China
- China Medical University Centre of Forensic Investigation, Shenyang110122, China
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Li C, Liu H, Li J, He X, Zhu H, Fu W, Xu HE. Molecular basis of ligand recognition and activation of the human succinate receptor SUCR1. Cell Res 2024; 34:594-596. [PMID: 38834763 PMCID: PMC11291503 DOI: 10.1038/s41422-024-00984-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 05/23/2024] [Indexed: 06/06/2024] Open
Affiliation(s)
- Changyao Li
- The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- Lingang Laboratory, Shanghai, China
| | - Heng Liu
- The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Jingru Li
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xinheng He
- The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Haoran Zhu
- School of Pharmacy, Fudan University, Shanghai, China
| | - Wei Fu
- School of Pharmacy, Fudan University, Shanghai, China.
| | - H Eric Xu
- The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
- Lingang Laboratory, Shanghai, China.
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
- University of Chinese Academy of Sciences, Beijing, China.
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7
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Jin C, Chen H, Xie L, Zhou Y, Liu LL, Wu J. GPCRs involved in metabolic diseases: pharmacotherapeutic development updates. Acta Pharmacol Sin 2024; 45:1321-1336. [PMID: 38326623 PMCID: PMC11192902 DOI: 10.1038/s41401-023-01215-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 12/11/2023] [Indexed: 02/09/2024]
Abstract
G protein-coupled receptors (GPCRs) are expressed in a variety of cell types and tissues, and activation of GPCRs is involved in enormous metabolic pathways, including nutrient synthesis, transportation, storage or insulin sensitivity, etc. This review intends to summarize the regulation of metabolic homeostasis and mechanisms by a series of GPCRs, such as GPR91, GPR55, GPR119, GPR109a, GPR142, GPR40, GPR41, GPR43 and GPR120. With deep understanding of GPCR's structure and signaling pathways, it is attempting to uncover the role of GPCRs in major metabolic diseases, including metabolic syndrome, diabetes, dyslipidemia and nonalcoholic steatohepatitis, for which the global prevalence has risen during last two decades. An extensive list of agonists and antagonists with their chemical structures in a nature of small molecular compounds for above-mentioned GPCRs is provided as pharmacologic candidates, and their preliminary data of preclinical studies are discussed. Moreover, their beneficial effects in correcting abnormalities of metabolic syndrome, diabetes and dyslipidemia are summarized when clinical trials have been undertaken. Thus, accumulating data suggest that these agonists or antagonists might become as new pharmacotherapeutic candidates for the treatment of metabolic diseases.
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Affiliation(s)
- Cheng Jin
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
- College of Clinical Medicine, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Hui Chen
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Li Xie
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Yuan Zhou
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Li-Li Liu
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, 200032, China.
| | - Jian Wu
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China.
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, 200032, China.
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8
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Liao X, Xie H, Yu S. Calycosin prevents NLRP3-induced gut fibrosis by regulating IL-33/ST2 axis. Heliyon 2024; 10:e30240. [PMID: 38726105 PMCID: PMC11078877 DOI: 10.1016/j.heliyon.2024.e30240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 04/20/2024] [Accepted: 04/22/2024] [Indexed: 05/12/2024] Open
Abstract
Intestinal interstitial fibrosis is a core event of inflammatory bowel disease (IBD) development. Calycosin has been recognized to carry various therapeutic bioactivities. However, the role of calycosin in intestinal interstitial fibrosis remains to be illustrated. This aim of this study was to explore the effects of calycosin on intestinal interstitial fibrosis in IBD and the underlying mechanisms. The in vitro and in vivo models were established by using TNBS-induced mouse IBD model and co-culture of intestinal epithelial cells and intestinal interstitial cells; moreover, lentivirus-mediated knockdown of NLRP3 expression was applied. The results showed that calycosin significantly improved the intestinal interstitial fibrosis of TNBS-induced IBD. Mechanistically, calycosin downregulated NLRP3 expression and inhibited the activation of IL-33/ST2 signaling in intestinal epithelial cells, which subsequently impedes intestinal interstitial cell migration and activation by regulating the secretion of IL-33/ST2 signaling-induced fibrosis mediators. Notably, combination of calycosin and NLRP3 signaling blockade improved the intestinal interstitial fibrosis extent. Altogether, this study suggests calycosin can improve intestinal interstitial fibrosis by downregulating NLRP3-IL-33/ST2 signaling, reducing inflammation and decreasing pro-fibrotic factors' secretion, which provides a new perspective for therapeutic options of IBD.
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Affiliation(s)
- Xiujun Liao
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Haiting Xie
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Saojun Yu
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
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9
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Chen H, Jin C, Xie L, Wu J. Succinate as a signaling molecule in the mediation of liver diseases. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166935. [PMID: 37976628 DOI: 10.1016/j.bbadis.2023.166935] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 10/25/2023] [Accepted: 10/27/2023] [Indexed: 11/19/2023]
Abstract
Succinate, one of the intermediates of the tricarboxylic acid (TCA) cycle, plays an essential role in the metabolism of mitochondria and the production of energy, and is considered as a signaling molecule in metabolism as well as in initiation and progression of hepatic diseases. Of note, succinate activates a downstream signaling pathway through GPR91, and elicits a variety of intracellular responses, such as succinylation, production of reactive oxygen species (ROS), stabilization of hypoxia-inducible factor-1α (HIF-1α), and significant impact in cellular metabolism because of the pivotal role in the TCA cycle. Therefore, it is intriguing to deeply elucidate signaling mechanisms of succinate in hepatic fibrosis, metabolic reprogramming in inflammatory or immune responses, as well as carcinogenesis. This manuscript intends to review current understanding of succinate in mediating metabolism, inflammatory and immunologic reactions in liver diseases in order to establish molecular basis for the development of therapeutic strategies.
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Affiliation(s)
- Hui Chen
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Cheng Jin
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; College of Clinical College, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Li Xie
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Jian Wu
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China.
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10
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Ruan G, Wu F, Shi D, Sun H, Wang F, Xu C. Metformin: update on mechanisms of action on liver diseases. Front Nutr 2023; 10:1327814. [PMID: 38192642 PMCID: PMC10773879 DOI: 10.3389/fnut.2023.1327814] [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: 10/25/2023] [Accepted: 11/27/2023] [Indexed: 01/10/2024] Open
Abstract
Substantial attention has been paid to the various effects of metformin on liver diseases; the liver is the targeted organ where metformin exerts its antihyperglycemic properties. In non-alcoholic fatty liver disease (NAFLD), studies have shown that metformin affects the ATP/AMP ratio to activate AMPK, subsequently governing lipid metabolism. The latest research showed that low-dose metformin targets the lysosomal AMPK pathway to decrease hepatic triglyceride levels through the PEN2-ATP6AP1 axis in an AMP-independent manner. Metformin regulates caspase-3, eukaryotic initiation factor-2a (eIF2a), and insulin receptor substrate-1 (IRS-1) in palmitate-exposed HepG2 cells, alleviating endoplasmic reticulum (ER) stress. Recent observations highlighted the critical association with intestinal flora, as confirmed by the finding that metformin decreased the relative abundance of Bacteroides fragilis while increasing Akkermansia muciniphila and Bifidobacterium bifidum. The suppression of intestinal farnesoid X receptor (FXR) and the elevation of short-chain fatty acids resulted in the upregulation of tight junction protein and the alleviation of hepatic inflammation induced by lipopolysaccharide (LPS). Additionally, metformin delayed the progression of cirrhosis by regulating the activation and proliferation of hepatic stellate cells (HSCs) via the TGF-β1/Smad3 and succinate-GPR91 pathways. In hepatocellular carcinoma (HCC), metformin impeded the cell cycle and enhanced the curative effect of antitumor medications. Moreover, metformin protects against chemical-induced and drug-induced liver injury (DILI) against hepatotoxic drugs. These findings suggest that metformin may have pharmacological efficacy against liver diseases.
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Affiliation(s)
- Gaoyi Ruan
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fangquan Wu
- Department of Pathophysiology, School of Basic Medicine Science, Wenzhou Medical University, Wenzhou, China
| | - Dibang Shi
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hongxia Sun
- Department of Pathophysiology, School of Basic Medicine Science, Wenzhou Medical University, Wenzhou, China
| | - Fangyan Wang
- Department of Pathophysiology, School of Basic Medicine Science, Wenzhou Medical University, Wenzhou, China
| | - Changlong Xu
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
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Wu W, Kaicen W, Bian X, Yang L, Ding S, Li Y, Li S, Zhuge A, Li L. Akkermansia muciniphila alleviates high-fat-diet-related metabolic-associated fatty liver disease by modulating gut microbiota and bile acids. Microb Biotechnol 2023; 16:1924-1939. [PMID: 37377410 PMCID: PMC10527187 DOI: 10.1111/1751-7915.14293] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 05/28/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023] Open
Abstract
It has been reported that Akkermansia muciniphila improves host metabolism and reduces inflammation; however, its potential effects on bile acid metabolism and metabolic patterns in metabolic-associated fatty liver disease (MAFLD) are unknown. In this study, we have analysed C57BL/6 mice under three feeding conditions: (i) a low-fat diet group (LP), (ii) a high-fat diet group (HP) and (iii) a high-fat diet group supplemented with A. muciniphila (HA). The results found that A. muciniphila administration relieved weight gain, hepatic steatosis and liver injury induced by the high-fat diet. A. muciniphila altered the gut microbiota with a decrease in Alistipes, Lactobacilli, Tyzzerella, Butyricimonas and Blautia, and an enrichment of Ruminiclostridium, Osclibacter, Allobaculum, Anaeroplasma and Rikenella. The gut microbiota changes correlated significantly with bile acids. Meanwhile, A. muciniphila also improved glucose tolerance, gut barriers and adipokines dysbiosis. Akkermansia muciniphila regulated the intestinal FXR-FGF15 axis and reshaped the construction of bile acids, with reduced secondary bile acids in the caecum and liver, including DCA and LCA. These findings provide new insights into the relationships between probiotics, microflora and metabolic disorders, highlighting the potential role of A. muciniphila in the management of MAFLD.
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Affiliation(s)
- Wenrui Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Wang Kaicen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Xiaoyuan Bian
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Liya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Shi Ding
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Yating Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Shengjie Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Aoxiang Zhuge
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Jinan Microecological Biomedicine Shandong LaboratoryJinanShandongChina
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Le CT, Nguyen G, Park SY, Dong HN, Cho YK, Lee JH, Im SS, Choi DH, Cho EH. Phloretin Ameliorates Succinate-Induced Liver Fibrosis by Regulating Hepatic Stellate Cells. Endocrinol Metab (Seoul) 2023; 38:395-405. [PMID: 37533177 PMCID: PMC10475967 DOI: 10.3803/enm.2023.1661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 04/27/2023] [Accepted: 06/13/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGRUOUND Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs transdifferentiated into active form. Phloretin showed its ability to protect the liver from injury, so in this research we would like to investigate the effect of phloretin on succinate-induced HSCs activation in vitro and liver fibrosis in vivo study. METHODS In in vitro, succinate was used to induce HSCs activation, and then the effect of phloretin on activated HSCs was examined. In in vivo, succinate was used to generated liver fibrosis in mouse and phloretin co-treated to check its protection on the liver. RESULTS Phloretin can reduce the increase of fibrogenic markers and inhibits the proliferation, migration, and contraction caused by succinate in in vitro experiments. Moreover, an upregulation of proteins associated with aerobic glycolysis occurred during the activation of HSCs, which was attenuated by phloretin treatment. In in vivo experiments, intraperitoneal injection of phloretin decreased expression of fibrotic and glycolytic markers in the livers of mice with sodium succinate diet-induced liver fibrosis. These results suggest that aerobic glycolysis plays critical role in activation of HSCs and succinate can induce liver fibrosis in mice, whereas phloretin has therapeutic potential for treating hepatic fibrosis. CONCLUSION Intraperitoneal injection of phloretin attenuated succinate-induced hepatic fibrosis and alleviates the succinate-induced HSCs activation.
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Affiliation(s)
- Cong Thuc Le
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Giang Nguyen
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - So Young Park
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Hanh Nguyen Dong
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Yun Kyung Cho
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae-Ho Lee
- Department of Physiology, Keimyung University School of Medicine, Daegu, Korea
| | - Seung-Soon Im
- Department of Physiology, Keimyung University School of Medicine, Daegu, Korea
| | - Dae-Hee Choi
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Eun-Hee Cho
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
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13
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Dwivedi NV, Datta S, El-Kersh K, Sadikot RT, Ganti AK, Batra SK, Jain M. GPCRs and fibroblast heterogeneity in fibroblast-associated diseases. FASEB J 2023; 37:e23101. [PMID: 37486603 PMCID: PMC10916681 DOI: 10.1096/fj.202301091] [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: 06/01/2023] [Accepted: 07/06/2023] [Indexed: 07/25/2023]
Abstract
G protein-coupled receptors (GPCRs) are the largest and most diverse class of signaling receptors. GPCRs regulate many functions in the human body and have earned the title of "most targeted receptors". About one-third of the commercially available drugs for various diseases target the GPCRs. Fibroblasts lay the architectural skeleton of the body, and play a key role in supporting the growth, maintenance, and repair of almost all tissues by responding to the cellular cues via diverse and intricate GPCR signaling pathways. This review discusses the dynamic architecture of the GPCRs and their intertwined signaling in pathological conditions such as idiopathic pulmonary fibrosis, cardiac fibrosis, pancreatic fibrosis, hepatic fibrosis, and cancer as opposed to the GPCR signaling of fibroblasts in physiological conditions. Understanding the dynamics of GPCR signaling in fibroblasts with disease progression can help in the recognition of the complex interplay of different GPCR subtypes in fibroblast-mediated diseases. This review highlights the importance of designing and adaptation of next-generation strategies such as GPCR-omics, focused target identification, polypharmacology, and effective personalized medicine approaches to achieve better therapeutic outcomes for fibrosis and fibrosis associated malignancies.
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Affiliation(s)
- Nidhi V Dwivedi
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Souvik Datta
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Karim El-Kersh
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Ruxana T Sadikot
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
- VA Nebraska Western Iowa Health Care System
| | - Apar K. Ganti
- VA Nebraska Western Iowa Health Care System
- Division of Oncology and Hematology, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA
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14
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Wu KK. Extracellular Succinate: A Physiological Messenger and a Pathological Trigger. Int J Mol Sci 2023; 24:11165. [PMID: 37446354 DOI: 10.3390/ijms241311165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/01/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
When tissues are under physiological stresses, such as vigorous exercise and cold exposure, skeletal muscle cells secrete succinate into the extracellular space for adaptation and survival. By contrast, environmental toxins and injurious agents induce cellular secretion of succinate to damage tissues, trigger inflammation, and induce tissue fibrosis. Extracellular succinate induces cellular changes and tissue adaptation or damage by ligating cell surface succinate receptor-1 (SUCNR-1) and activating downstream signaling pathways and transcriptional programs. Since SUCNR-1 mediates not only pathological processes but also physiological functions, targeting it for drug development is hampered by incomplete knowledge about the characteristics of its physiological vs. pathological actions. This review summarizes the current status of extracellular succinate in health and disease and discusses the underlying mechanisms and therapeutic implications.
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Affiliation(s)
- Kenneth K Wu
- Institute of Cellular and System Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan
- Institute of Biotechnology, College of Life Science, National Tsing-Hua University, Hsinchu 30013, Taiwan
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan
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15
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Marsal-Beltran A, Rodríguez-Castellano A, Astiarraga B, Calvo E, Rada P, Madeira A, Rodríguez-Peña MM, Llauradó G, Núñez-Roa C, Gómez-Santos B, Maymó-Masip E, Bosch R, Frutos MD, Moreno-Navarrete JM, Ramos-Molina B, Aspichueta P, Joven J, Fernández-Real JM, Quer JC, Valverde ÁM, Pardo A, Vendrell J, Ceperuelo-Mallafré V, Fernández-Veledo S. Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD. Metabolism 2023:155630. [PMID: 37315889 DOI: 10.1016/j.metabol.2023.155630] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 06/06/2023] [Accepted: 06/09/2023] [Indexed: 06/16/2023]
Abstract
OBJECTIVE Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes. METHODS We studied the phenotype of wild-type and Sucnr1-/- mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages. RESULTS Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm. CONCLUSIONS We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.
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Affiliation(s)
- Anna Marsal-Beltran
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; Universitat Rovira i Virgili (URV), 43201 Reus, Spain
| | - Adrià Rodríguez-Castellano
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; Universitat Rovira i Virgili (URV), 43201 Reus, Spain
| | - Brenno Astiarraga
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - Enrique Calvo
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - Patricia Rada
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain
| | - Ana Madeira
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - M-Mar Rodríguez-Peña
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - Gemma Llauradó
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; Department of Endocrinology and Nutrition, Hospital del Mar, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Catalina Núñez-Roa
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - Beatriz Gómez-Santos
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, 48940 Leioa, Spain
| | - Elsa Maymó-Masip
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - Ramon Bosch
- Department of Pathology, Oncological Pathology and Bioinformatics Research Group, Hospital de Tortosa Verge de la Cinta - IISPV, 43500 Tortosa, Spain
| | - María Dolores Frutos
- Department of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, 30120 Murcia, Spain
| | - José-María Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition and Insititut d'Investigació Biomèdica de Girona (IDIBGI), Dr. Josep Trueta University Hospital, Department of Medicine, University of Girona, 17007 Girona, Spain; CIBER de Fisiopatología de la Obesidad (CIBEROBN) - Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Bruno Ramos-Molina
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), 30120 Murcia, Spain
| | - Patricia Aspichueta
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, 48940 Leioa, Spain; Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain; CIBER de Enfermedades Hepáticas y Digestivas (CIBEREHD)- Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Jorge Joven
- Universitat Rovira i Virgili (URV), 43201 Reus, Spain; Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili, 43204 Reus, Spain
| | - José-Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition and Insititut d'Investigació Biomèdica de Girona (IDIBGI), Dr. Josep Trueta University Hospital, Department of Medicine, University of Girona, 17007 Girona, Spain; CIBER de Fisiopatología de la Obesidad (CIBEROBN) - Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Juan Carlos Quer
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; Universitat Rovira i Virgili (URV), 43201 Reus, Spain
| | - Ángela M Valverde
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain
| | - Albert Pardo
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; Universitat Rovira i Virgili (URV), 43201 Reus, Spain
| | - Joan Vendrell
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; Universitat Rovira i Virgili (URV), 43201 Reus, Spain
| | - Victòria Ceperuelo-Mallafré
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; Universitat Rovira i Virgili (URV), 43201 Reus, Spain.
| | - Sonia Fernández-Veledo
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; Universitat Rovira i Virgili (URV), 43201 Reus, Spain.
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Research progress of metformin in the treatment of liver fibrosis. Int Immunopharmacol 2023; 116:109738. [PMID: 36696857 DOI: 10.1016/j.intimp.2023.109738] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/12/2023] [Accepted: 01/12/2023] [Indexed: 01/24/2023]
Abstract
Liver fibrosis is a disease with significant morbidity and mortality. It is a chronic pathological process characterized by an imbalance of extracellular matrix production and degradation in liver tissue. Metformin is a type of hypoglycemic biguanide drug, which can be used in the treatment of liver fibrosis, but its anti-fibrotic effect and mechanism of action are unclear. The purpose of this article is to review the research progress of metformin in the treatment of liver fibrosis and to provide a theoretical basis for its application in the treatment of liver fibrosis.
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Najm R, Hachim MY, Kandasamy RK. Divulging a Pleiotropic Role of Succinate Receptor SUCNR1 in Renal Cell Carcinoma Microenvironment. Cancers (Basel) 2022; 14:cancers14246064. [PMID: 36551549 PMCID: PMC9776839 DOI: 10.3390/cancers14246064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 11/29/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
The succinate receptor, SUCNR1, has been attributed to tumor progression, metastasis, and immune response modulation upon its activation via the oncometabolite succinate. Nonetheless, little is known about the prognostic relevance of SUCNR1 and its association with tumor immune infiltrates and microbiota in renal cell carcinoma (RCC). Herein, publicly available platforms including Human Protein Atlas, cBioPortal, TIMER2.0, and TISIDB were utilized to depict a divergent implication of SUCNR1 in the immune microenvironment of clear cell RCC (KIRC) and papillary RCC (KIRP); the two major subtypes of RCC. Our results showed that the SUCNR1 expression level was augmented in RCC compared to other solid cancers, yet with opposite survival rate predictions in RCC subtypes. Consequently, a higher expression level of SUCNR1 was associated with a good disease-specific survival rate (p = 5.797 × 10-5) in KIRC patients albeit a poor prognostic prediction in KIRP patients (p = 1.9282 × 10-3). Intriguingly, SUCNR1 was mainly correlated to immunomodulators and diverse immune infiltrates in KIRP. Additionally, the SUCNR1 was mostly associated with a repertoire of microbes including beneficial bacteria that likely influenced a better disease-specific survival rate in KIRC. Our findings illustrate a significant novel subtype-specific role of SUCNR1 in RCC which potentially modulates tumor immune infiltration and microbiome signature, hence altering the prognosis of cancer patients.
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Affiliation(s)
- Rania Najm
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Mahmood Yaseen Hachim
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Richard K. Kandasamy
- Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway
- Department of Laboratory Medicine and Pathology, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Correspondence: or
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Nguyen G, Park SY, Do DV, Choi DH, Cho EH. Gemigliptin Alleviates Succinate-Induced Hepatic Stellate Cell Activation by Ameliorating Mitochondrial Dysfunction. Endocrinol Metab (Seoul) 2022; 37:918-928. [PMID: 36377343 PMCID: PMC9816499 DOI: 10.3803/enm.2022.1530] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 09/26/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGRUOUND Dipeptidyl peptidase-4 inhibitors (DPP-4Is) are used clinically as oral antidiabetic agents. Although DPP-4Is are known to ameliorate liver fibrosis, the protective mechanism of DPP-4Is in liver fibrosis remains obscure. In this study, gemigliptin was used to investigate the potential of DPP-4Is to alleviate the progression of liver fibrosis. METHODS To clarify the effects and mechanisms of gemigliptin, we conducted various experiments in LX-2 cells (immortalized human hepatic stellate cells [HSCs], the principal effectors of hepatic fibrogenesis), which were activated by succinate and exhibited elevated expression of α-smooth muscle actin, collagen type 1, and pro-inflammatory cytokines and increased cell proliferation. In vivo, we examined the effects and mechanisms of gemigliptin on a high-fat, high-cholesterol-induced mouse model of nonalcoholic steatohepatitis (NASH). RESULTS Gemigliptin decreased the expression of fibrogenesis markers and reduced the abnormal proliferation of HSCs. In addition, gemigliptin reduced the succinate-induced production of mitochondrial reactive oxygen species (ROS), intracellular ROS, and mitochondrial fission in HSCs. Furthermore, in the mouse model of NASH-induced liver fibrosis, gemigliptin alleviated both liver fibrosis and mitochondrial dysfunction. CONCLUSION Gemigliptin protected against HSC activation and liver fibrosis by alleviating mitochondrial dysfunction and ROS production, indicating its potential as a strategy for preventing the development of liver disease.
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Affiliation(s)
- Giang Nguyen
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - So Young Park
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Dinh Vinh Do
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Dae-Hee Choi
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Eun-Hee Cho
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
- Corresponding author: Eun-Hee Cho. Department of Internal Medicine, Kangwon National University School of Medicine, 1 Gangwondaehak-gil, Chuncheon 24341, Korea Tel: +82-33-258-9167, Fax: +82-33-258-2455, E-mail:
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Kuo CC, Wu JY, Wu KK. Cancer-derived extracellular succinate: a driver of cancer metastasis. J Biomed Sci 2022; 29:93. [DOI: 10.1186/s12929-022-00878-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 11/01/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractSuccinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of SDH subunits (SDHD and SDHB) in hereditary tumors such as paraganglioma or reduction of SDHB expression in cancer results in matrix succinate accumulation which is transported to cytoplasma and secreted into the extracellular milieu. Excessive cytosolic succinate is known to stabilize hypoxia inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylase. Recent reports indicate that cancer-secreted succinate enhances cancer cell migration and promotes cancer metastasis by activating succinate receptor-1 (SUCNR-1)-mediated signaling and transcription pathways. Cancer-derived extracellular succinate enhances cancer cell and macrophage migration through SUCNR-1 → PI-3 K → HIF-1α pathway. Extracellular succinate induces tumor angiogenesis through SUCNR-1-mediated ERK1/2 and STAT3 activation resulting in upregulation of vascular endothelial growth factor (VEGF) expression. Succinate increases SUCNR-1 expression in cancer cells which is considered as a target for developing new anti-metastasis drugs. Furthermore, serum succinate which is elevated in cancer patients may be a theranostic biomarker for selecting patients for SUCNR-1 antagonist therapy.
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Lee WC, Yu HR, Tain YL, Wu KL, Chuang YC, Chan JY. Vinpocetine Ameliorates Metabolic-Syndrome-Associated Bladder Overactivity in Fructose-Fed Rats by Restoring Succinate-Modulated cAMP Levels and Exerting Anti-Inflammatory Effects in the Bladder Detrusor Muscle. Biomedicines 2022; 10:2716. [PMID: 36359236 PMCID: PMC9687486 DOI: 10.3390/biomedicines10112716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 11/03/2023] Open
Abstract
Succinate and its receptor, the G protein-coupled receptor 91 (GPR91), have pathological implications in metabolic syndrome (MetS) and its associated bladder dysfunction, particularly in decreasing bladder cAMP levels and promoting proinflammation. Using fructose-fed rats (FFRs), a rat model of MetS, we investigate the effects of vinpocetine (a phosphodiesterase-1 inhibitor) and celecoxib (a selective cyclooxygenase-2 inhibitor) on MetS-associated bladder overactivity. Phenotypes of the overactive bladder, including increased micturition frequency and a shortened intercontractile interval in cystometry, were observed in FFRs, together with elevated succinate levels in the liver and serum and the downregulation of GPR91 in the liver and urinary bladder. Treatments with vinpocetine and celecoxib improved tissue fibrosis and ameliorated the overexpression of the inflammatory cytokines, such as IL-1β, in the liver and bladder. In bladder organ bath studies, vinpocetine, but not celecoxib, treatment restored the contraction and relaxation responses of the detrusor muscle strip in response to KCl, carbachol, and forskolin stimulation. At a molecular level, vinpocetine and celecoxib treatments modulated the downstream messengers of GPR91 (i.e., ERK1/2 and JNK), suppressed NF-κB and IL-1β expressions in the bladder, and prevented the fibrogenesis observed in FFRs. The exogenous application of succinate to a bladder organ bath significantly reduced the forskolin-induced cAMP production by the detrusor muscle, which was notably restored in the presence of vinpocetine. Together, these results suggest that vinpocetine may alleviate the MetS-associated bladder overactivity by restoring the succinate-modulated detrusor cAMP production and exerting the anti-inflammatory effects in the bladder detrusor muscle.
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Affiliation(s)
- Wei-Chia Lee
- Division of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Hong-Ren Yu
- Department of Paediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - You-Lin Tain
- Department of Paediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Kay L.H. Wu
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Yao-Chi Chuang
- Division of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Julie Y.H. Chan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
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21
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Hughey CC, Puchalska P, Crawford PA. Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159209. [DOI: 10.1016/j.bbalip.2022.159209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 06/25/2022] [Accepted: 07/27/2022] [Indexed: 11/28/2022]
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22
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Detraux D, Renard P. Succinate as a New Actor in Pluripotency and Early Development? Metabolites 2022; 12:651. [PMID: 35888775 PMCID: PMC9325148 DOI: 10.3390/metabo12070651] [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] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/01/2022] [Accepted: 07/13/2022] [Indexed: 02/07/2023] Open
Abstract
Pluripotent cells have been stabilized from pre- and post-implantation blastocysts, representing respectively naïve and primed stages of embryonic stem cells (ESCs) with distinct epigenetic, metabolic and transcriptomic features. Beside these two well characterized pluripotent stages, several intermediate states have been reported, as well as a small subpopulation of cells that have reacquired features of the 2C-embryo (2C-like cells) in naïve mouse ESC culture. Altogether, these represent a continuum of distinct pluripotency stages, characterized by metabolic transitions, for which we propose a new role for a long-known metabolite: succinate. Mostly seen as the metabolite of the TCA, succinate is also at the crossroad of several mitochondrial biochemical pathways. Its role also extends far beyond the mitochondrion, as it can be secreted, modify proteins by lysine succinylation and inhibit the activity of alpha-ketoglutarate-dependent dioxygenases, such as prolyl hydroxylase (PHDs) or histone and DNA demethylases. When released in the extracellular compartment, succinate can trigger several key transduction pathways after binding to SUCNR1, a G-Protein Coupled Receptor. In this review, we highlight the different intra- and extracellular roles that succinate might play in the fields of early pluripotency and embryo development.
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Affiliation(s)
| | - Patricia Renard
- Laboratory of Biochemistry and Cell Biology (URBC), Namur Research Institute for Life Sciences (NARILIS), University of Namur (UNamur), 5000 Namur, Belgium;
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23
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Feng J, Lu M, Li W, Li J, Meng P, Li Z, Gao X, Zhang Y. PPARγ alleviates peritoneal fibrosis progression along with promoting GLUT1 expression and suppressing peritoneal mesothelial cell proliferation. Mol Cell Biochem 2022; 477:1959-1971. [PMID: 35380292 PMCID: PMC9206601 DOI: 10.1007/s11010-022-04419-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 03/17/2022] [Indexed: 11/17/2022]
Abstract
OBJECTIVE Peritoneal fibrosis (PF) is commonly induced by bioincompatible dialysate exposure during peritoneal dialysis, but the underlying mechanisms remain elusive. This study aimed to investigate the roles of peroxisome proliferator-activated receptor gamma (PPARγ) in PF pathogenesis. METHODS Rat and cellular PF models were established by high glucose dialysate and lipopolysaccharide treatments. Serum creatinine, urea nitrogen, and glucose contents were detected by ELISA. Histological evaluation was done through H&E and Masson staining. GLUT1, PPARγ, and other protein expression were measured by qRT-PCR, western blotting, and IHC. PPARγ and GLUT1 subcellular distribution were detected using confocal microscopy. Cell proliferation was assessed by MTT and Edu staining. RESULTS Serum creatinine, urea nitrogen and glucose, and PPARγ and GLUT1 expression in rat PF model were reduced by PPARγ agonists Rosiglitazone or 15d-PGJ2 and elevated by antagonist GW9662. Rosiglitazone or 15d-PGJ2 repressed and GW9662 aggravated peritoneal fibrosis in rat PF model. PPARγ and GLUT1 were mainly localized in nucleus and cytosols of peritoneal mesothelial cells, respectively, which were reduced in cellular PF model, enhanced by Rosiglitazone or 15d-PGJ2, and repressed by GW9662. TGF-β and a-SMA expression was elevated in cellular PF model, which was inhibited by Rosiglitazone or 15d-PGJ2 and promoted by GW9662. PPARγ silencing reduced GLUT1, elevated a-SMA and TGF-b expression, and promoted peritoneal mesothelial cell proliferation, which were oppositely changed by PPARγ overexpression. CONCLUSION PPARγ inhibited high glucose-induced peritoneal fibrosis progression through elevating GLUT1 expression and repressing peritoneal mesothelial cell proliferation.
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Affiliation(s)
- Junxia Feng
- Department of Nephrology, Affiliated Huadu Hospital, Southern Medical University (People's Hospital of Huadu District), 48 Xinhua Road, 510800, Guangzhou, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Meizhi Lu
- Department of Nephrology, Affiliated Huadu Hospital, Southern Medical University (People's Hospital of Huadu District), 48 Xinhua Road, 510800, Guangzhou, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Wenhao Li
- Department of Nephrology, Affiliated Huadu Hospital, Southern Medical University (People's Hospital of Huadu District), 48 Xinhua Road, 510800, Guangzhou, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jingchun Li
- Department of Nephrology, Affiliated Huadu Hospital, Southern Medical University (People's Hospital of Huadu District), 48 Xinhua Road, 510800, Guangzhou, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Ping Meng
- Department of Nephrology, Affiliated Huadu Hospital, Southern Medical University (People's Hospital of Huadu District), 48 Xinhua Road, 510800, Guangzhou, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zukai Li
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Xuejuan Gao
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, Jinan University, Guangzhou, China.
| | - Yunfang Zhang
- Department of Nephrology, Affiliated Huadu Hospital, Southern Medical University (People's Hospital of Huadu District), 48 Xinhua Road, 510800, Guangzhou, China.
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.
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Pardella E, Ippolito L, Giannoni E, Chiarugi P. Nutritional and metabolic signalling through GPCRs. FEBS Lett 2022; 596:2364-2381. [PMID: 35776088 DOI: 10.1002/1873-3468.14441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/17/2022] [Accepted: 06/20/2022] [Indexed: 11/11/2022]
Abstract
Deregulated metabolism is a well-known feature of several challenging diseases, including diabetes, obesity and cancer. Besides their important role as intracellular bioenergetic molecules, dietary nutrients and metabolic intermediates are released in the extracellular environment. As such, they may achieve unconventional roles as hormone-like molecules by activating cell-surface G-protein-coupled receptors (GPCRs) that regulate several pathophysiological processes. In this review, we provide an insight into the role of lactate, succinate, fatty acids, amino acids, ketogenesis-derived and β-oxidation-derived intermediates as extracellular signalling molecules. Moreover, the mechanisms by which their cognate metabolite-sensing GPCRs integrate nutritional and metabolic signals with specific intracellular pathways will be described. A better comprehension of these aspects is of fundamental importance to identify GPCRs as novel druggable targets.
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Affiliation(s)
- Elisa Pardella
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134, Florence, Italy
| | - Luigi Ippolito
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134, Florence, Italy
| | - Elisa Giannoni
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134, Florence, Italy
| | - Paola Chiarugi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134, Florence, Italy
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25
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Rojas Á, García-Lozano MR, Gil-Gómez A, Romero-Gómez M, Ampuero J. Glutaminolysis-ammonia-urea Cycle Axis, Non-alcoholic Fatty Liver Disease Progression and Development of Novel Therapies. J Clin Transl Hepatol 2022; 10:356-362. [PMID: 35528989 PMCID: PMC9039703 DOI: 10.14218/jcth.2021.00247] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 07/29/2021] [Accepted: 10/14/2021] [Indexed: 12/04/2022] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide, reflecting the current epidemics of obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome. NAFLD is characterized by the accumulation of fat in the liver, and is known to be a cause of cirrhosis. Although many pathways have been proposed, the cause of NAFLD-linked fibrosis progression is still unclear, which posed challenges for the development of new therapies to prevent NASH-related cirrhosis and hepatocellular carcinoma. Cirrhosis is associated with activation of hepatic stellate cells (HSC) and accumulation of excess extracellular matrix proteins, and inhibiting the activation of HSCs would be expected to slow the progression of NAFLD-cirrhosis. Multiple molecular signals and pathways such as oxidative stress and glutaminolysis have been reported to promote HSC activation. Both mechanisms are plausible antifibrotic targets in NASH, as the activation of HSCs the proliferation of myofibroblasts depend on those processes. This review summarizes the role of the glutaminolysis-ammonia-urea cycle axis in the context of NAFLD progression, and shows how the axis could be a novel therapeutic target.
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Affiliation(s)
- Ángela Rojas
- Department of Unit of Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
- SeLiver group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital/CSIC/ University of Seville, Seville, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - María Rosario García-Lozano
- Department of Unit of Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
- SeLiver group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital/CSIC/ University of Seville, Seville, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071, Seville, Spain
| | - Antonio Gil-Gómez
- Department of Unit of Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
- SeLiver group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital/CSIC/ University of Seville, Seville, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Manuel Romero-Gómez
- Department of Unit of Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
- SeLiver group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital/CSIC/ University of Seville, Seville, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Javier Ampuero
- Department of Unit of Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
- SeLiver group at the Institute of Biomedicine of Seville (IBIS), Virgen del Rocío University Hospital/CSIC/ University of Seville, Seville, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Correspondence to: Javier Ampuero, Digestive Disease Department and CIBERehd, Virgen del Rocio University Hospital, Avenida Manuel Siurot s/n, Sevilla 41013, Spain. ORCID: https://orcid.org/0000-0002-8332-2122. Tel: +34-955-015761, Fax: +34-955-015899, E-mail:
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26
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Nucera S, Ruga S, Cardamone A, Coppoletta AR, Guarnieri L, Zito MC, Bosco F, Macrì R, Scarano F, Scicchitano M, Maiuolo J, Carresi C, Mollace R, Cariati L, Mazzarella G, Palma E, Gliozzi M, Musolino V, Cascini GL, Mollace V. MAFLD progression contributes to altered thalamus metabolism and brain structure. Sci Rep 2022; 12:1207. [PMID: 35075185 PMCID: PMC8786899 DOI: 10.1038/s41598-022-05228-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 01/07/2022] [Indexed: 12/02/2022] Open
Abstract
Metabolic associated fatty liver disease (MAFLD), commonly known as non-alcoholic fatty liver disease, represents a continuum of events characterized by excessive hepatic fat accumulation which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and in some severe cases hepatocellular carcinoma. MAFLD might be considered as a multisystem disease that affects not only the liver but involves wider implications, relating to several organs and systems, the brain included. The present study aims to investigate changes associated with MAFLD-induced alteration of thalamic metabolism in vivo. DIAMOND (Diet-induced animal model of non-alcoholic fatty liver disease) mice were fed a chow diet and tap water (NC NW) or fat Western Diet (WD SW) for up to 28 weeks. At the baseline and weeks 4, 8, 20, 28 the thalamic neurochemical profile and total cerebral brain volume were evaluated longitudinally in both diet groups using 1H-MRS. To confirm the disease progression, at each time point, a subgroup of animals was sacrificed, the livers excised and placed in formalin. Liver histology was assessed and reviewed by an expert liver pathologist. MAFLD development significantly increases the thalamic levels of total N-acetylaspartate, total creatine, total choline, and taurine. Furthermore, in the WD SW group a reduction in total cerebral brain volume has been observed (p < 0.05 vs NC NW). Our results suggest that thalamic energy metabolism is affected by MAFLD progression. This metabolic imbalance, that is quantifiable by 1H-MRS in vivo, might cause structural damage to brain cells and dysfunctions of neurotransmitter release.
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Affiliation(s)
- Saverio Nucera
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Stefano Ruga
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Antonio Cardamone
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Anna Rita Coppoletta
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Lorenza Guarnieri
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Maria Caterina Zito
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Francesca Bosco
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Roberta Macrì
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Federica Scarano
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Miriam Scicchitano
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Jessica Maiuolo
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Cristina Carresi
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Rocco Mollace
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Luca Cariati
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Giuseppe Mazzarella
- Nuclear Medicine Unit, Department of Diagnostic Imaging, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Ernesto Palma
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Micaela Gliozzi
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy.
| | - Vincenzo Musolino
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Giuseppe Lucio Cascini
- Nuclear Medicine Unit, Department of Diagnostic Imaging, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Vincenzo Mollace
- Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
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Zhang IW, López-Vicario C, Duran-Güell M, Clària J. Mitochondrial Dysfunction in Advanced Liver Disease: Emerging Concepts. Front Mol Biosci 2021; 8:772174. [PMID: 34888354 PMCID: PMC8650317 DOI: 10.3389/fmolb.2021.772174] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/04/2021] [Indexed: 12/12/2022] Open
Abstract
Mitochondria are entrusted with the challenging task of providing energy through the generation of ATP, the universal cellular currency, thereby being highly flexible to different acute and chronic nutrient demands of the cell. The fact that mitochondrial diseases (genetic disorders caused by mutations in the nuclear or mitochondrial genome) manifest through a remarkable clinical variation of symptoms in affected individuals underlines the far-reaching implications of mitochondrial dysfunction. The study of mitochondrial function in genetic or non-genetic diseases therefore requires a multi-angled approach. Taking into account that the liver is among the organs richest in mitochondria, it stands to reason that in the process of unravelling the pathogenesis of liver-related diseases, researchers give special focus to characterizing mitochondrial function. However, mitochondrial dysfunction is not a uniformly defined term. It can refer to a decline in energy production, increase in reactive oxygen species and so forth. Therefore, any study on mitochondrial dysfunction first needs to define the dysfunction to be investigated. Here, we review the alterations of mitochondrial function in liver cirrhosis with emphasis on acutely decompensated liver cirrhosis and acute-on-chronic liver failure (ACLF), the latter being a form of acute decompensation characterized by a generalized state of systemic hyperinflammation/immunosuppression and high mortality rate. The studies that we discuss were either carried out in liver tissue itself of these patients, or in circulating leukocytes, whose mitochondrial alterations might reflect tissue and organ mitochondrial dysfunction. In addition, we present different methodological approaches that can be of utility to address the diverse aspects of hepatocyte and leukocyte mitochondrial function in liver disease. They include assays to measure metabolic fluxes using the comparatively novel Biolog’s MitoPlates in a 96-well format as well as assessment of mitochondrial respiration by high-resolution respirometry using Oroboros’ O2k-technology and Agilent Seahorse XF technology.
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Affiliation(s)
- Ingrid W Zhang
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain.,European Foundation for the Study of Chronic Liver Failure (EF Clif) and Grifols Chair, Barcelona, Spain
| | - Cristina López-Vicario
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain.,European Foundation for the Study of Chronic Liver Failure (EF Clif) and Grifols Chair, Barcelona, Spain.,CIBERehd, Barcelona, Spain
| | - Marta Duran-Güell
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain.,European Foundation for the Study of Chronic Liver Failure (EF Clif) and Grifols Chair, Barcelona, Spain
| | - Joan Clària
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain.,European Foundation for the Study of Chronic Liver Failure (EF Clif) and Grifols Chair, Barcelona, Spain.,CIBERehd, Barcelona, Spain.,Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain
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28
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Wu KK. Control of Tissue Fibrosis by 5-Methoxytryptophan, an Innate Anti-Inflammatory Metabolite. Front Pharmacol 2021; 12:759199. [PMID: 34858185 PMCID: PMC8632247 DOI: 10.3389/fphar.2021.759199] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/28/2021] [Indexed: 12/23/2022] Open
Abstract
Tissue fibrosis causes debilitating human diseases such as liver cirrhosis, heart failure, chronic kidney disease and pulmonary insufficiency. It is a dynamic process orchestrated by specific subsets of monocyte-macrophages, fibroblasts, pericytes and hepatic stellate cells. Fibrosis is linked to tissue inflammation. Pro-inflammatory macrophages promote fibrosis by driving myofibroblast differentiation and macrophage myofibroblast transition. Myofibroblasts express α-smooth muscle cell actin (α-SMA) and secrete extracellular matrix (ECM) proteins notably collagen I and III. Deposition of ECM proteins at injury sites and interstitial tissues distorts normal structure and impairs vital functions. Despite advances in the mechanisms of fibrosis at cellular, molecular and genetic levels, prevention and treatment of fibrotic diseases remain poorly developed. Recent reports suggest that 5-methoxytryptophan (5-MTP) is effective in attenuating injury-induced liver, kidney, cardiac and pulmonary fibrosis. It inhibits macrophage activation and blocks fibroblast differentiation to myofibroblasts. Furthermore, it inhibits hepatic stellate cell differentiation into myofibroblasts. As 5-MTP is an endogenous molecule derived from tryptophan catabolism via tryptophan hydroxylase pathway, it is well-suited as a lead compound for developing new anti-fibrotic drugs. This article provides an overview of 5-MTP synthesis, and a critical review of its anti-fibrotic activities. Its mechanisms of actions and potential therapeutic value will be discussed.
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Affiliation(s)
- Kenneth K Wu
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.,Institute of Biotechnology, College of Life Science, National Tsing-Hua University, Hsinchu, Taiwan
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29
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Priming, Triggering, Adaptation and Senescence (PTAS): A Hypothesis for a Common Damage Mechanism of Steatohepatitis. Int J Mol Sci 2021; 22:ijms222212545. [PMID: 34830427 PMCID: PMC8624051 DOI: 10.3390/ijms222212545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 11/17/2022] Open
Abstract
Understanding the pathomechanism of steatohepatitis (SH) is hampered by the difficulty of distinguishing between causes and consequences, by the broad spectrum of aetiologies that can produce the phenotype, and by the long time-span during which SH develops, often without clinical symptoms. We propose that SH develops in four phases with transitions: (i) priming lowers stress defence; (ii) triggering leads to acute damage; (iii) adaptation, possibly associated with cellular senescence, mitigates tissue damage, leads to the phenotype, and preserves liver function at a lower level; (iv) finally, senescence prevents neoplastic transformation but favours fibrosis (cirrhosis) and inflammation and further reduction in liver function. Escape from senescence eventually leads to hepatocellular carcinoma. This hypothesis for a pathomechanism of SH is supported by clinical and experimental observations. It allows organizing the various findings to uncover remaining gaps in our knowledge and, finally, to provide possible diagnostic and intervention strategies for each stage of SH development.
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Foresight regarding drug candidates acting on the succinate-GPR91 signalling pathway for non-alcoholic steatohepatitis (NASH) treatment. Biomed Pharmacother 2021; 144:112298. [PMID: 34649219 DOI: 10.1016/j.biopha.2021.112298] [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: 08/30/2021] [Revised: 09/29/2021] [Accepted: 10/05/2021] [Indexed: 11/24/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and it is a liver manifestation of metabolic syndrome, with a histological spectrum from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH can evolve into progressive liver fibrosis and eventually lead to liver cirrhosis. The pathological mechanism of NASH is multifactorial, involving a series of metabolic disorders and changes that trigger low-level inflammation in the liver and other organs. In the pathogenesis of NASH, the signal transduction pathway involving succinate and the succinate receptor (G-protein-coupled receptor 91, GPR91) regulates inflammatory cell activation and liver fibrosis. This review describes the mechanism of the succinate-GPR91 signalling pathway in NASH and summarizes the drugs that act on this pathway, with the aim of providing a new approach to NASH treatment.
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An YA, Chen S, Deng Y, Wang ZV, Funcke JB, Shah M, Shan B, Gordillo R, Yoshino J, Klein S, Kusminski CM, Scherer PE. The mitochondrial dicarboxylate carrier prevents hepatic lipotoxicity by inhibiting white adipocyte lipolysis. J Hepatol 2021; 75:387-399. [PMID: 33746082 PMCID: PMC8292187 DOI: 10.1016/j.jhep.2021.03.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 01/25/2021] [Accepted: 03/02/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS We have previously reported that the mitochondrial dicarboxylate carrier (mDIC [SLC25A10]) is predominantly expressed in the white adipose tissue (WAT) and subject to regulation by metabolic cues. However, the specific physiological functions of mDIC and the reasons for its abundant presence in adipocytes are poorly understood. METHODS To systemically investigate the impact of mDIC function in adipocytes in vivo, we generated loss- and gain-of-function mouse models, selectively eliminating or overexpressing mDIC in mature adipocytes, respectively. RESULTS In in vitro differentiated white adipocytes, mDIC is responsible for succinate transport from the mitochondrial matrix to the cytosol, from where succinate can act on the succinate receptor SUCNR1 and inhibit lipolysis by dampening the cAMP- phosphorylated hormone-sensitive lipase (pHSL) pathway. We eliminated mDIC expression in adipocytes in a doxycycline (dox)-inducible manner (mDICiKO) and demonstrated that such a deletion results in enhanced adipocyte lipolysis and promotes high-fat diet (HFD)-induced adipocyte dysfunction, liver lipotoxicity, and systemic insulin resistance. Conversely, in a mouse model with dox-inducible, adipocyte-specific overexpression of mDIC (mDICiOE), we observed suppression of adipocyte lipolysis both in vivo and ex vivo. mDICiOE mice are potently protected from liver lipotoxicity upon HFD feeding. Furthermore, they show resistance to HFD-induced weight gain and adipose tissue expansion with concomitant improvements in glucose tolerance and insulin sensitivity. Beyond our data in rodents, we found that human WAT SLC25A10 mRNA levels are positively correlated with insulin sensitivity and negatively correlated with intrahepatic triglyceride levels, suggesting a critical role of mDIC in regulating overall metabolic homeostasis in humans as well. CONCLUSIONS In summary, we highlight that mDIC plays an essential role in governing adipocyte lipolysis and preventing liver lipotoxicity in response to a HFD. LAY SUMMARY Dysfunctional fat tissue plays an important role in the development of fatty liver disease and liver injury. Our present study identifies a mitochondrial transporter, mDIC, which tightly controls the release of free fatty acids from adipocytes to the liver through the export of succinate from mitochondria. We believe this mDIC-succinate axis could be targeted for the treatment of fatty liver disease.
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Affiliation(s)
- Yu A. An
- Touchstone Diabetes Center, Department of Internal Medicine
| | - Shiuhwei Chen
- Touchstone Diabetes Center, Department of Internal Medicine
| | - Yingfeng Deng
- Touchstone Diabetes Center, Department of Internal Medicine
| | - Zhao V. Wang
- Division of Cardiology, Department of Internal Medicine
| | | | - Manasi Shah
- Division of Endocrinology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Bo Shan
- Touchstone Diabetes Center, Department of Internal Medicine
| | - Ruth Gordillo
- Touchstone Diabetes Center, Department of Internal Medicine
| | - Jun Yoshino
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Samuel Klein
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA
| | | | - Philipp E. Scherer
- Touchstone Diabetes Center, Department of Internal Medicine,Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX, USA,Correspondence should be addressed to: Dr. Philipp E. Scherer, Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Tel: 214-6488715; Fax: 214-648-8720;
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Wang Z, Chen L, Huang Y, Luo M, Wang H, Jiang Z, Zheng J, Yang Z, Chen Z, Zhang C, Long L, Wang Y, Li X, Liao F, Gan Y, Luo P, Liu Y, Wang Y, XuTan, Zhou Z, Zhang A, Shi C. Pharmaceutical targeting of succinate dehydrogenase in fibroblasts controls bleomycin-induced lung fibrosis. Redox Biol 2021; 46:102082. [PMID: 34343908 PMCID: PMC8342973 DOI: 10.1016/j.redox.2021.102082] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/23/2021] [Indexed: 12/20/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to chronically compromising lung function and death. However, very little is known about the metabolic alterations of fibroblasts in IPF, and there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Here we show a glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts from fibrotic lung, and perturbation of glycolysis and FAO affects fibroblasts transdifferentiation. In addition, there is a significant accumulation of succinate both in fibrotic lung tissues and myofibroblasts, where succinate dehydrogenase (SDH) operates in reverse by reducing fumarate to succinate. Then succinate contributes to glycolysis upregulation and FAO downregulation by stabilizing HIF-1α, which promotes the development of lung fibrosis. In addition, we identify a near-infrared small molecule dye, IR-780, as a targeting agent which stimulates mild inhibition of succinate dehydrogenase subunit A (SDHA) in fibroblasts, and which inhibits TGF-β1 induced SDH and succinate elevation, then to prevent fibrosis formation and respiratory dysfunction. Further, enhanced cell retention of IR-780 is shown to promote severe inhibition of SDHA in myofibroblasts, which may contribute to excessive ROS generation and selectively induces myofibroblasts to apoptosis, and then therapeutically improves established lung fibrosis in vivo. These findings indicate that targeting metabolic dysregulation has significant implications for therapies aimed at lung fibrosis and succinate dehydrogenase is an exciting new therapeutic target to treat IPF.
Glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts lead to lung fibrosis. Succinate contributes to metabolic dysregulation of fibroblasts by stabilizing HIF-1α. Succinate dehydrogenase is an exciting new therapeutic target to treat IPF. IR-780 can be a promising agent to control lung fibrosis by targeting succinate dehydrogenase.
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Affiliation(s)
- Ziwen Wang
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Department of Cardiology, Geriatric Cardiovascular Disease Research and Treatment Center, The 82nd Group Army Hospital of PLA (252 Hospital of PLA), Baoding, Hebei, 071000, China
| | - Long Chen
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yu Huang
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, Guizhou Medical University, Guiyang, 550025, China
| | - Min Luo
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, Guizhou Medical University, Guiyang, 550025, China
| | - Huilan Wang
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Institute of Clinical Medicine, Southwest Medical University, Luzhou, 646000, China
| | - Zhongyong Jiang
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Jiancheng Zheng
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Zeyu Yang
- Breast and Thyroid Surgical Department, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, China
| | - Zelin Chen
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Chi Zhang
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Lei Long
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yawei Wang
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Xueru Li
- Department of Ophthalmology, Third Affiliated Hospital of Chongqing Medical University (Gener Hospital), Chongqing, 401120, China
| | - Fengying Liao
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yibo Gan
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Peng Luo
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yunsheng Liu
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yu Wang
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - XuTan
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Ziyuan Zhou
- Department of Environmental Health, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
| | - Aihua Zhang
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, Guizhou Medical University, Guiyang, 550025, China.
| | - Chunmeng Shi
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
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Signals from the Circle: Tricarboxylic Acid Cycle Intermediates as Myometabokines. Metabolites 2021; 11:metabo11080474. [PMID: 34436415 PMCID: PMC8398969 DOI: 10.3390/metabo11080474] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/15/2022] Open
Abstract
Regular physical activity is an effective strategy to prevent and ameliorate aging-associated diseases. In particular, training increases muscle performance and improves whole-body metabolism. Since exercise affects the whole organism, it has countless health benefits. The systemic effects of exercise can, in part, be explained by communication between the contracting skeletal muscle and other organs and cell types. While small proteins and peptides known as myokines are the most prominent candidates to mediate this tissue cross-talk, recent investigations have paid increasing attention to metabolites. The purpose of this review is to highlight the potential role of tricarboxylic acid (TCA) metabolites as humoral mediators of exercise adaptation processes. We focus on TCA metabolites that are released from human skeletal muscle in response to exercise and provide an overview of their potential auto-, para- or endocrine health-promoting effects.
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Staňková P, Kučera O, Peterová E, Elkalaf M, Rychtrmoc D, Melek J, Podhola M, Zubáňová V, Červinková Z. Western Diet Decreases the Liver Mitochondrial Oxidative Flux of Succinate: Insight from a Murine NAFLD Model. Int J Mol Sci 2021; 22:6908. [PMID: 34199098 PMCID: PMC8268937 DOI: 10.3390/ijms22136908] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/20/2021] [Accepted: 06/23/2021] [Indexed: 12/12/2022] Open
Abstract
Mitochondria play an essential role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Previously, we found that succinate-activated respiration was the most affected mitochondrial parameter in mice with mild NAFLD. In this study, we focused on the role of succinate dehydrogenase (SDH) in NAFLD pathogenesis. To induce the progression of NAFLD to nonalcoholic steatohepatitis (NASH), C57BL/6J mice were fed a Western-style diet (WD) or control diet for 30 weeks. NAFLD severity was evaluated histologically and the expression of selected proteins and genes was assessed. Mitochondrial respiration was measured by high-resolution respirometry. Liver redox status was assessed using glutathione, malondialdehyde, and mitochondrial production of reactive oxygen species (ROS). Metabolomic analysis was performed by GC/MS. WD consumption for 30 weeks led to reduced succinate-activated respiration. We also observed decreased SDH activity, decreased expression of the SDH activator sirtuin 3, decreased gene expression of SDH subunits, and increased levels of hepatic succinate, an important signaling molecule. Succinate receptor 1 (SUCNR1) gene and protein expression were reduced in the livers of WD-fed mice. We did not observe signs of oxidative damage compared to the control group. The changes observed in WD-fed mice appear to be adaptive to prevent mitochondrial respiratory chain overload and massive ROS production.
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Affiliation(s)
- Pavla Staňková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (E.P.); (M.E.); (D.R.); (J.M.); (V.Z.); (Z.Č.)
| | - Otto Kučera
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (E.P.); (M.E.); (D.R.); (J.M.); (V.Z.); (Z.Č.)
| | - Eva Peterová
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (E.P.); (M.E.); (D.R.); (J.M.); (V.Z.); (Z.Č.)
- Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic
| | - Moustafa Elkalaf
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (E.P.); (M.E.); (D.R.); (J.M.); (V.Z.); (Z.Č.)
- Department of Pathophysiology, Third Faculty of Medicine, Charles University Prague, Ruská 87, 100 00 Prague, Czech Republic
| | - David Rychtrmoc
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (E.P.); (M.E.); (D.R.); (J.M.); (V.Z.); (Z.Č.)
| | - Jan Melek
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (E.P.); (M.E.); (D.R.); (J.M.); (V.Z.); (Z.Č.)
| | - Miroslav Podhola
- The Fingerland Department of Pathology, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic;
| | - Veronika Zubáňová
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (E.P.); (M.E.); (D.R.); (J.M.); (V.Z.); (Z.Č.)
- Department of Clinical Biochemistry and Diagnostics, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic
| | - Zuzana Červinková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (E.P.); (M.E.); (D.R.); (J.M.); (V.Z.); (Z.Č.)
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Jiang L, Schnabl B. Gut Microbiota in Liver Disease: What Do We Know and What Do We Not Know? Physiology (Bethesda) 2021; 35:261-274. [PMID: 32490750 DOI: 10.1152/physiol.00005.2020] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The gut and the liver have a bidirectional communication via the biliary system and the portal vein. The intestinal microbiota and microbial products play an important role for modulating liver diseases such as alcohol-associated liver disease, non-alcoholic fatty liver disease and steatohepatitis, and cholestatic liver diseases. Here, we review the role of the gut microbiota and its products for the pathogenesis and therapy of chronic liver diseases.
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Affiliation(s)
- Lu Jiang
- Department of Medicine, University of California San Diego, La Jolla, California; and Department of Medicine, VA San Diego Healthcare System, San Diego, California
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California; and Department of Medicine, VA San Diego Healthcare System, San Diego, California
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Ho CH, Huang JH, Sun MS, Tzeng IS, Hsu YC, Kuo CY. Wild Bitter Melon Extract Regulates LPS-Induced Hepatic Stellate Cell Activation, Inflammation, Endoplasmic Reticulum Stress, and Ferroptosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:6671129. [PMID: 34239589 PMCID: PMC8241502 DOI: 10.1155/2021/6671129] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 06/17/2021] [Indexed: 12/21/2022]
Abstract
The activation of hepatic stellate cells (HSCs) is a key component of liver fibrosis. Two antifibrosis pathways have been identified, the reversion to quiescent-type HSCs and the clearance of HSCs through apoptosis. Lipopolysaccharide- (LPS-) induced HSCs activation and proliferation have been associated with the development of liver fibrosis. We determined the pharmacological effects of wild bitter melon (WM) on HSC activation following LPS treatment and investigated whether WM treatment affected cell death pathways under LPS-treated conditions, including ferroptosis. WM treatment caused cell death, both with and without LPS treatment. WM treatment caused reactive oxygen species (ROS) accumulation without LPS treatment and reversed the decrease in lipid ROS production in HSCs after LPS treatment. We examined the effects of WM treatment on fibrosis, endoplasmic reticulum (ER) stress, inflammation, and ferroptosis in LPS-activated HSCs. The western blotting analysis revealed that the WM treatment of LPS-activated HSCs induced the downregulation of the connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), integrin-β1, phospho-JNK (p-JNK), glutathione peroxidase 4 (GPX4), and cystine/glutamate transporter (SLC7A11) and the upregulation of CCAAT enhancer-binding protein homologous protein (CHOP). These results support WM as an antifibrotic agent that may represent a potential therapeutic solution for the management of liver fibrosis.
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Affiliation(s)
- Chang-Hsun Ho
- Department of Anesthesiology, Show Chwan Memorial Hospital, Changhua, Taiwan
| | - Jen-Hsuan Huang
- Department of Anesthesiology, Show Chwan Memorial Hospital, Changhua, Taiwan
| | - Maw-Sheng Sun
- Department of Anesthesiology, Show Chwan Memorial Hospital, Changhua, Taiwan
- Department of Nursing, Meiho University, Pingtung, Taiwan
| | - I-Shiang Tzeng
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Yi-Chiung Hsu
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan
| | - Chan-Yen Kuo
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
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Gilgenkrantz H, Mallat A, Moreau R, Lotersztajn S. Targeting cell-intrinsic metabolism for antifibrotic therapy. J Hepatol 2021; 74:1442-1454. [PMID: 33631228 DOI: 10.1016/j.jhep.2021.02.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/02/2021] [Accepted: 02/04/2021] [Indexed: 12/12/2022]
Abstract
In recent years, there have been major advances in our understanding of the mechanisms underlying fibrosis progression and regression, and how coordinated interactions between parenchymal and non-parenchymal cells impact on the fibrogenic process. Recent studies have highlighted that metabolic reprogramming of parenchymal cells, immune cells (immunometabolism) and hepatic stellate cells is required to support the energetic and anabolic demands of phenotypic changes and effector functions. In this review, we summarise how targeting cell-intrinsic metabolic modifications of the main fibrogenic cell actors may impact on fibrosis progression and we discuss the antifibrogenic potential of metabolically targeted interventions.
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Affiliation(s)
- Helene Gilgenkrantz
- Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d'Excellence Inflamex, F-75018 Paris, France
| | - Ariane Mallat
- Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d'Excellence Inflamex, F-75018 Paris, France
| | - Richard Moreau
- Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d'Excellence Inflamex, F-75018 Paris, France
| | - Sophie Lotersztajn
- Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d'Excellence Inflamex, F-75018 Paris, France.
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Liu D, Yu Q, Li Z, Zhang L, Hu M, Wang C, Liu Z. UGT1A1 dysfunction increases liver burden and aggravates hepatocyte damage caused by long-term bilirubin metabolism disorder. Biochem Pharmacol 2021; 190:114592. [PMID: 33961837 DOI: 10.1016/j.bcp.2021.114592] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/29/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022]
Abstract
UGT1A1 is the only enzyme that can metabolize bilirubin, and its encoding gene is frequently mutated. UGT1A1*6 (G71R) is a common mutant in Asia which leads to the decrease of UGT1A1 activity and abnormal bilirubin metabolism. However, it is not clear whether low UGT1A1 activity-induced bilirubin metabolism disorder increases hepatocyte fragility. ugt1a+/- mice were used to simulate the UGT1A1*6 (G71R) population. Under the same CCl4 induction condition, ugt1a+/- mice showed severer liver damage and fibrosis, indicating that ugt1a1 dysfunction increased liver burden and aggravated hepatocyte damage. In the animal experiment with a continuous intraperitoneal injection of bilirubin, the ugt1a+/- mice livers had more serious unconjugated bilirubin accumulation. The accumulated bilirubin leads to hyperphosphorylation of IκB-α, Ikk-β, and p65 and a significant increase of inflammatory factor. The α-SMA and Collagen I proteins markedly up-regulated in the ugt1a+/- mice livers. Immunofluorescence and confocal microscopy showed that hepatic stellate cells and Kupffer cells were activated in ugt1a+/- mice. Comprehensive results show that there was a crosstalk relationship between low UGT1A1 activity-bilirubin-liver damage. Furthermore, cell experiments confirmed that unconjugated bilirubin activated the NF-κB pathway and induced DNA damage in hepatocytes, leading to the significant increase of inflammatory factors. UGT1A1 knockdown in hepatocytes aggravated the toxicity of unconjugated bilirubin. Conversely, overexpression of UGT1A1 had a protective effect on hepatocytes. Finally, Schisandrin B, an active ingredient with hepatoprotective effects, extracted from a traditional Chinese medicinal herb, which could protect the liver from bilirubin metabolism disorders caused by ugt1a1 deficiency by downregulating p65 phosphorylation, inhibiting Kupffer cells, reducing inflammation levels. Our data clarified the mechanism of liver vulnerability caused by cross-talk between low UGT1A1 activity bilirubin, and provided a reference for individualized prevention of liver fragility in Gilbert's syndrome.
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Affiliation(s)
- Dan Liu
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, China
| | - Qi Yu
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Zibo Li
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Lin Zhang
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Ming Hu
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China; Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77030, United States
| | - Caiyan Wang
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China.
| | - Zhongqiu Liu
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China.
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Mills EL, Harmon C, Jedrychowski MP, Xiao H, Garrity R, Tran NV, Bradshaw GA, Fu A, Szpyt J, Reddy A, Prendeville H, Danial NN, Gygi SP, Lynch L, Chouchani ET. UCP1 governs liver extracellular succinate and inflammatory pathogenesis. Nat Metab 2021; 3:604-617. [PMID: 34002097 PMCID: PMC8207988 DOI: 10.1038/s42255-021-00389-5] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 04/09/2021] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD), the most prevalent liver pathology worldwide, is intimately linked with obesity and type 2 diabetes. Liver inflammation is a hallmark of NAFLD and is thought to contribute to tissue fibrosis and disease pathogenesis. Uncoupling protein 1 (UCP1) is exclusively expressed in brown and beige adipocytes, and has been extensively studied for its capacity to elevate thermogenesis and reverse obesity. Here we identify an endocrine pathway regulated by UCP1 that antagonizes liver inflammation and pathology, independent of effects on obesity. We show that, without UCP1, brown and beige fat exhibit a diminished capacity to clear succinate from the circulation. Moreover, UCP1KO mice exhibit elevated extracellular succinate in liver tissue that drives inflammation through ligation of its cognate receptor succinate receptor 1 (SUCNR1) in liver-resident stellate cell and macrophage populations. Conversely, increasing brown and beige adipocyte content in mice antagonizes SUCNR1-dependent inflammatory signalling in the liver. We show that this UCP1-succinate-SUCNR1 axis is necessary to regulate liver immune cell infiltration and pathology, and systemic glucose intolerance in an obesogenic environment. As such, the therapeutic use of brown and beige adipocytes and UCP1 extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.
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Affiliation(s)
- Evanna L Mills
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Cathal Harmon
- Department of Immunology, Harvard Medical School, Boston, MA, USA
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, USA
| | - Mark P Jedrychowski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Haopeng Xiao
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Ryan Garrity
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Nhien V Tran
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Gary A Bradshaw
- Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA
| | - Accalia Fu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - John Szpyt
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Anita Reddy
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Hannah Prendeville
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Nika N Danial
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Steven P Gygi
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Lydia Lynch
- Department of Immunology, Harvard Medical School, Boston, MA, USA
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, USA
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Edward T Chouchani
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
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40
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Gamede M, Mabuza L, Ngubane P, Khathi A. Preventing the onset of diabetes-induced chronic kidney disease during prediabetes: The effects of oleanolic acid on selected markers of chronic kidney disease in a diet-induced prediabetic rat model. Biomed Pharmacother 2021; 139:111570. [PMID: 33932738 DOI: 10.1016/j.biopha.2021.111570] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 03/24/2021] [Accepted: 03/31/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The prevalence of prediabetes correlates with increased incidence of chronic kidney disease (CKD). This study was aimed at investigating the effects of oleanolic acid (OA) on markers associated with CKD in the prediabetic rat model. METHODS Prediabetes was induced by exposing male Sprague Dawley rats (150-180 g) to high-fat high- carbohydrate (HFHC) diet for 20 weeks. The prediabetic animals were further subdivided according to their treatment and treated for 12 weeks with either OA (80 mg/kg p.o) or metformin (500 mg/kg p.o) both with and without dietary intervention. 24 h fluid intake and urine output were measured every fourth week of the treatment period while the urine samples were also used for podocin quantification through PCR. The animals were then sacrificed with urine, plasma and kidneys being harvested for biochemical analysis including the measurement of aldosterone, kidney-injury-molecule-1(KIM-1), blood and urine electrolytes, estimated glomerular filtration rate (eGFR), and albumin/creatinine (Alb/Cr) ratio. RESULTS This study observed that OA could reduce oxidative stress in the kidney while restoring plasma aldosterone and KIM-1 as well as urine electrolytes which were found to be augmented in prediabetic animals. This also correlated with normalization of GFR and Alb/Cr ratio in the OA-treated groups in both the absence and presence of dietary intervention. CONCLUSIONS These findings suggest that OA can ameliorate renal complications in a prediabetic rat model. However, more research is needed for the elucidation of molecular mechanisms behind these effects.
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Affiliation(s)
- Mlindeli Gamede
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
| | - Lindokuhle Mabuza
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Phikelelani Ngubane
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Andile Khathi
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
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41
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Kurtz R, Anderman MF, Shepard BD. GPCRs get fatty: the role of G protein-coupled receptor signaling in the development and progression of nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 2021; 320:G304-G318. [PMID: 33205999 PMCID: PMC8202238 DOI: 10.1152/ajpgi.00275.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), characterized by the abnormal deposition of lipids within the liver not due to alcohol consumption, is a growing epidemic affecting over 30% of the United States population. Both simple fatty liver and its more severe counterpart, nonalcoholic steatohepatitis, represent one of the most common forms of liver disease. Recently, several G protein-coupled receptors have emerged as targets for therapeutic intervention for these disorders. These include those with known hepatic function as well as those involved in global metabolic regulation. In this review, we highlight these emerging therapeutic targets, focusing on several common themes including their activation by microbial metabolites, stimulatory effect on insulin and incretin secretion, and contribution to glucose tolerance. The overlap in ligands, localization, and downstream effects of activation indicate the interdependent nature of these receptors and highlight the importance of this signaling family in the development and prevention of NAFLD.
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Affiliation(s)
- Ryan Kurtz
- Department of Human Science, Georgetown University, Washington, District of Columbia
| | - Meghan F. Anderman
- Department of Human Science, Georgetown University, Washington, District of Columbia
| | - Blythe D. Shepard
- Department of Human Science, Georgetown University, Washington, District of Columbia
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42
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Choi I, Son H, Baek JH. Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses. Life (Basel) 2021; 11:69. [PMID: 33477822 PMCID: PMC7832849 DOI: 10.3390/life11010069] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 02/06/2023] Open
Abstract
The tricarboxylic acid cycle (TCA) is a series of chemical reactions used in aerobic organisms to generate energy via the oxidation of acetylcoenzyme A (CoA) derived from carbohydrates, fatty acids and proteins. In the eukaryotic system, the TCA cycle occurs completely in mitochondria, while the intermediates of the TCA cycle are retained inside mitochondria due to their polarity and hydrophilicity. Under cell stress conditions, mitochondria can become disrupted and release their contents, which act as danger signals in the cytosol. Of note, the TCA cycle intermediates may also leak from dysfunctioning mitochondria and regulate cellular processes. Increasing evidence shows that the metabolites of the TCA cycle are substantially involved in the regulation of immune responses. In this review, we aimed to provide a comprehensive systematic overview of the molecular mechanisms of each TCA cycle intermediate that may play key roles in regulating cellular immunity in cell stress and discuss its implication for immune activation and suppression.
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Affiliation(s)
| | | | - Jea-Hyun Baek
- School of Life Science, Handong Global University, Pohang, Gyeongbuk 37554, Korea; (I.C.); (H.S.)
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43
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Tang J, Xiong K, Zhang T, Han Han. Application of Metabolomics in Diagnosis and Treatment of Chronic Liver Diseases. Crit Rev Anal Chem 2020; 52:906-916. [PMID: 33146026 DOI: 10.1080/10408347.2020.1842172] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Chronic liver disease represents stepwise destruction of the liver parenchyma after chronic liver injury, which is often difficult to be diagnosed accurately. Thus, the development of specific biomarkers of chronic liver disease is important. Metabolomics is a powerful tool for biomarker exploration, which enables the exploration of disease pathogenesis or drug action mechanisms at the global metabolic level. The metabolomics workflow generally includes collection, preparation, and analysis of samples, and data processing and bioinformatics. A metabolomics study can simultaneously detect the dysfunctions in the glucose, lipid, amino-acid, and nucleotide metabolisms. Hence, it facilitates the obtaining of a better understanding of the pathogenesis of chronic liver disease and its diagnosis. Many effective drugs could reverse the change of comprehensive biochemical phenotypes induced by chronic liver disease. They can even potentially restore the normal metabolic signatures of patients. Increasingly more researchers have begun to apply metabolomics technologies to diagnose chronic liver disease and investigate the mechanism of action of effective drugs or the variations in drug responses. We are convinced that deepening the understanding of the metabolic alterations could extend their use as powerful biomarkers, promoting the more effective clinical diagnosis and treatment of chronic liver disease in the future.
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Affiliation(s)
- Jie Tang
- Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kai Xiong
- Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tong Zhang
- Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Han Han
- Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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44
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Guo J, Zhang S, Fang L, Huang J, Wang Q, Wang C, Chen M. In utero exposure to phenanthrene induces hepatic steatosis in F1 adult female mice. CHEMOSPHERE 2020; 258:127360. [PMID: 32554016 DOI: 10.1016/j.chemosphere.2020.127360] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/28/2020] [Accepted: 06/06/2020] [Indexed: 06/11/2023]
Abstract
Environmental pollutants are thought to be a risk factor for the prevalence of hepatic steatosis. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous, and human exposure is inevitable. In the present study, phenanthrene (Phe) was used as a representative PAH to investigate the effects of in utero exposure to PAH on hepatic lipid metabolism and the toxicological mechanism involved. Pregnant mice (C57BL/6J) were orally administered Phe (0, 60, 600 and 6000 μg kg-1 body weight) once every 3 days with 6 doses in total. F1 female mice aged 125 days showed significantly elevated hepatic lipid levels in the liver. The protein expression of hepatic peroxisome proliferator-activated receptors (PPARβ and PPARγ) and retinoid X receptors (RXRs) was upregulated; the transcription of genes related to lipogenesis, such as srebp1 (encoding sterol regulatory element binding proteins), acca (acetyl-CoA carboxylase), fasn (fatty acid synthase) and pcsk9 (proprotein convertase subtilisin/kexin type 9), showed an upregulation, while the mRNA levels of the lipolysis gene lcat (encoding lecithin cholesterol acyl transferase) were downregulated. These results could be responsible for lipid accumulation. The promoter methylation levels of pparγ were reduced and were the lowest in the 600 μg kg-1 group, and the promoter methylation levels of lcat were significantly increased in all the Phe treatments. These changes were matched with the alterations in their mRNA levels, suggesting that prenatal Phe exposure could induce abnormal lipid metabolism in later life via epigenetic modification.
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Affiliation(s)
- Jiaojiao Guo
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Shenli Zhang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Lu Fang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Jie Huang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Qian Wang
- College of Environment & Ecology, Xiamen University, Xiamen, PR China
| | - Chonggang Wang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, PR China.
| | - Meng Chen
- College of Environment & Ecology, Xiamen University, Xiamen, PR China.
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Dallons M, Alpan E, Schepkens C, Tagliatti V, Colet JM. GPR91 Receptor Mediates Protection against Doxorubicin-Induced Cardiotoxicity without Altering Its Anticancer Efficacy. An In Vitro Study on H9C2 Cardiomyoblasts and Breast Cancer-Derived MCF-7 Cells. Cells 2020; 9:E2177. [PMID: 32992522 PMCID: PMC7599858 DOI: 10.3390/cells9102177] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/17/2020] [Accepted: 09/25/2020] [Indexed: 11/16/2022] Open
Abstract
Doxorubicin (DOX) is an anticancer drug widely used in oncology, especially for breast cancer. The main limitation of DOX treatment is its cardiotoxicity due to the cumulative dose. Clinically, DOX-induced cardiomyopathy develops as a progressive heart failure caused by a progressive cardiomyocyte's death. For long, the oxidative stress induced by DOX was considered as the main toxic mechanism responsible for heart damage, but it is now controverted, and other processes are investigated to develop cardioprotective strategies. Previously, we studied DOX-induced cardiotoxicity and dexrazoxane (DEX), the only cardioprotective compound authorized by the FDA, by 1H-NMR metabonomics in H9C2 cells. We observed an increased succinate secretion in the extracellular fluid of DEX-exposed cardiomyocytes, a finding that led us to the hypothesis of a possible protective role of this agonist of the GPR91 receptor. The objective of the present work was to study the effect of succinate (SUC) and cis-epoxysuccinate (cis-ES), two agonists of the GPR91 receptor, on DOX-induced cardiotoxicity to H9C2 cells. To this purpose, several toxicity parameters, including cell viability, oxidative stress and apoptosis, as well as the GPR91 expression, were measured to assess the effects of DEX, SUC and cis-ES either alone or in combination with DOX in H9C2 cells. A 1H-NMR-based metabonomic study was carried out on cellular fluids collected after 24 h to highlight the metabolic changes induced by those protective compounds. Moreover, the effects of each agonist given either alone or in combination with DOX were evaluated on MCF-7 breast cancer cells. GPR91 expression was confirmed in H9C2 cells, while no expression was found in MCF-7 cells. Under such experimental conditions, both SUC and cis-ES decreased partially the cellular mortality, the oxidative stress and the apoptosis induced by DOX. The SUC protective effect was similar to the DEX effect, but the protective effect of cis-ES was higher on oxidative stress and apoptosis. In addition, the metabonomics findings pointed out several metabolic pathways involved in the cardioprotective effects of both GPR91 agonists: the stimulation of aerobic metabolism with glucose as the main fuel, redox balance and phospholipids synthesis. Finally, none of the GPR91 agonists jeopardized the pharmacological effects of DOX on MCF-7 breast cancer cells.
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Affiliation(s)
| | | | | | | | - Jean-Marie Colet
- Department of Human Biology & Toxicology, Faculty of Medicine and Pharmacy, University of Mons, Place du Parc 20, 7000 Mons, Belgium; (M.D.); (E.A.); (C.S.); (V.T.)
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Liu XJ, Xie L, Du K, Liu C, Zhang NP, Gu CJ, Wang Y, Abdelmalek MF, Dong WY, Liu XP, Niu C, Yang C, Diehl AM, Wu J. Succinate-GPR-91 receptor signalling is responsible for nonalcoholic steatohepatitis-associated fibrosis: Effects of DHA supplementation. Liver Int 2020; 40:830-843. [PMID: 31903720 PMCID: PMC9990138 DOI: 10.1111/liv.14370] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 12/02/2019] [Accepted: 12/30/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Treatment of non-alcoholic steatohepatitis (NASH) is challenging, because suppressing fibrotic progression has not been achieved consistently by drug candidates currently in clinical trials. The aim of this study was to investigate the molecular interplays underlying NASH-associated fibrosis in a mouse NASH model and human specimens. METHODS Mice were divided into 4 groups: Controls; NASH (high fat/Calorie diet plus high fructose and glucose in drinking water, HFCD-HF/G) for 16 weeks; HFCD-HF/G plus docosahexaenoic acid (DHA) for 16 or 8 weeks. RESULTS Along with NASH progression, fibrotic deposition was documented in HFCD-HF/G-fed mice. Liver succinate content was significantly increased along with decreased expression of succinate dehydrogenase-A (SDH-A) in these mice; whereas, GPR-91 receptor expression was much enhanced in histology compared to control mice, and co-localized histologically with hepatic stellate cells (HSCs). Succinate content was increased in fatty acid-overloaded primary hepatocytes with significant oxidant stress and lipotoxicity. Exposure to succinate led to up-regulation of GPR-91 receptor in primary and immortalized HSCs. In contrast, suppression of GPR-91 receptor expression abolished succinate stimulatory role in GPR-91 expression and extracellular matrix production in HSCs. All these changes were minimized or abrogated by DHA supplementation in vivo or in vitro. Moreover, GPR-91 receptor expression correlates with severity of fibrosis in human NASH biopsy specimens. CONCLUSION Succinate accumulation in steatotoic hepatocytes may result in HSC activation through GPR-91 receptor signalling in NASH progression, and the cross-talk between hepatocytes and HSC through GPR-91 signalling is most likely to be the molecular basis of fibrogenesis in NASH.
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Affiliation(s)
- Xue-Jing Liu
- Department of Medical Microbiology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Li Xie
- Department of Medical Microbiology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Kuo Du
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Chang Liu
- Department of Medical Microbiology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ning-Ping Zhang
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China.,Dept. of Gastroenterology & Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chen-Jian Gu
- Department of Medical Microbiology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ying Wang
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Manal F Abdelmalek
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Wen-Yue Dong
- Shanghai Institute of Plant Physiology and Ecology, Shanghai Institutes of Biologic Sciences (SIBS), Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Science, Beijing, China
| | - Xiu-Ping Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Chen Niu
- Department of Medical Microbiology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Chen Yang
- Shanghai Institute of Plant Physiology and Ecology, Shanghai Institutes of Biologic Sciences (SIBS), Chinese Academy of Sciences, Shanghai, China
| | - Anna Mae Diehl
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Jian Wu
- Department of Medical Microbiology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China.,Dept. of Gastroenterology & Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
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Staňková P, Kučera O, Peterová E, Lotková H, Maseko TE, Nožičková K, Červinková Z. Adaptation of Mitochondrial Substrate Flux in a Mouse Model of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2020; 21:1101. [PMID: 32046101 PMCID: PMC7036817 DOI: 10.3390/ijms21031101] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/02/2020] [Accepted: 02/05/2020] [Indexed: 12/30/2022] Open
Abstract
Maladaptation of mitochondrial oxidative flux seems to be a considerable feature of nonalcoholic fatty liver disease (NAFLD). The aim of this work was to induce NAFLD in mice fed a Western-style diet (WD) and to evaluate liver mitochondrial functions. Experiments were performed on male C57BL/6J mice fed with a control diet or a WD for 24 weeks. Histological changes in liver and adipose tissue as well as hepatic expression of fibrotic and inflammatory genes and proteins were evaluated. The mitochondrial respiration was assessed by high-resolution respirometry. Oxidative stress was evaluated by measuring lipoperoxidation, glutathione, and reactive oxygen species level. Feeding mice a WD induced adipose tissue inflammation and massive liver steatosis accompanied by mild inflammation and fibrosis. We found decreased succinate-activated mitochondrial respiration and decreased succinate dehydrogenase (SDH) activity in the mice fed a WD. The oxidative flux with other substrates was not affected. We observed increased ketogenic capacity, but no impact on the capacity for fatty acid oxidation. We did not confirm the presence of oxidative stress. Mitochondria in this stage of the disease are adapted to increased substrate flux. However, inhibition of SDH can lead to the accumulation of succinate, an important signaling molecule associated with inflammation, fibrosis, and carcinogenesis.
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Affiliation(s)
- Pavla Staňková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (H.L.); (T.E.M.); (K.N.); (Z.Č.)
| | - Otto Kučera
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (H.L.); (T.E.M.); (K.N.); (Z.Č.)
| | - Eva Peterová
- Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic;
| | - Halka Lotková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (H.L.); (T.E.M.); (K.N.); (Z.Č.)
| | - Tumisang Edward Maseko
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (H.L.); (T.E.M.); (K.N.); (Z.Č.)
| | - Kateřina Nožičková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (H.L.); (T.E.M.); (K.N.); (Z.Č.)
| | - Zuzana Červinková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (H.L.); (T.E.M.); (K.N.); (Z.Č.)
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48
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Khomich O, Ivanov AV, Bartosch B. Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis. Cells 2019; 9:24. [PMID: 31861818 PMCID: PMC7016711 DOI: 10.3390/cells9010024] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/09/2019] [Accepted: 12/18/2019] [Indexed: 12/17/2022] Open
Abstract
Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.
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Affiliation(s)
- Olga Khomich
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, CEDEX 03, 69424 Lyon, France;
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Alexander V. Ivanov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Birke Bartosch
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, CEDEX 03, 69424 Lyon, France;
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49
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Rao C, Ni YR, Zhao YM, Zhang YQ, Zhou RT, Liu CB, Han L, Wu JF. Class C1 decoy oligodeoxynucleotide inhibits profibrotic genes expression in rat hepatic stellate cells. Mol Med Rep 2019; 21:667-674. [PMID: 31974596 PMCID: PMC6947877 DOI: 10.3892/mmr.2019.10881] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 11/07/2019] [Indexed: 12/12/2022] Open
Abstract
The aim of the present study was to investigate whether class C1 decoy oligodeoxynucleotides (ODNs) can inhibit the expression of pro‑fibrotic genes associated with rat hepatic stellate cell (HSC) activation and hepatic fibrosis. Luciferase reporter assays were performed to test the promoter activities of transforming growth factor (TGF)‑β and its downstream target genes following transfection of decoy ODNs and plasmids into HSC‑T6 cells, and western blot assays were performed to measure the protein expression of those genes following decoy ODN transfection. Class C1 decoy ODNs were confirmed to inhibit the promoter activity of TGF‑β and its downstream target genes, such as type 1 collagen (COLI)α1, tissue inhibitor of metalloproteinases (TIMP)1 and α‑smooth muscle actin by Gaussia luciferase reporter assay, and to further downregulate the expression of TGF‑β, SMAD3, COLIα1 and TIMP1 by western blotting in activated HSC‑T6 cells. In conclusion, class C1 decoy ODNs inhibited pro‑fibrotic gene expression in rat HSCS by downregulating TGF‑β signaling.
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Affiliation(s)
- Chun Rao
- Department of Pathology, The People's Hospital of China Three Gorges University and the First People's Hospital of Yichang, Yichang, Hubei 443000, P.R. China
| | - Yi-Ran Ni
- Department of Anatomy and Histology, Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Yan-Min Zhao
- Department of Anatomy and Histology, Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Yan-Qiong Zhang
- Department of Anatomy and Histology, Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Rui-Ting Zhou
- Department of Anatomy and Histology, Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Chang-Bai Liu
- Department of Anatomy and Histology, Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Lin Han
- Department of Pathology, The People's Hospital of China Three Gorges University and the First People's Hospital of Yichang, Yichang, Hubei 443000, P.R. China
| | - Jiang-Feng Wu
- Department of Pathology, The People's Hospital of China Three Gorges University and the First People's Hospital of Yichang, Yichang, Hubei 443000, P.R. China
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50
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Keiran N, Ceperuelo-Mallafré V, Calvo E, Hernández-Alvarez MI, Ejarque M, Núñez-Roa C, Horrillo D, Maymó-Masip E, Rodríguez MM, Fradera R, de la Rosa JV, Jorba R, Megia A, Zorzano A, Medina-Gómez G, Serena C, Castrillo A, Vendrell J, Fernández-Veledo S. SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity. Nat Immunol 2019; 20:581-592. [PMID: 30962591 DOI: 10.1038/s41590-019-0372-7] [Citation(s) in RCA: 163] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 03/05/2019] [Indexed: 12/14/2022]
Abstract
Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.
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Affiliation(s)
- Noelia Keiran
- Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Victoria Ceperuelo-Mallafré
- Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Enrique Calvo
- Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Maria Isabel Hernández-Alvarez
- Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.,Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Miriam Ejarque
- Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Catalina Núñez-Roa
- Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Daniel Horrillo
- Departamento de Ciencias Básicas de la Salud, Área de Bioquímica y Biología Molecular, Universidad Rey Juan Carlos, Madrid, Spain
| | - Elsa Maymó-Masip
- Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - M Mar Rodríguez
- Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Rosa Fradera
- General and Digestive Surgery Service, Hospital St. Pau i Sta Tecla, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain
| | - Juan Vladimir de la Rosa
- Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.,Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitaria (IUBIS), Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
| | - Rosa Jorba
- General and Digestive Surgery Service, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain
| | - Ana Megia
- Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Antonio Zorzano
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.,Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain
| | - Gema Medina-Gómez
- Departamento de Ciencias Básicas de la Salud, Área de Bioquímica y Biología Molecular, Universidad Rey Juan Carlos, Madrid, Spain
| | - Carolina Serena
- Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Antonio Castrillo
- Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.,Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitaria (IUBIS), Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
| | - Joan Vendrell
- Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain. .,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain. .,Universitat Rovira i Virgili, Tarragona, Spain.
| | - Sonia Fernández-Veledo
- Unitat de Recerca, Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain. .,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
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