|
1
|
Ling L, Li R, Xu M, Zhou J, Hu M, Zhang X, Zhang XJ. Species differences of fatty liver diseases: comparisons between human and feline. Am J Physiol Endocrinol Metab 2025; 328:E46-E61. [PMID: 39636211 DOI: 10.1152/ajpendo.00014.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 12/07/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most widespread chronic liver disease that poses significant threats to public health due to changes in dietary habits and lifestyle patterns. The transition from simple steatosis to nonalcoholic steatohepatitis (NASH) markedly increases the risk of developing cirrhosis, hepatocellular carcinoma, and liver failure in patients. However, there is only one Food and Drug Administration-approved therapeutic drug in the world, and the clinical demand is huge. There is significant clinical heterogeneity among patients with NAFLD, and it is challenging to fully understand human NAFLD using only a single animal model. Interestingly, felines, like humans, are particularly prone to spontaneous fatty liver disease. This review summarized and compared the etiology, clinical features, pathological characteristics, and molecular pathogenesis between human fatty liver and feline hepatic lipidosis (FHL). We analyzed the key similarities and differences between those two species, aiming to provide theoretical foundations for developing effective strategies for the treatment of NAFLD in clinics.
Collapse
Affiliation(s)
- Like Ling
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Ruilin Li
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Mengqiong Xu
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Junjie Zhou
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Manli Hu
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Xin Zhang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Xiao-Jing Zhang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| |
Collapse
|
|
2
|
Yang H, Ran S, Zhou Y, Shi Q, Yu J, Wang W, Sun C, Li D, Hu Y, Pan C, Yuan Q, Zhen Y, Liu Q, Song L. Exposure to Succinate Leads to Steatosis in Non-Obese Non-Alcoholic Fatty Liver Disease by Inhibiting AMPK/PPARα/FGF21-Dependent Fatty Acid Oxidation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:21052-21064. [PMID: 39268842 DOI: 10.1021/acs.jafc.4c05671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/15/2024]
Abstract
Succinate is an important metabolite and a critical chemical with diverse applications in the food, pharmaceutical, and agriculture industries. Recent studies have demonstrated several protective or detrimental functions of succinate in diseases; however, the effect of succinate on lipid metabolism is still unclear. Here, we identified a role of succinate in nonobese nonalcoholic fatty liver disease (NAFLD). Specifically, the level of succinate is increased in the livers and serum of mice with hepatic steatosis. The administration of succinate promotes triglyceride (TG) deposition and hepatic steatosis by suppressing fatty acid oxidation (FAO) in nonobese NAFLD mouse models. RNA-Seq revealed that succinate suppressed fibroblast growth factor 21 (FGF21) expression. Then, the restoration of FGF21 was sufficient to alleviate hepatic steatosis and FAO inhibition induced by succinate treatment in vitro and in vivo. Furthermore, the inhibition of FGF21 expression and FAO mediated by succinate was dependent on the AMPK/PPARα axis. This study provides evidence linking succinate exposure to abnormal hepatic lipid metabolism and the progression of nonobese NAFLD.
Collapse
Affiliation(s)
- Hong Yang
- Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China
| | - Suye Ran
- Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Yuxia Zhou
- Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Qing Shi
- Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Jiangnan Yu
- Department of Gastroenterology, Guizhou Hospital of the First Affiliated Hospital, Sun Yat-sen University, Guiyang, Guizhou 550000, China
| | - Wenjuan Wang
- Department of Gastroenterology, Xingyi People's Hospital, Xingyi, Guizhou 562400, China
| | - Chengqin Sun
- Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Dengke Li
- Luoyang Vocational and Technical College, Luoyang, Henan 471000, China
| | - Yue Hu
- Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China
| | - Chen Pan
- Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China
| | - Qi Yuan
- Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China
| | - Yunhuan Zhen
- Department of Colorectal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China
| | - Qi Liu
- Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China
| | - Lingyu Song
- Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China
| |
Collapse
|
|
3
|
Wang YL, Liu C, Yang YY, Zhang L, Guo X, Niu C, Zhang NP, Ding J, Wu J. Dynamic changes of gut microbiota in mouse models of metabolic dysfunction-associated steatohepatitis and its transition to hepatocellular carcinoma. FASEB J 2024; 38:e23766. [PMID: 38967214 DOI: 10.1096/fj.202400573rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/07/2024] [Accepted: 06/13/2024] [Indexed: 07/06/2024]
Abstract
Dysbiosis of gut microbiota may account for pathobiology in simple fatty liver (SFL), metabolic dysfunction-associated steatohepatitis (MASH), fibrotic progression, and transformation to MASH-associated hepatocellular carcinoma (MASH-HCC). The aim of the present study is to investigate gut dysbiosis in this progression. Fecal microbial rRNA-16S sequencing, absolute quantification, histopathologic, and biochemical tests were performed in mice fed high fat/calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) or control diet (CD) for 2, 16 weeks, or 14 months. Histopathologic examination verified an early stage of SFL, MASH, fibrotic, or MASH-HCC progression with disturbance of lipid metabolism, liver injury, and impaired gut mucosal barrier as indicated by loss of occludin in ileum mucosa. Gut dysbiosis occurred as early as 2 weeks with reduced α diversity, expansion of Kineothrix, Lactococcus, Akkermansia; and shrinkage in Bifidobacterium, Lactobacillus, etc., at a genus level. Dysbiosis was found as early as MAHS initiation, and was much more profound through the MASH-fibrotic and oncogenic progression. Moreover, the expansion of specific species, such as Lactobacillus johnsonii and Kineothrix alysoides, was confirmed by an optimized method for absolute quantification. Dynamic alterations of gut microbiota were characterized in three stages of early SFL, MASH, and its HCC transformation. The findings suggest that the extent of dysbiosis was accompanied with MASH progression and its transformation to HCC, and the shrinking or emerging of specific microbial species may account at least in part for pathologic, metabolic, and immunologic alterations in fibrogenic progression and malignant transition in the liver.
Collapse
Affiliation(s)
- Yu-Li Wang
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Chang Liu
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Yong-Yu Yang
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Li Zhang
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Xiao Guo
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Chen Niu
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Ning-Ping Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
| | - Jia Ding
- Department of Gastroenterology, Shanghai Jing'an District Central Hospital, Fudan University, Shanghai, China
| | - Jian Wu
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
| |
Collapse
|
|
4
|
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.
Collapse
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.
| |
Collapse
|
|
5
|
He Y, Han Y, Zou L, Yao T, Zhang Y, Lv X, Jiang M, Long L, Li M, Cheng X, Jiang G, Peng Z, Tao L, Meng J, Xie W. Succinate promotes pulmonary fibrosis through GPR91 and predicts death in idiopathic pulmonary fibrosis. Sci Rep 2024; 14:14376. [PMID: 38909094 PMCID: PMC11193722 DOI: 10.1038/s41598-024-64844-5] [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: 04/04/2023] [Accepted: 06/13/2024] [Indexed: 06/24/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites in the serum of patients with pulmonary fibrosis, we aimed to investigate the diagnostic and prognostic value of energy metabolites in IPF, and further elucidated the mechanism of their involvement in pulmonary fibrosis. Through metabolomics research, it was discovered that the TCA cycle intermediates changed dramatically in IPF patients. In another validation cohort of 55 patients with IPF compared to 19 healthy controls, it was found that succinate, an intermediate product of TCA cycle, has diagnostic and prognostic value in IPF. The cut-off levels of serum succinate were 98.36 μM for distinguishing IPF from healthy controls (sensitivity, 83.64%; specificity, 63.16%; likelihood ratio, 2.27, respectively). Moreover, a high serum succinate level was independently associated with higher rates of disease progression (OR 13.087, 95%CI (2.819-60.761)) and mortality (HR 3.418, 95% CI (1.308-8.927)). In addition, accumulation of succinate and increased expression of the succinate receptor GPR91 were found in both IPF patients and BLM mouse models of pulmonary fibrosis. Reducing succinate accumulation in BLM mice alleviated pulmonary fibrosis and 21d mortality, while exogenous administration of succinate can aggravate pulmonary fibrosis in BLM mice. Furthermore, GPR91 deficiency protected against lung fibrosis caused by BLM. In vitro, succinate promoted the activation of lung fibroblasts by activating ERK pathway through GPR91. In summary, succinate is a promising biomarker for diagnosis and prognosis of IPF. The accumulation of succinate may promote fibroblast activation through GPR91 and pulmonary fibrosis.
Collapse
Affiliation(s)
- Yijun He
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Yuanyuan Han
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Lijun Zou
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Tingting Yao
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Yan Zhang
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Xin Lv
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Mao Jiang
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Lingzhi Long
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Mengyu Li
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Xiaoyun Cheng
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
- Department of Pulmonary and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Guoliang Jiang
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
| | - Zhangzhe Peng
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- National International Collaborative Research Center for Medical Metabolomics, Changsha, China
| | - Lijian Tao
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- National International Collaborative Research Center for Medical Metabolomics, Changsha, China
| | - Jie Meng
- Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Changsha, 410013, Hunan, China.
- Hunan Key Laboratory of Organ Fibrosis, Changsha, China.
- National International Collaborative Research Center for Medical Metabolomics, Changsha, China.
| | - Wei Xie
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China.
| |
Collapse
|
|
6
|
Li J, Ma Z, Yang Z, Yang M, Li C, Li M, Li X, Chen X, Ma H, Chen W, Ye X, Li X. Integrating transcriptomics and network pharmacology to reveal the mechanisms of total Rhizoma Coptidis alkaloids against nonalcoholic steatohepatitis. JOURNAL OF ETHNOPHARMACOLOGY 2024; 322:117600. [PMID: 38103844 DOI: 10.1016/j.jep.2023.117600] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/28/2023] [Accepted: 12/13/2023] [Indexed: 12/19/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Non-alcoholic steatohepatitis (NASH) has emerged as a major cause of cirrhosis and hepatocellular carcinoma, posing a significant threat to public health. Rhizoma Coptidis, a traditional Chinese medicinal herb has been shown to have significant curative effects on liver diseases. Total Rhizoma Coptidis Alkaloids (TRCA) is a primarily alkaloid mixture extracted from Rhizoma Coptidis, and its constituents are widely accepted to have hepatoprotective effects. AIM OF THE STUDY This work aimed to investigate the efficacy and potential mechanisms of TRCA in ameliorating NASH through both in vitro experiments and in vivo mouse models. MATERIALS AND METHODS The study employed a mice model induced by a high-fat diet (HFD) to evaluate the effectiveness and pharmacological mechanisms of TRCA in alleviating NASH. Transcriptomic sequencing and network pharmacology were used to explore the possible targets and mechanisms of TRCA to ameliorate NASH. Further validation was performed in free fatty acid (FFA)-induced human hepatocytes (LO2) and human hepatocellular carcinoma cells (HepG2). RESULTS TRCA effectively ameliorated the main features of NASH such as lipid accumulation, hepatitis and hepatic fibrosis in the liver tissue of mice induced by HFD, as well as improved glucose tolerance and insulin resistance in mice. Combined with transcriptomic and network pharmacological analyses, 68 core targets associated with the improvement of NASH by TRCA were obtained. According to the KEGG results, the core targets were significantly enriched in the PI3K-AKT signaling pathway whereas TRCA ameliorated the aberrant down-regulation of the PI3K-AKT signaling pathway induced by HFD. Furthermore, the five highest-ranked genes were obtained by PPI network analysis. Moreover, our findings suggest that TRCA may impede the progression of HFD-induced NASH by regulating the expression of PPARG, MMP9, ALB, CCL2, and EGFR. CONCLUSIONS TRCA can ameliorate HFD-induced liver injury by modulating aberrant downregulation of the PI3K-AKT signaling pathway. Key proteins such as PPARG, MMP9, ALB, CCL2, and EGFR may be critical targets for TRCA to ameliorate NASH. This finding supports using Rhizoma Coptidis, a well-known herbal medicine, as a potential therapeutic agent for NASH.
Collapse
Affiliation(s)
- Juan Li
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
| | - Zhengcai Ma
- School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Zhipeng Yang
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
| | - Maochun Yang
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
| | - Changsheng Li
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
| | - Mengmeng Li
- School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Xiaoduo Li
- School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Xiantao Chen
- School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Hang Ma
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
| | - Wanqun Chen
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400000, China.
| | - Xiaoli Ye
- School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Xuegang Li
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
| |
Collapse
|
|
7
|
Zhang L, Yang Y, Xie L, Zhou Y, Zhong Z, Ding J, Wang Z, Wang Y, Liu X, Yu F, Wu J. JCAD deficiency delayed liver regenerative repair through the Hippo-YAP signalling pathway. Clin Transl Med 2024; 14:e1630. [PMID: 38509842 PMCID: PMC10955226 DOI: 10.1002/ctm2.1630] [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: 11/21/2023] [Revised: 02/25/2024] [Accepted: 02/29/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND AND AIMS Liver regeneration retardation post partial hepatectomy (PH) is a common clinical problem after liver transplantation. Identification of key regulators in liver regeneration post PH may be beneficial for clinically improving the prognosis of patients after liver transplantation. This study aimed to clarify the function of junctional protein-associated with coronary artery disease (JCAD) in liver regeneration post PH and to reveal the underlying mechanisms. METHODS JCAD knockout (JCAD-KO), liver-specific JCAD-KO (Jcad△Hep) mice and their control group were subjected to 70% PH. RNA sequencing was conducted to unravel the related signalling pathways. Primary hepatocytes from KO mice were treated with epidermal growth factor (EGF) to evaluate DNA replication. Fluorescent ubiquitination-based cell cycle indicator (FUCCI) live-imaging system was used to visualise the phases of cell cycle. RESULTS Both global and liver-specific JCAD deficiency postponed liver regeneration after PH as indicated by reduced gene expression of cell cycle transition and DNA replication. Prolonged retention in G1 phase and failure to transition over the cell cycle checkpoint in JCAD-KO cell line was indicated by a FUCCI live-imaging system as well as pharmacologic blockage. JCAD replenishment by adenovirus reversed the impaired DNA synthesis in JCAD-KO primary hepatocyte in exposure to EGF, which was abrogated by a Yes-associated protein (YAP) inhibitor, verteporfin. Mechanistically, JCAD competed with large tumour suppressor 2 (LATS2) for WWC1 interaction, leading to LATS2 inhibition and thereafter YAP activation, and enhanced expression of cell cycle-associated genes. CONCLUSION JCAD deficiency led to delayed regeneration after PH as a result of blockage in cell cycle progression through the Hippo-YAP signalling pathway. These findings uncovered novel functions of JCAD and suggested a potential strategy for improving graft growth and function post liver transplantation. KEY POINTS JCAD deficiency leads to an impaired liver growth after PH due to cell division blockage. JCAD competes with LATS2 for WWC1 interaction, resulting in LATS2 inhibition, YAP activation and enhanced expression of cell cycle-associated genes. Delineation of JCADHippoYAP signalling pathway would facilitate to improve prognosis of acute liver failure and graft growth in living-donor liver transplantation.
Collapse
Affiliation(s)
- Li Zhang
- Department of Medical Microbiology & ParasitologyMOE/NHC/CAMS Key Laboratory of Medical Molecular VirologySchool of Basic Medical SciencesFudan University Shanghai Medical CollegeShanghaiChina
| | - Yong‐Yu Yang
- Department of Medical Microbiology & ParasitologyMOE/NHC/CAMS Key Laboratory of Medical Molecular VirologySchool of Basic Medical SciencesFudan University Shanghai Medical CollegeShanghaiChina
| | - Li Xie
- Department of Medical Microbiology & ParasitologyMOE/NHC/CAMS Key Laboratory of Medical Molecular VirologySchool of Basic Medical SciencesFudan University Shanghai Medical CollegeShanghaiChina
| | - Yuan Zhou
- Department of Medical Microbiology & ParasitologyMOE/NHC/CAMS Key Laboratory of Medical Molecular VirologySchool of Basic Medical SciencesFudan University Shanghai Medical CollegeShanghaiChina
| | - Zhenxing Zhong
- Institute of PediatricsChildren's Hospital of Fudan UniversityShanghai Key Laboratory of Medical EpigeneticsInternational Co‐Laboratory of Medical Epigenetics and MetabolismInstitutes of Biomedical SciencesFudan University Shanghai Medical CollegeShanghaiChina
| | - Jia Ding
- Jing'an Central District HospitalShanghaiChina
| | - Zhong‐Hua Wang
- Department of Medical Microbiology & ParasitologyMOE/NHC/CAMS Key Laboratory of Medical Molecular VirologySchool of Basic Medical SciencesFudan University Shanghai Medical CollegeShanghaiChina
| | - Yu‐Li Wang
- Department of Medical Microbiology & ParasitologyMOE/NHC/CAMS Key Laboratory of Medical Molecular VirologySchool of Basic Medical SciencesFudan University Shanghai Medical CollegeShanghaiChina
| | - Xiu‐Ping Liu
- Department of Pathology and Laboratory MedicineSchool of Basic Medical SciencesFudan UniversityShanghaiChina
| | - Fa‐Xing Yu
- Institute of PediatricsChildren's Hospital of Fudan UniversityShanghai Key Laboratory of Medical EpigeneticsInternational Co‐Laboratory of Medical Epigenetics and MetabolismInstitutes of Biomedical SciencesFudan University Shanghai Medical CollegeShanghaiChina
| | - Jian Wu
- Department of Medical Microbiology & ParasitologyMOE/NHC/CAMS Key Laboratory of Medical Molecular VirologySchool of Basic Medical SciencesFudan University Shanghai Medical CollegeShanghaiChina
- Department of Gastroenterology & HepatologyZhongshan Hospital of Fudan UniversityShanghaiChina
- Shanghai Institute of Liver DiseasesFudan University Shanghai Medical CollegeShanghaiChina
| |
Collapse
|
|
8
|
Fernández-Veledo S, Marsal-Beltran A, Vendrell J. Type 2 diabetes and succinate: unmasking an age-old molecule. Diabetologia 2024; 67:430-442. [PMID: 38182909 PMCID: PMC10844351 DOI: 10.1007/s00125-023-06063-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/18/2023] [Indexed: 01/07/2024]
Abstract
Beyond their conventional roles in intracellular energy production, some traditional metabolites also function as extracellular messengers that activate cell-surface G-protein-coupled receptors (GPCRs) akin to hormones and neurotransmitters. These signalling metabolites, often derived from nutrients, the gut microbiota or the host's intermediary metabolism, are now acknowledged as key regulators of various metabolic and immune responses. This review delves into the multi-dimensional aspects of succinate, a dual metabolite with roots in both the mitochondria and microbiome. It also connects the dots between succinate's role in the Krebs cycle, mitochondrial respiration, and its double-edge function as a signalling transmitter within and outside the cell. We aim to provide an overview of the role of the succinate-succinate receptor 1 (SUCNR1) axis in diabetes, discussing the potential use of succinate as a biomarker and the novel prospect of targeting SUCNR1 to manage complications associated with diabetes. We further propose strategies to manipulate the succinate-SUCNR1 axis for better diabetes management; this includes pharmacological modulation of SUCNR1 and innovative approaches to manage succinate concentrations, such as succinate administration and indirect strategies, like microbiota modulation. The dual nature of succinate, both in terms of origins and roles, offers a rich landscape for understanding the intricate connections within metabolic diseases, like diabetes, and indicates promising pathways for developing new therapeutic strategies.
Collapse
Affiliation(s)
- Sonia Fernández-Veledo
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV)-CERCA, Tarragona, Spain.
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
- Universitat Rovira I Virgili (URV), Reus, Spain.
| | - Anna Marsal-Beltran
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV)-CERCA, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Universitat Rovira I Virgili (URV), Reus, Spain
| | - Joan Vendrell
- Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV)-CERCA, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Universitat Rovira I Virgili (URV), Reus, Spain
| |
Collapse
|
|
9
|
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: 3] [Impact Index Per Article: 3.0] [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.
Collapse
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.
| |
Collapse
|
|
10
|
Tian Q, Ruan J, Wang Y, Xiao Y, Cheng Q, Chen Y, Li M, Chang K, Yi X. Extracellular succinate derived from ectopic milieu drives adhesion and implantation growth of ectopic endometrial stromal cells via the SUCNR1 signal in endometriosis. Cell Commun Signal 2024; 22:82. [PMID: 38291428 PMCID: PMC10826047 DOI: 10.1186/s12964-023-01415-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 12/02/2023] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND As a dual-function metabolite, succinate has emerged in cell function and plays a key signaling role in linking mitochondrial function to other cellular functions. Succinate accumulation in the cytoplasm is commonly associated with hypoxia in the microenvironment and immune cell activation. Extracellular succinate released into the microenvironment is considered an inflammatory alarm that can be sensed by its membrane receptor SUCNR1, which boosts proinflammatory responses and acts akin to classical hormones and cytokines. Succinate plays an important role in the development of inflammatory diseases. Whether succinate facilitates the progression of endometriosis (EMs), characterized by chronic inflammation and peritoneal adhesion, is worth exploring. OBJECTIVE We mimicked the ectopic milieu in vitro and in vivo to evaluate the main source and potential role of succinate in endometriosis. We assessed the molecular and functional effects of succinate on macrophages and peritoneal mesothelial cells in peritoneal cavity. The effect of succinate/SUCNR1 signaling on ectopic endometrial stromal cells (ESCs) was further explored in this study. METHODS In this study, we used targeted organic acid metabolomics analysis and in vitro assays to assess the potential accumulation of succinate in the peritoneal fluid of EMs patients. We examined its correlation with disease severity, Visual Analogue Scale, and the Endometriosis Fertility Index. Flow cytometry, enzyme linked immunosorbent assay, western blot assay, quantitative real-time PCR, and other molecular biology techniques were used to explore the potential mechanisms. RESULTS By mimicking the ectopic milieu, we constructed an in vitro co-culture system and found that M1 polarized macrophages and that the peritoneal mesothelial cell line (HMrSV5) mainly released succinate into their microenvironment and activated the succinate receptor (SUCNR1) signal, which further polarized the macrophages and significantly enhanced the invasive survival of ESCs, and the adhesion to the peritoneum. We further investigated the pathological effects of extracellular succinate in vivo using a xenograft mouse models of endometriosis. CONCLUSIONS Succinate-SUCNR1 signaling facilitates the creation of inflammatory cells and plays a vital role in EMs progression and peritoneal adhesion. Our work on the molecular mechanisms underlying succinate accumulation and function will help elucidate the phenotypic mysteries of pain and infertility in EMs. Video Abstract.
Collapse
Affiliation(s)
- Qi Tian
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China
| | - Jingyao Ruan
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China
| | - Yuning Wang
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China
| | - Yinping Xiao
- Department of Pathology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China
| | - Qi Cheng
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China
| | - Yun Chen
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China
| | - Mingqing Li
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200011, People's Republic of China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Kaikai Chang
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
| | - Xiaofang Yi
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
| |
Collapse
|
|
11
|
Guo F, Xu F, Li S, Zhang Y, Lv D, Zheng L, Gan Y, Zhou M, Zhao K, Xu S, Wu B, Deng Z, Fu P. Amifostine ameliorates bleomycin-induced murine pulmonary fibrosis via NAD +/SIRT1/AMPK pathway-mediated effects on mitochondrial function and cellular metabolism. Eur J Med Res 2024; 29:68. [PMID: 38245795 PMCID: PMC10799491 DOI: 10.1186/s40001-023-01623-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 12/25/2023] [Indexed: 01/22/2024] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease characterized by irreversible scarring of the lung parenchyma. Despite various interventions aimed at mitigating several different molecular aspects of the disease, only two drugs with limited clinical efficacy have so far been approved for IPF therapy. OBJECTIVE We investigated the therapeutic efficacy of amifostine, a detoxifying drug clinically used for radiation-caused cytotoxicity, in bleomycin-induced murine pulmonary fibrosis. METHODS C57BL6/J mice were intratracheally instilled with 3 U/kg of bleomycin. Three doses of amifostine (WR-2721, 200 mg/kg) were administered intraperitoneally on days 1, 3, and 5 after the bleomycin challenge. Bronchoalveolar lavage fluid (BALF) was collected on day 7 and day 21 for the assessment of lung inflammation, metabolites, and fibrotic injury. Human fibroblasts were treated in vitro with transforming growth factor beta 1 (TGF-β1), followed by amifostine (WR-1065, 1-4 µg/mL) treatment. The effects of TGF-β1 and amifostine on the mitochondrial production of reactive oxygen species (ROS) were assessed by live cell imaging of MitoSOX. Cellular metabolism was assessed by the extracellular acidification rate (ECAR), the oxygen consumption rate (OCR), and the concentrations of various energy-related metabolites as measured by mass spectrum (MS). Western blot analysis was performed to investigate the effect of amifostine on sirtuin 1 (SIRT1) and adenosine monophosphate activated kinase (AMPK). RESULTS Three doses of amifostine significantly attenuated lung inflammation and pulmonary fibrosis. Pretreatment and post-treatment of human fibroblast cells with amifostine blocked TGF-β1-induced mitochondrial ROS production and mitochondrial dysfunction in human fibroblast cells. Further, treatment of fibroblasts with TGF-β1 shifted energy metabolism away from mitochondrial oxidative phosphorylation (OXPHOS) and towards glycolysis, as observed by an altered metabolite profile including a decreased ratio of NAD + /NADH and increased lactate concentration. Treatment with amifostine significantly restored energy metabolism and activated SIRT1, which in turn activated AMPK. The activation of AMPK was required to mediate the effects of amifostine on mitochondrial homeostasis and pulmonary fibrosis. This study provides evidence that repurposing of the clinically used drug amifostine may have therapeutic applications for IPF treatment. CONCLUSION Amifostine inhibits bleomycin-induced pulmonary fibrosis by restoring mitochondrial function and cellular metabolism.
Collapse
Affiliation(s)
- Feng Guo
- Department of Biochemistry, Health Science Center, Ningbo University, Ningbo, 315041, China
- Central Laboratory of the Medical Research Center, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Feng Xu
- Central Laboratory of the Medical Research Center, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Shujuan Li
- Department of Biochemistry, Health Science Center, Ningbo University, Ningbo, 315041, China
| | - Yun Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Ningbo University, Ningbo University, Ningbo, 315041, China
| | - Dan Lv
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Ningbo University, Ningbo University, Ningbo, 315041, China
| | - Lin Zheng
- Department of Laboratory Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Yongxiong Gan
- Department of Emergency Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Miao Zhou
- Department of Biochemistry, Health Science Center, Ningbo University, Ningbo, 315041, China
| | - Keyu Zhao
- Department of Dermatology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Shuling Xu
- Department of Dermatology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Bin Wu
- Department of Pulmonary and Critical Care Medicine, South China Hospital Affiliated to Shenzhen University, Shenzhen, China
| | - Zaichun Deng
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Ningbo University, Ningbo University, Ningbo, 315041, China.
| | - Panfeng Fu
- Department of Biochemistry, Health Science Center, Ningbo University, Ningbo, 315041, China.
- Central Laboratory of the Medical Research Center, The First Affiliated Hospital of Ningbo University, Ningbo, China.
| |
Collapse
|
|
12
|
Herranz JM, López-Pascual A, Clavería-Cabello A, Uriarte I, Latasa MU, Irigaray-Miramon A, Adán-Villaescusa E, Castelló-Uribe B, Sangro B, Arechederra M, Berasain C, Avila MA, Fernández-Barrena MG. Comprehensive analysis of epigenetic and epitranscriptomic genes' expression in human NAFLD. J Physiol Biochem 2023; 79:901-924. [PMID: 37620598 PMCID: PMC10636027 DOI: 10.1007/s13105-023-00976-y] [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: 06/15/2023] [Accepted: 07/19/2023] [Indexed: 08/26/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition with a complex etiology. Its incidence is increasing globally in parallel with the obesity epidemic, and it is now considered the most common liver disease in Western countries. The precise mechanisms underlying the development and progression of NAFLD are complex and still poorly understood. The dysregulation of epigenetic and epitranscriptomic mechanisms is increasingly recognized to play pathogenic roles in multiple conditions, including chronic liver diseases. Here, we have performed a comprehensive analysis of the expression of epigenetic and epitranscriptomic genes in a total of 903 liver tissue samples corresponding to patients with normal liver, obese patients, and patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), advancing stages in NAFLD progression. We integrated ten transcriptomic datasets in an unbiased manner, enabling their robust analysis and comparison. We describe the complete landscape of epigenetic and epitranscriptomic genes' expression along the course of the disease. We identify signatures of genes significantly dysregulated in association with disease progression, particularly with liver fibrosis development. Most of these epigenetic and epitranscriptomic effectors have not been previously described in human NAFLD, and their altered expression may have pathogenic implications. We also performed a comprehensive analysis of the expression of enzymes involved in the metabolism of the substrates and cofactors of epigenetic and epitranscriptomic effectors. This study provides novel information on NAFLD pathogenesis and may also guide the identification of drug targets to treat this condition and its progression towards hepatocellular carcinoma.
Collapse
Affiliation(s)
- Jose M Herranz
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Amaya López-Pascual
- Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Alex Clavería-Cabello
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Iker Uriarte
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - M Ujúe Latasa
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Ainara Irigaray-Miramon
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Elena Adán-Villaescusa
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Borja Castelló-Uribe
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Bruno Sangro
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - María Arechederra
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Carmen Berasain
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Matías A Avila
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Maite G Fernández-Barrena
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain.
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.
| |
Collapse
|
|
13
|
Morales-González V, Galeano-Sánchez D, Covaleda-Vargas JE, Rodriguez Y, Monsalve DM, Pardo-Rodriguez D, Cala MP, Acosta-Ampudia Y, Ramírez-Santana C. Metabolic fingerprinting of systemic sclerosis: a systematic review. Front Mol Biosci 2023; 10:1215039. [PMID: 37614441 PMCID: PMC10442829 DOI: 10.3389/fmolb.2023.1215039] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 07/27/2023] [Indexed: 08/25/2023] Open
Abstract
Introduction: Systemic sclerosis (SSc) is a chronic autoimmune disease, marked by an unpredictable course, high morbidity, and increased mortality risk that occurs especially in the diffuse and rapidly progressive forms of the disease, characterized by fibrosis of the skin and internal organs and endothelial dysfunction. Recent studies suggest that the identification of altered metabolic pathways may play a key role in understanding the pathophysiology of the disease. Therefore, metabolomics might be pivotal in a better understanding of these pathogenic mechanisms. Methods: Through a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA), searches were done in the PubMed, EMBASE, Web of Science, and Scopus databases from 2000 to September 2022. Three researchers independently reviewed the literature and extracted the data based on predefined inclusion and exclusion criteria. Results: Of the screened studies, 26 fulfilled the inclusion criteria. A total of 151 metabolites were differentially distributed between SSc patients and healthy controls (HC). The main deregulated metabolites were those derived from amino acids, specifically homocysteine (Hcy), proline, alpha-N-phenylacetyl-L-glutamine, glutamine, asymmetric dimethylarginine (ADMA), citrulline and ornithine, kynurenine (Kyn), and tryptophan (Trp), as well as acylcarnitines associated with long-chain fatty acids and tricarboxylic acids such as citrate and succinate. Additionally, differences in metabolic profiling between SSc subtypes were identified. The diffuse cutaneous systemic sclerosis (dcSSc) subtype showed upregulated amino acid-related pathways involved in fibrosis, endothelial dysfunction, and gut dysbiosis. Lastly, potential biomarkers were evaluated for the diagnosis of SSc, the identification of the dcSSc subtype, pulmonary arterial hypertension, and interstitial lung disease. These potential biomarkers are within amino acids, nucleotides, carboxylic acids, and carbohydrate metabolism. Discussion: The altered metabolite mechanisms identified in this study mostly point to perturbations in amino acid-related pathways, fatty acid beta-oxidation, and in the tricarboxylic acid cycle, possibly associated with inflammation, vascular damage, fibrosis, and gut dysbiosis. Further studies in targeted metabolomics are required to evaluate potential biomarkers for diagnosis, prognosis, and treatment response.
Collapse
Affiliation(s)
- Victoria Morales-González
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad Del Rosario, Bogotá, Colombia
| | - Daniel Galeano-Sánchez
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad Del Rosario, Bogotá, Colombia
| | - Jaime Enrique Covaleda-Vargas
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad Del Rosario, Bogotá, Colombia
| | - Yhojan Rodriguez
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad Del Rosario, Bogotá, Colombia
| | - Diana M. Monsalve
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad Del Rosario, Bogotá, Colombia
| | - Daniel Pardo-Rodriguez
- Metabolomics Core Facility—MetCore, Vicepresidency for Research, Universidad de Los Andes, Bogotá, Colombia
| | - Mónica P. Cala
- Metabolomics Core Facility—MetCore, Vicepresidency for Research, Universidad de Los Andes, Bogotá, Colombia
| | - Yeny Acosta-Ampudia
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad Del Rosario, Bogotá, Colombia
| | - Carolina Ramírez-Santana
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad Del Rosario, Bogotá, Colombia
| |
Collapse
|
|
14
|
Zhou Y, Zhang L, Ma Y, Xie L, Yang YY, Jin C, Chen H, Zhou Y, Song GQ, Ding J, Wu J. Secretome of senescent hepatic stellate cells favors malignant transformation from nonalcoholic steatohepatitis-fibrotic progression to hepatocellular carcinoma. Theranostics 2023; 13:4430-4448. [PMID: 37649614 PMCID: PMC10465212 DOI: 10.7150/thno.85369] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 07/31/2023] [Indexed: 09/01/2023] Open
Abstract
Background: Hepatic fibrosis is a premalignant lesion, and how injured hepatocytes transform into malignancy in a fibrotic microenvironment is poorly understood. Senescence is one of major fates of activated hepatic stellate cells (HSCs). Paucity of literature is available regarding the influence of senescent HSCs on behavior of steatotic hepatocytes. Methods: Senescent HSCs were identified in a murine model of nonalcoholic steatohepatitis (NASH)-fibrosis-hepatocellular carcinoma (HCC) and human NASH-HCC specimens. Secretome of senescent HSCs was analyzed by label-free mass-spectrum (NanoRPLC-MS/MS) and verified quantitatively. Results: Senescent HSCs were increased along with the progression from nonalcoholic fatty liver (NAFL), NASH to NASH-fibrosis, and reached a peak at the stage of advanced fibrosis and then decreased when hepatocellular dysplasia or HCC was developed. Critical components affecting proliferation, epithelial-mesenchymal transition (EMT) or migration were identified from secretome of senescent HSCs, and may activate morphogenic hedgehog or oncogenic Wnt signaling pathways to accelerate malignant transformation of steatotic or dysplastic hepatocytes. Primary hepatocytes stimulated with conditioned medium from senescent HSCs, in co-culture or co-cultured in 3D spheroids with senescent HSCs exhibited an enhanced proliferating or EMT profile. Conclusion: Senescent HSCs secreted a characterized protein profile favoring malignant transformation of steatotic or dysplastic hepatocytes through activating morphogenic hedgehog or oncogenic Wnt signaling pathways in the progression from NASH to malignancy.
Collapse
Affiliation(s)
- Yuan Zhou
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Li Zhang
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Yue Ma
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, 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 200032, China
| | - Yong-yu Yang
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, 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 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 200032, China
| | - Ying Zhou
- Joint Laboratory of Biomaterials and Translational Medicine, Puheng Technology Co., Ltd, Suzhou 215163, China
| | - Guang-qi Song
- Joint Laboratory of Biomaterials and Translational Medicine, Puheng Technology Co., Ltd, Suzhou 215163, China
| | - Jia Ding
- Department of Gastroenterology, Shanghai Jing'an District Central Hospital, Fudan University, Shanghai 200040, 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 200032, China
- Department of Gastroenterology & Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China
| |
Collapse
|
|
15
|
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.
Collapse
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
| |
Collapse
|
|
16
|
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.
Collapse
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.
| |
Collapse
|
|
17
|
Pu M, Zhang J, Zeng Y, Hong F, Qi W, Yang X, Gao G, Zhou T. Succinate-SUCNR1 induces renal tubular cell apoptosis. Am J Physiol Cell Physiol 2023; 324:C467-C476. [PMID: 36622070 DOI: 10.1152/ajpcell.00327.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Succinate has long been known to be only an intermediate product of the tricarboxylic acid cycle until identified as a natural ligand for SUCNR1 in 2004. SUCNR1 is widely expressed throughout the body, especially in the kidney. Abnormally elevated succinate is associated with many diseases, including obesity, type 2 diabetes, nonalcoholic fatty liver disease, and ischemia injury, but it is not known whether succinate can cause kidney damage. This study showed that succinate induced apparent renal injury after treatment for 12 wk, characterized by a reduction in 24 h urine and the significant detachment of the brush border of proximal tubular epithelial cells, tubular dilation, cast formation, and vacuolar degeneration of tubular cells in succinate-treated mice. Besides, succinate caused tubular epithelial cell apoptosis in kidneys and HK-2 cells. Mechanistically, succinate triggered cell apoptosis via SUCNR1 activation. In addition, succinate upregulated ERK by binding to SUCNR1, and inhibition of ERK using PD98059 abolished the proapoptotic effects of succinate in HK-2 cells. In summary, our study provides the first evidence that succinate acts as a risk factor and contributes to renal injury, and further research is required to discern the pathological effects of succinate on renal functions.
Collapse
Affiliation(s)
- Min Pu
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Jing Zhang
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yongcheng Zeng
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Fuyan Hong
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Weiwei Qi
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Xia Yang
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Guoquan Gao
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products, Sun Yat-sen University, Guangzhou, China
| | - Ti Zhou
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,China Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
18
|
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.
Collapse
|
|
19
|
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.
Collapse
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
| |
Collapse
|
|
20
|
Wei X, Yin F, Wu M, Xie Q, Zhao X, Zhu C, Xie R, Chen C, Liu M, Wang X, Ren R, Kang G, Zhu C, Cong J, Wang H, Wang X. G protein-coupled receptor 35 attenuates nonalcoholic steatohepatitis by reprogramming cholesterol homeostasis in hepatocytes. Acta Pharm Sin B 2022; 13:1128-1144. [PMID: 36970193 PMCID: PMC10031266 DOI: 10.1016/j.apsb.2022.10.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/08/2022] [Accepted: 08/18/2022] [Indexed: 11/15/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Fat accumulation "sensitizes" the liver to insult and leads to nonalcoholic steatohepatitis (NASH). G protein-coupled receptor 35 (GPR35) is involved in metabolic stresses, but its role in NAFLD is unknown. We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis. Specifically, we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis, whereas loss of GPR35 had the opposite effect. Administration of the GPR35 agonist kynurenic acid (Kyna) suppressed HFCF diet-induced steatohepatitis in mice. Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4 (STARD4) through the ERK1/2 signaling pathway, ultimately resulting in hepatic cholesterol esterification and bile acid synthesis (BAS). The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1, promoting the conversion of cholesterol to bile acid. The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice. STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice. Our findings indicate that the GPR35-STARD4 axis is a promising therapeutic target for NAFLD.
Collapse
Affiliation(s)
- Xiaoli Wei
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230036, China
| | - Fan Yin
- Department of Pharmacy, Huainan First People's Hospital, the First Affiliated Hospital of Anhui University of Science and Technology, Huainan 232001, China
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Miaomiao Wu
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230036, China
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Qianqian Xie
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Xueqin Zhao
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Cheng Zhu
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230036, China
| | - Ruiqian Xie
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Chongqing Chen
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Menghua Liu
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Xueying Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230036, China
| | - Ruixue Ren
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230036, China
| | - Guijie Kang
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Chenwen Zhu
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230036, China
| | - Jingjing Cong
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230036, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
- Corresponding authors.
| | - Xuefu Wang
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
- Corresponding authors.
| |
Collapse
|
|
21
|
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]
|
|
22
|
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.
Collapse
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
| |
Collapse
|
|
23
|
Updates on novel pharmacotherapeutics for the treatment of nonalcoholic steatohepatitis. Acta Pharmacol Sin 2022; 43:1180-1190. [PMID: 35190696 PMCID: PMC9061746 DOI: 10.1038/s41401-022-00860-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 01/03/2022] [Indexed: 12/14/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD), characterized with hepatocellular steatosis, ballooning, lobular inflammation, fibrotic progression, and insulin resistance. NASH may progress to cirrhosis and hepatocellular carcinoma (HCC), which are the major indications for liver transplantation and the causes for mortality. Thus far, there are no approved pharmacotherapeutics for the treatment of NASH. Given the complexity of NASH pathogenesis at multifaceted aspects, such as lipotoxicity, inflammation, insulin resistance, mitochondrial dysfunction and fibrotic progression, pharmacotherapeutics under investigation target different key pathogenic pathways to gain either the resolution of steatohepatitis or regression of fibrosis, ideally both. Varieties of pharmacologic candidates have been tested in clinical trials and have generated some positive results. On the other hand, recent failure or termination of a few phase II and III trials is disappointing in this field. In face to growing challenges in pharmaceutical development, this review intends to summarize the latest data of new medications which have completed phase II or III trials, and discuss the rationale and preliminary results of several combinatory options. It is anticipated that with improved understanding of NASH pathogenesis and critical endpoints, efficient pharmacotherapeutics will be available for the treatment of NASH with an acceptable safety profile.
Collapse
|
|
24
|
Tedesco L, Rossi F, Ruocco C, Ragni M, Carruba MO, Valerio A, Nisoli E. An original amino acid formula favours in vitro corneal epithelial wound healing by promoting Fn1, ITGB1, and PGC-1α expression. Exp Eye Res 2022; 219:109060. [PMID: 35390334 DOI: 10.1016/j.exer.2022.109060] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/17/2022] [Accepted: 03/30/2022] [Indexed: 11/04/2022]
Abstract
Corneal disorders are frequent, involving most diabetic patients; among its manifestations, they include delayed wound healing. Since maintenance of mitochondrial homeostasis is fundamental for the cell, stimulation of mitochondrial biogenesis represents a unique therapeutic tool for preventing and treating disorders with a deficit in energy metabolism. We have recently demonstrated that a branched-chain amino acid (BCAA)-enriched mixture (BCAAem) supported mitochondrial biogenesis in cardiac and skeletal muscle, reduced liver damage caused by alcohol, and prevented the doxorubicin-dependent mitochondrial damage in cardiomyocytes. The present study aimed to investigate a new amino acid mixture, named six amino acids (6AA), to promote corneal epithelial wound healing by regulating mitochondrial biogenesis. A murine epithelium cell line (TKE2) exposed to this mixture showed increased mitochondrial biogenesis markers, fibronectin 1 (Fn1) and integrin beta 1 (ITGB1) involved in extracellular matrix synthesis and cell migration. Most importantly, the 6AA mixture completely restored the wound in scratch assays, confirming the potential of this new formula in eye disorders like keratopathy. Moreover, our results demonstrate for the first time that peroxisome proliferator-receptor γ coactivator 1 α (PGC-1α) is expressed in TKE2 cells, which controls mitochondrial function and corneal repair process. These results could be relevant for the treatment mainly focused on corneal re-epithelialisation.
Collapse
Affiliation(s)
- Laura Tedesco
- Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, via Vanvitelli, 32 - 20129, Milan, Italy.
| | - Fabio Rossi
- Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, via Vanvitelli, 32 - 20129, Milan, Italy
| | - Chiara Ruocco
- Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, via Vanvitelli, 32 - 20129, Milan, Italy
| | - Maurizio Ragni
- Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, via Vanvitelli, 32 - 20129, Milan, Italy
| | - Michele O Carruba
- Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, via Vanvitelli, 32 - 20129, Milan, Italy
| | - Alessandra Valerio
- Department of Molecular and Translational Medicine, Brescia University, Brescia, Italy
| | - Enzo Nisoli
- Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, via Vanvitelli, 32 - 20129, Milan, Italy
| |
Collapse
|
|
25
|
Hepatic macrophage targeted siRNA lipid nanoparticles treat non-alcoholic steatohepatitis. J Control Release 2022; 343:175-186. [DOI: 10.1016/j.jconrel.2022.01.038] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 12/12/2021] [Accepted: 01/23/2022] [Indexed: 12/12/2022]
|
|
26
|
Wang ZH, Zheng KI, Wang XD, Qiao J, Li YY, Zhang L, Zheng MH, Wu J. LC-MS-based lipidomic analysis in distinguishing patients with nonalcoholic steatohepatitis from nonalcoholic fatty liver. Hepatobiliary Pancreat Dis Int 2021; 20:452-459. [PMID: 34256994 DOI: 10.1016/j.hbpd.2021.05.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 05/19/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). However, there is no reliable non-invasive parameter in distinguishing NASH from NAFL in clinical practice. The present study was to find a non-invasive way to differentiate these two categories of NAFLD via lipidomic analysis. METHODS Lipidomic analysis was used to determine the changes of lipid moieties in blood from 20 NAFL and 10 NASH patients with liver biopsy. Liver histology was evaluated after hematoxylin and eosin staining and Masson's trichrome staining. The profile of lipid metabolites in correlation with steatosis, inflammation, hepatocellular necroptosis, fibrosis, and NAFLD activity score (NAS) was analyzed. RESULTS Compared with NAFL patients, NASH patients had higher degree of steatosis, ballooning degeneration, lobular inflammation. A total of 434 different lipid molecules were identified, which were mainly composed of various phospholipids and triacylglycerols. Many lipids, such as phosphatidylcholine (PC) (P-22:0/18:1), sphingomyelin (SM) (d14:0/18:0), SM (d14:0/24:0), SM (d14:0/22:0), phosphatidylethanolamine (PE) (18:0/22:5), PC (O-22:2/12:0), and PC (26:1/11:0) were elevated in the NASH group compared to those in the NAFL group. Specific analysis revealed an overall lipidomic profile shift from NAFL to NASH, and identified valuable lipid moieties, such as PCs [PC (14:0/18:2), PE (18:0/22:5) and PC (26:1/11:0)] or plasmalogens [PC (O-22:0/0:0), PC (O-18:0/0:0), PC (O-16:0/0:0)], which were significantly altered in NASH patients. In addition, PC (14:0/18:2), phosphatidic acid (18:2/24:4) were positively correlated with NAS; whereas PC (18:0/0:0) was correlated positively with fibrosis score. CONCLUSIONS The present study revealed overall lipidomic profile shift from NAFL to NASH, identified valuable lipid moieties which may be non-invasive biomarkers in the categorization of NAFLD. The correlations between lipid moieties and NAS and fibrosis scores indicate that these lipid biomarkers may be used to predict the severity of the disease.
Collapse
Affiliation(s)
- Zhong-Hua Wang
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Kenneth I Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Xiao-Dong Wang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou 325000, China; The Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou 325000, China
| | - Jin Qiao
- Department of General Practice, Huaihai Middle Road Community Health Service Center of Huangpu District, Shanghai 200025, China
| | - Yang-Yang Li
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Li Zhang
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou 325000, China; The Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou 325000, China
| | - Jian Wu
- Department of Medical Microbiology and 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 and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Laboratory of Fatty Liver and Metabolic Diseases, Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China.
| |
Collapse
|
|
27
|
Liu C, Wang YL, Yang YY, Zhang NP, Niu C, Shen XZ, Wu J. Novel approaches to intervene gut microbiota in the treatment of chronic liver diseases. FASEB J 2021; 35:e21871. [PMID: 34473374 DOI: 10.1096/fj.202100939r] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/05/2021] [Accepted: 08/09/2021] [Indexed: 02/07/2023]
Abstract
Recent investigations of gut microbiota have contributed to understanding of the critical role of microbial community in pathophysiology. Dysbiosis not only causes disturbance directly to the gastrointestinal tract but also affects the liver through gut-liver axis. Various types of dysbiosis have been documented in alcoholic liver disease (ALD), nonalcoholic fatty liver disease, autoimmune hepatitis (AIH), primary sclerosing cholangitis, and may be crucial for the initiation, progression, or deterioration to end-stage liver disease. A few microbial species have been identified as the causal factors leading to these chronic illnesses that either do not have clear etiologies or lack effective treatment. Notably, cytolysin-producing Enterococcus faecalis, Klebsiella pneumoniae and Enterococcus gallinarum were defined for ALD, NASH, and AIH, respectively. These groundbreaking discoveries drive a rapid development in innovative therapeutics, such as fecal microbial transplantation and implementation of specific bacteriophages in addition to prebiotics, probiotics, or synbiotics for intervention of dysbiosis. Although most emerging interventions are in preclinical development or early clinical trials, a better delineation of specific dysbiosis in these disorders at metabolic, immunogenic, or molecular levels in establishing particular causal effects aids in modulating or correcting the microbial community which is the part of daily life for human being.
Collapse
Affiliation(s)
- Chang Liu
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Yu-Li Wang
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Yong-Yu Yang
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Ning-Ping Zhang
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
| | - Chen Niu
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China
| | - Xi-Zhong Shen
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
| | - Jian Wu
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China.,Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
| |
Collapse
|
|
28
|
Fernández-Veledo S, Ceperuelo-Mallafré V, Vendrell J. Rethinking succinate: an unexpected hormone-like metabolite in energy homeostasis. Trends Endocrinol Metab 2021; 32:680-692. [PMID: 34301438 DOI: 10.1016/j.tem.2021.06.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 02/07/2023]
Abstract
There has been an explosion of interest in the signaling capacity of energy metabolites. A prime example is the Krebs cycle substrate succinate, an archetypal respiratory substrate with functions beyond energy production as an intracellular and extracellular signaling molecule. Long associated with inflammation, emerging evidence supports a key role for succinate in metabolic processes relating to energy management. As the natural ligand for SUCNR1, a G protein-coupled receptor, succinate is akin to hormones and likely functions as a reporter of metabolism and stress. In this review, we reconcile new and old observations to outline a regulatory role for succinate in metabolic homeostasis. We highlight the importance of the succinate-SUCNR1 axis in metabolic diseases as an integrator of macrophage immune response, and we discuss new metabolic functions recently ascribed to succinate in specific tissues. Because circulating succinate has emerged as a promising biomarker in chronic metabolic diseases, a better understanding of the physiopathological role of the succinate-SUCNR1 axis in metabolism might open new avenues for clinical use in patients with obesity or diabetes.
Collapse
Affiliation(s)
- Sonia Fernández-Veledo
- Department of Endocrinology and Nutrition and Research Unit, University Hospital of Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
| | - Victòria Ceperuelo-Mallafré
- Department of Endocrinology and Nutrition and Research Unit, University Hospital of Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Department of Medicine and Surgery, University Rovira I Virgili, Tarragona, Spain
| | - Joan Vendrell
- Department of Endocrinology and Nutrition and Research Unit, University Hospital of Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Department of Medicine and Surgery, University Rovira I Virgili, Tarragona, Spain
| |
Collapse
|
|
29
|
Henderson J, O'Reilly S. The emerging role of metabolism in fibrosis. Trends Endocrinol Metab 2021; 32:639-653. [PMID: 34024695 DOI: 10.1016/j.tem.2021.05.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 05/04/2021] [Indexed: 12/21/2022]
Abstract
The metabolic shift that cancer cells undergo towards aerobic glycolysis was identified as a defining feature in tumours almost 100 years ago; however, it has only recently become apparent that similar metabolic reprogramming is a key feature in other diseases - with fibrosis now entering the fray. In this perspective, an overview of the recent evidence implicating increased glycolysis and glutaminolysis as mediators of fibrosis is presented, with a particular emphasis on the novel therapeutic possibilities this introduces. Furthermore, the impact that metabolic reprogramming has on redox homeostasis is discussed, providing an insight into how this often-overlooked mechanism may drive the pathogenesis.
Collapse
Affiliation(s)
- John Henderson
- Department of Applied Sciences, Northumbria University, Ellison Place, Newcastle upon Tyne NE1 8ST, UK
| | - Steven O'Reilly
- Biosciences, Durham University, South Road, Durham DH1 3LE, UK. steven.o'
| |
Collapse
|
|
30
|
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.
Collapse
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.
| |
Collapse
|
|
31
|
Western Diet Decreases the Liver Mitochondrial Oxidative Flux of Succinate: Insight from a Murine NAFLD Model. Int J Mol Sci 2021; 22:ijms22136908. [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] [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.
Collapse
|
|
32
|
Zhu LY, Liu C, Li ZR, Niu C, Wu J. NLRP3 deficiency did not attenuate NASH development under high fat calorie diet plus high fructose and glucose in drinking water. J Transl Med 2021; 101:588-599. [PMID: 33526807 DOI: 10.1038/s41374-021-00535-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 12/27/2022] Open
Abstract
NOD-like receptor protein 3 (NLRP3) promotes the inflammatory response during progression of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). This study aimed to further delineate the role of NLRP3 in NASH development by abolishing its expression in mice. A high-fat and calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) was used to establish NASH in both wild-type (WT) and NLRP3 knock-out (KO) mice. Hepatocellular injury, hepatic steatosis and fibrosis, as well as inflammatory response and insulin resistance in the liver and epidydimal white adipose tissue (eWAT) were determined. Elevated body weight, liver weight and serum alanine transaminase level, increased hepatic triglyceride accumulation and collagen deposition, and worsened systemic insulin resistance were observed in Nlrp3-/- mice compared to WT mice under HFCD-HF/G feeding. Upregulated hepatic transcription of tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1), and enhanced infiltration of inducible nitric oxide synthase-positive (iNOS+) M1 macrophages were also documented in HFCD-HF/G-fed Nlrp3-/- mice in comparison to HFCD-HF/G-fed WT mice. Moreover, transcription of TNF-α and MCP-1 and infiltration of iNOS+ M1 macrophages were increased in the liver of Nlrp3-/- mice under control diet. NLRP3 deficiency did not attenuate, but instead aggravated NASH development under HFCD-HF/G feeding. The worsened extent of NASH might be attributed to enhanced hepatic MCP-1 expression and M1 macrophage infiltration in Nlrp3-/- mice. Our study points to additional caution when NLRP3 blockade is considered as a therapeutic strategy in the treatment of human NASH.
Collapse
Affiliation(s)
- Liu-Yan Zhu
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Chang Liu
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Zong-Rui Li
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Chen Niu
- Department of Medical Microbiology and 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 and 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.
| |
Collapse
|
|
33
|
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.
Collapse
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
| |
Collapse
|
|
34
|
Yang M, Zhang CY. G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment. World J Gastroenterol 2021; 27:677-691. [PMID: 33716447 PMCID: PMC7934005 DOI: 10.3748/wjg.v27.i8.677] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/24/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a broad-spectrum disease, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis, which can progress to cirrhosis and liver cancer. Abnormal hepatic lipid accumulation is the major manifestation of this disease, and lipotoxicity promotes NAFLD progression. In addition, intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins, resulting in progression of NAFLD to fibrosis and even cirrhosis. G protein-coupled receptors (GPCRs) have been shown to play essential roles in metabolic disorders, such as NAFLD and obesity, through their function as receptors for bile acids and free fatty acids. In addition, GPCRs link gut microbiota-mediated connections in a variety of diseases, such as intestinal diseases, hepatic steatosis, diabetes, and cardiovascular diseases. The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids. GPCR agonists, including peptides and natural products like docosahexaenoic acid, have been applied to investigate their role in liver diseases. Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome. This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment. Overall, understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.
Collapse
Affiliation(s)
- Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
| | - Chun-Ye Zhang
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65212, United States
| |
Collapse
|
|
35
|
Li X, Xie L, Qu X, Zhao B, Fu W, Wu B, Wu J. GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses. FASEB J 2020; 34:13091-13105. [PMID: 32812686 DOI: 10.1096/fj.202001037r] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/08/2020] [Accepted: 06/23/2020] [Indexed: 12/18/2022]
Abstract
Succinate receptor GPR91 is one of G protein-coupled receptors (GPCRs), and is expressed in a variety of cell types and tissues. Succinate is its natural ligand, and its activation represents that an intrinsic metabolic intermediate exerts a regulatory role on many critical life processes involving pathophysiologic mechanisms, such as innate immunity, inflammation, tissue repair, and oncogenesis. With the illustration of 3-dimensional crystal structure of the receptor and discovery of its antagonists, it is possible to dissect the succinate-GPR91-G protein signaling pathways in different cell types under pathophysiological conditions. Deep understanding of the GPR91-ligand binding mode with various agonists and antagonists would aid in elucidating the molecular basis of a spectrum of chronic illnesses, such as hypertension, diabetes, and their renal and retina complications, metabolic-associated fatty liver diseases, such as nonalcoholic steatohepatitis and its fibrotic progression, inflammatory bowel diseases (Crohn's disease and ulcerative colitis), age-related macular degeneration, rheumatoid arthritis, and progressive behaviors of malignancies. With better delineation of critical regulatory role of the succinate-GPR91 axis in these illnesses, therapeutic intervention may be developed by specifically targeting this signaling pathway with small molecular antagonists or other strategies.
Collapse
Affiliation(s)
- Xinyi Li
- 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
| | - Xiangli Qu
- 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
| | - Bangyi Zhao
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China
| | - Wei Fu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China
| | - Beili Wu
- 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
| | - Jian Wu
- Department of Medical Microbiology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Department of Gastroenterology & Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, China
| |
Collapse
|
|
36
|
Liu XJ, Liu C, Zhu LY, Fan CL, Niu C, Liu XP, Liu HL, Wu J. Hepalatide ameliorated progression of nonalcoholic steatohepatitis in mice. Biomed Pharmacother 2020; 126:110053. [PMID: 32200254 DOI: 10.1016/j.biopha.2020.110053] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 02/20/2020] [Accepted: 02/25/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND No FDA-approved medications are available for the treatment of nonalcoholic steatohepatitis (NASH). The present study aimed to assess the effects of Hepalatide, a sodium taurocholate cotransporting polypeptide (NTCP) receptor-binding agent, on metabolic and histopathologic changes of a mouse model of NASH caused by high fat/calorie diet plus high fructose/glucose in drinking water (HFCD-HF/G) for 16 weeks. METHODS Male mice were randomly divided into 4 groups: controls (normal diet), HFCD-HF/G group, HFCD-HF/G plus low or high dose of Hepalatide (20 or 60 mg/kg, LH or HH, s.c. from 9 to 16 weeks). RESULTS Compared to HFCD-HF/G-fed mice, serum triglyceride and cholesterol levels in mice fed HFCD-HF/G plus LH or HH were decreased. The treatment with Hepalatide decreased serum alanine aminotransferase levels significantly. Liver histology and TUNEL staining showed that Hepalatide remarkably attenuated inflammation, hepatocellular steatosis and apoptosis. Hepalatide treatment decreased fasting blood glucose, serum insulin and HOMA insulin resistance index in the HH group. Moreover, Masson's staining, semi-quantitative score of fibrosis, and hydroxyproline content demonstrated that Hepalatide mitigated fibrotic progression in this murine NASH model. Additionally, most components of liver and few serum bile acids were increased in mice treated with HH. CONCLUSION Hepalatide effectively alleviated the pathological process, metabolic profile, hepatocellular steatosis and injury, insulin resistance, halted hepatic fibrotic progression in a mouse model of NASH, most likely through the increase of serum bile acids.
Collapse
Affiliation(s)
- Xue-Jing Liu
- Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Chang Liu
- Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Liu-Yan Zhu
- Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Cui-Li Fan
- Shanghai Hep Pharmaceutical Co., Ltd., Shanghai, 201203, China
| | - Chen Niu
- Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Xiu-Ping Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Hong-Li Liu
- Shanghai Hep Pharmaceutical Co., Ltd., Shanghai, 201203, China.
| | - Jian Wu
- Department of Medical Microbiology & Parasitology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China; Laboratory of Fatty Liver and Metabolic Diseases, Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, 200032, China; Dept. of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China.
| |
Collapse
|