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Xie H, Wang J, Zhao Q. Identification of potential metabolic biomarkers and immune cell infiltration for metabolic associated steatohepatitis by bioinformatics analysis and machine learning. Sci Rep 2025; 15:16596. [PMID: 40360670 PMCID: PMC12075577 DOI: 10.1038/s41598-025-86397-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 01/10/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Metabolic associated steatohepatitis (MASH) represents a severe subtype of metabolic associated fatty liver disease (MASLD), with an increased risk of progression to cirrhosis and hepatocellular carcinoma. The nomenclature shift from nonalcoholic steatohepatitis (NASH)/nonalcoholic fatty liver disease (NAFLD) to MASH/MASLD, underscores the pivotal role of metabolic factors in disease progression. Diagnosis of MASH currently hinges on liver biopsy, a procedure whose invasive nature limits its clinical utility. This study aims to identify and validate metabolism-related genes (MRGs) markers for the non-invasive diagnosis of MASH. METHODS This study extracted multiple datasets from the GEO database to identify metabolism-related differentially expressed genes (MRDEGs). Protein-Protein Interaction (PPI) network and machine learning algorithms, including Least Absolute Shrinkage and Selection Operator (LASSO) regression, Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Random Forest (RF), were applied to screen for signature MRDEGs. The diagnostic performance of these MRDEGs was evaluated using the Receiver Operating Characteristic (ROC) curve and further validated using independent external datasets. Additionally, enrichment analysis was performed to uncover key driver pathways in MASH. The infiltration levels of various immune cell types were assessed using single sample Gene Set Enrichment Analysis (ssGSEA). Finally, Spearman correlation analysis confirmed the association between signature genes and immune cells. RESULTS We successfully identified seven signature MRDEGs, including CYP7A1, GCK, AKR1B10, HPRT1, GPD1, FADS2, and ENO3, through PPI network analysis and machine learning algorithms. The gene model displayed exceptional diagnostic performance in the training and validation cohorts, as evidenced by the area under ROC curve (AUC) exceeding 0.9. Further enrichment analysis revealed that signature MEDEGs were primarily involved in multiple biological pathways related to glucose and lipid metabolism. Immune infiltration analysis indicated a significant increase in the infiltration levels of activated CD8 T cells, gamma-delta T cells, natural killer cells, and CD56bright NK cells in patients with MASH. CONCLUSION This study successfully identified seven signature MRDEGs as significant diagnostic biomarkers for MASH. The findings not only offer novel strategies for non-invasive diagnosis of MASH but also highlight the substantial role of immune cell infiltration in the progression of MASH.
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Affiliation(s)
- Haoran Xie
- Hepatobiliary Pancreatic Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Junjun Wang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiuyan Zhao
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China.
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Chen H, Gong Y, Wu F, Wu M, Li S, Chen B, Wang J, Qiu M, Xu Y, Zhao W, Chen T. WWP1-SHARP1-C/EBPβ positive feedback loop modulates development of metabolic dysfunction-associated steatotic liver disease. Metabolism 2025; 169:156271. [PMID: 40280477 DOI: 10.1016/j.metabol.2025.156271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 04/10/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND & AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant global health threat. The molecular mechanisms underlying regulation of MASLD remain largely unknown. This study aimed to investigate the role of the WW domain-containing ubiquitin E3 ligase 1 (WWP1)-enhancer-of-split and hairy-related protein 1 (SHARP1)-C/EBPβ signal loop in MASLD. METHODS In vivo and in vitro models of MASLD were established applying high-fat diet-fed (HFD) mice and free fatty acid (FFA)-treated hepatocytes. The relationships among SHARP1, WWP1, and C/EBPβ were examined using bioinformatics, immunoprecipitation, immunofluorescence, luciferase assays, chromatin immunoprecipitation. MASLD progression was evaluated based on food intake, energy expenditure, insulin resistance, hepatic steatosis, inflammation and white fat growth. RESULTS SHARP1 were significantly reduced in the MASLD livers of mouse and human and in FA-treated hepatocytes. Hepatocyte-specific SHARP1 overexpression significantly inhibited MASLD development in HFD-fed mice. Wild-type SHARP1, but not deficient SHARP1 (SHARP1-K/R and SHARP1-P/A), was ubiquitinated and degraded by the E3 ligase WWP1. Wild-type SHARP1 was not ubiquitinated when WWP1 was deficient (WWP1-C886A, WWP1-C890A, WWP1-ΔWW3). Deficient SHARP1 exhibited better inhibitory activity against MASLD than the wild-type SHARP1. WWP1 overexpression reversed the suppression of MASLD induced by wild-type SHARP1 but did not affect that induced by deficient SHARP1. Deficient WWP1 did not inhibit the wild-type SHARP1-induced MASLD amelioration. Furthermore, in FA-treated hepatocytes, the interaction between SHARP1 and C/EBPβ weakened, resulting in more C/EBPβ binding to the Wwp1 promoter and subsequent WWP1 upregulation. SHARP1 overexpression or WWP1 interference partially blocked the effects of C/EBPβ on MASLD. Hesperidin was identified as a novel WWP1 inhibitor, and it significantly blocked WWP1 overexpression-induced MASLD progression. CONCLUSION The WWP1-SHARP1-C/EBPβ signal loop accelerates MASLD progression. This study provides novel insights into novel biomarkers and treatment approaches for MASLD.
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Affiliation(s)
- Hao Chen
- Department of Pathology, School of Basic Medical Sciences, Wannan Medical College, Wuhu, China; The First Affiliated Hospital, Jinan University, Guangzhou, China; Guangxi Technology Innovation Cooperation Base of Prevention and Control Pathogenic Microbes With Drug Resistance, Youjiang Medical University for Nationalities, Baise, China
| | - Yuanxun Gong
- Guangxi Key Laboratory for Preclinical and Translational Research on Bone and Joint Degenerative Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Fei Wu
- School of Clinical Medicine, Wannan Medical College, Wuhu, China; Department of Oncology, Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Man Wu
- School of Clinical Medicine, Wannan Medical College, Wuhu, China
| | - Shu Li
- Department of Pathophysiology, School of Basic Medical Sciences, Wannan Medical College, Wuhu, China
| | - Bofeng Chen
- School of Public Health, Wannan Medical College, Wuhu, China
| | - Jie Wang
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Min Qiu
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Ying Xu
- School of Clinical Medicine, The First Affiliated Hospital, Chengdu Medical College, Chengdu, China; School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Wei Zhao
- School of Clinical Medicine, The First Affiliated Hospital, Chengdu Medical College, Chengdu, China; School of Laboratory Medicine, Chengdu Medical College, Chengdu, China.
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Wang Y, Lv B, Liu N, Tao S, Dou J, Li J, Deng R, Yang X, Jiang G. The mechanism of bile acid metabolism regulating lipid metabolism and inflammatory response in T2DM through the gut-liver axis. Heliyon 2024; 10:e35421. [PMID: 39229512 PMCID: PMC11369409 DOI: 10.1016/j.heliyon.2024.e35421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 06/27/2024] [Accepted: 07/29/2024] [Indexed: 09/05/2024] Open
Abstract
Aims The main objective of this study was to analyze the changes of intestinal microflora and how bile acid metabolic pathways affect lipid metabolism in T2DM through the gut-liver axis. Methods Firstly, 16S rRNA sequencing, metabolomics and transcriptomic sequencing were performed on plasma and feces of clinical subjects to determine the changes of intestinal flora and its metabolites. Finally, T2DM mice model was verified in vivo. Results T2DM patients have significant intestinal flora metabolism disorders. The differential fecal metabolites were mainly enriched in primary bile acid biosynthesis and cholesterol metabolism pathways in T2DM patients. After verification, the changes in gut microbiota and metabolites in T2DM patients (including up-regulated bacteria associated with BA metabolism, such as lactobacillus and bifidobacterial, and down-regulated bacteria capable of producing SCFAs such as Faecalibacterium, Bacteroides, Romboutsia and Roseburia); and the changes in the flora and metabolites that result in impairment of intestinal barrier function and changes of protein expression in the blood, intestine and liver of T2DM patients (including FGFR4↑, TRPM5↑ and CYP27A1↓, which are related to BA and lipid metabolism homeostasis, and TLR6↑, MYD88↑ and NF-κB↑, which are related to inflammatory response). These aspects together contribute to the development of further disorders of glucolipid metabolism and systemic inflammation in T2DM patients. Conclusions Changes in intestinal flora and its metabolites may affect lipid metabolism and systemic inflammatory response in T2DM patients through the gut-liver axis mediated by bile acids.
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Affiliation(s)
- Yan Wang
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Bohan Lv
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Nannan Liu
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Siyu Tao
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Jinfang Dou
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Jun Li
- Department of Endocrinology, Beijing He ping li Hospital, Beijing, China
| | - Ruxue Deng
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Xiuyan Yang
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Guangjian Jiang
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
- Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Xinjiang, China
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Doueiry C, Kappler CS, Martinez-Morant C, Duncan SA. A PNPLA3-Deficient iPSC-Derived Hepatocyte Screen Identifies Pathways to Potentially Reduce Steatosis in Metabolic Dysfunction-Associated Fatty Liver Disease. Int J Mol Sci 2024; 25:7277. [PMID: 39000384 PMCID: PMC11242544 DOI: 10.3390/ijms25137277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/25/2024] [Accepted: 06/29/2024] [Indexed: 07/16/2024] Open
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is increasing in adults and children. Unfortunately, effective pharmacological treatments remain unavailable. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase domain-containing protein (PNPLA3 I148M) have the most significant genetic association with the disease at all stages of its progression. A roadblock to identifying potential treatments for PNPLA3-induced NAFLD is the lack of a human cell platform that recapitulates the PNPLA3 I148M-mediated onset of lipid accumulation. Hepatocyte-like cells were generated from PNPLA3-/- and PNPLA3I148M/M-induced pluripotent stem cells (iPSCs). Lipid levels were measured by staining with BODIPY 493/503 and were found to increase in PNPLA3 variant iPSC-derived hepatocytes. A small-molecule screen identified multiple compounds that target Src/PI3K/Akt signaling and could eradicate lipid accumulation in these cells. We found that drugs currently in clinical trials for cancer treatment that target the same pathways also reduced lipid accumulation in PNPLA3 variant cells.
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Affiliation(s)
- Caren Doueiry
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA; (C.D.); (C.M.-M.)
- Medical Scientist Training Program, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Christiana S. Kappler
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA; (C.D.); (C.M.-M.)
| | - Carla Martinez-Morant
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA; (C.D.); (C.M.-M.)
| | - Stephen A. Duncan
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA; (C.D.); (C.M.-M.)
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Lin X, Zhang J, Chu Y, Nie Q, Zhang J. Berberine prevents NAFLD and HCC by modulating metabolic disorders. Pharmacol Ther 2024; 254:108593. [PMID: 38301771 DOI: 10.1016/j.pharmthera.2024.108593] [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: 10/25/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 02/03/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a global metabolic disease with high prevalence in both adults and children. Importantly, NAFLD is becoming the main cause of hepatocellular carcinoma (HCC). Berberine (BBR), a naturally occurring plant component, has been demonstrated to have advantageous effects on a number of metabolic pathways as well as the ability to kill liver tumor cells by causing cell death and other routes. This permits us to speculate and make assumptions about the value of BBR in the prevention and defense against NAFLD and HCC by a global modulation of metabolic disorders. Herein, we briefly describe the etiology of NAFLD and NAFLD-related HCC, with a particular emphasis on analyzing the potential mechanisms of BBR in the treatment of NAFLD from aspects including increasing insulin sensitivity, controlling the intestinal milieu, and controlling lipid metabolism. We also elucidate the mechanism of BBR in the treatment of HCC. More significantly, we provided a list of clinical studies for BBR in NAFLD. Taking into account our conclusions and perspectives, we can make further progress in the treatment of BBR in NAFLD and NAFLD-related HCC.
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Affiliation(s)
- Xinyue Lin
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Juanhong Zhang
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China; College of Life Science, Northwest Normal University, Lanzhou 730070, China
| | - Yajun Chu
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Qiuying Nie
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Junmin Zhang
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
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Chen T, Meng Y, Zhou Z, Li H, Wan L, Kang A, Guo W, Ren K, Song X, Chen Y, Zhao W. GAS5 protects against nonalcoholic fatty liver disease via miR-28a-5p/MARCH7/NLRP3 axis-mediated pyroptosis. Cell Death Differ 2023; 30:1829-1848. [PMID: 37337032 PMCID: PMC10307850 DOI: 10.1038/s41418-023-01183-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 05/14/2023] [Accepted: 06/12/2023] [Indexed: 06/21/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterised by hepatic steatosis, inflammation, and insulin resistance. The role of long noncoding RNA (lncRNA)-regulated pyroptosis in NAFLD development remains largely unknown. This study aimed to investigate whether NAFLD development is controlled by lncRNA growth-arrest specific transcript 5 (GAS5)/miR-28a-5p/membrane associated ring-CH-type finger 7 (MARCH7)-mediated pyroptosis using in vivo and in vitro models. First, GAS5 expression was decreased but miR-28a-5p expression was increased in the livers of NAFLD patients, high-fat diet (HFD)-fed mice and leptin-deficient obese (Ob/Ob) mice. Furthermore, GAS5 suppressed while miR-28a-5p promoted NAFLD development, and overexpression of miR-28a-5p reversed the GAS5 overexpression-induced attenuation of NAFLD. Mechanistically, GAS5 served as a sponge of miR-28a-5p, and miR-28a-5p enhanced pyroptosis by targeting the 3' untranslated region (UTR) of the E3 ligase MARCH7 during NAFLD development. MARCH7 interacted with the NOD-like receptor protein 3 (NLRP3) protein, resulting in proteasomal degradation of NLRP3 to inhibit pyroptosis. As expected, MARCH7 knockdown abolished the miR-28a-5p knockdown-induced inhibition of NAFLD development, and the ubiquitin E3 ligase-inactive mutant (W589A/I556A) of MARCH7 failed to inhibit NAFLD development. In conclusion, GAS5 protected against NAFLD development by binding to miR-28a-5p, miR-28a-5p promoted NAFLD development by targeting MARCH7, and MARCH7 ameliorated NAFLD by suppressing NLRP3-mediated pyroptosis. The GAS5/miR-28a-5p/MARCH7/NLRP3 axis plays an important role in NAFLD progression, and it might be a biomarker for NAFLD.
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Affiliation(s)
- Tianxing Chen
- Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, China
| | - Yao Meng
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Zhihang Zhou
- Department of Gastroenterology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Haitao Li
- Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, China
| | - Lingfeng Wan
- Department of Infectious Disease, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Aiwen Kang
- Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, China
| | - Wei Guo
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Ke Ren
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Xueru Song
- Department of Pathology, The First Affiliated Hospital, Zhejiang University, Zhejiang, China
| | - Yu Chen
- Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, Hong Kong
| | - Wei Zhao
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China.
- Clinical Laboratory, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
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Mao YJ, Ying MM, Xu G. Identification of hub genes and small molecule therapeutic drugs related to simple steatosis with secondary analysis of existing microarray data. ALL LIFE 2022. [DOI: 10.1080/26895293.2022.2114550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Yi-Jie Mao
- Department of Clinical Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou, People’s Republic of China
| | - Miao-Miao Ying
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Gang Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China
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Granja SC, Longatto-Filho A, de Campos PB, Oliveira CP, Stefano JT, Martins-Filho SN, Chagas AL, Herman P, D'Albuquerque LC, Reis Alvares-da-Silva M, Carrilho FJ, Baltazar F, Alves VAF. Non-Alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: Immunohistochemical Assessment of Markers of Cancer Cell Metabolism. Pathobiology 2022; 89:157-165. [PMID: 35042213 DOI: 10.1159/000521034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 11/17/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) has been associated to non-alcoholic fatty liver disease (NAFLD). We sought to investigate the immunoexpression of several glycolytic metabolism-associated markers in patients with HCC associated to NAFLD and associate these factors to their clinical-pathological characteristics. METHODS We evaluated 35 HCC specimens from 21 patients diagnosed with non-alcoholic steatohepatitis (NASH) undergoing liver resection (12 patients), liver transplantation (8 patients), or both (1 patient). Histological features, clinical aspects, demographic and biochemical data, as well as the immunohistochemical reactivity for monocarboxylate transporters 1, 2, and 4; their chaperone CD147; carbonic anhydrase IX; and glucose transporter-1 (GLUT1) were assessed. RESULTS Metabolic-associated cirrhosis was present in 12 of the 21 patients (8 child A and 4 child B scores). From 9 patients without cirrhosis, 3 presented NASH F3 and 6 NASH F2. Sixteen (76%) had diabetes mellitus, 17 (81%) arterial hypertension, and 19 (90%) body mass index above 25 kg/m2; 8 (38%) had dyslipidemia. From 35 nodules, steatosis was found in 26, ballooning in 31 nodules, 25 of them diagnosed as steatohepatitic subtype of HCC. MCT4 immunoexpression was associated with extensive intratumoral fibrosis, advanced clinical stages, and shorter overall survival. GLUT1 was noticeable in nodules with extensive intratumoral steatosis, higher intratumoral fibrosis, and advanced clinical stages. Immunohistochemical expression of the metabolic biomarkers MCT4 and GLUT1 was higher in patients with Barcelona-clinic liver cancer B or C. GLUT1 correlated with higher degree of steatosis, marked ballooning, intratumoral fibrosis, and higher parenchymal necroinflammatory activity. CONCLUSION Our data indicate that the expression of the glycolytic phenotype of metabolic markers, especially GLUT1 and MCT4, correlates with a more severe course of HCC occurring in NASH patients.
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Affiliation(s)
- Sara Costa Granja
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Research Centre in Health and Environment (CISA), School of Health (ESS), Polytechnic Institute of Porto (P.PORTO), Porto, Portugal
- Department of Pathological, Cytological and Thanatological Anatomy, ESS|P.PORTO, Porto, Portugal
| | - Adhemar Longatto-Filho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Department of Pathology (LIM-14), University of São Paulo School of Medicine, São Paulo, Brazil
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil
| | - Priscila B de Campos
- Department of Gastroenterology (LIM-07/ 37), University of São Paulo School of Medicine, São Paulo, Brazil
| | - Claudia P Oliveira
- Department of Gastroenterology (LIM-07/ 37), University of São Paulo School of Medicine, São Paulo, Brazil
| | - José T Stefano
- Department of Gastroenterology (LIM-07/ 37), University of São Paulo School of Medicine, São Paulo, Brazil
| | | | - Aline L Chagas
- Department of Gastroenterology (LIM-07/ 37), University of São Paulo School of Medicine, São Paulo, Brazil
| | - Paulo Herman
- Department of Gastroenterology (LIM-07/ 37), University of São Paulo School of Medicine, São Paulo, Brazil
| | - Luiz C D'Albuquerque
- Department of Gastroenterology (LIM-07/ 37), University of São Paulo School of Medicine, São Paulo, Brazil
| | - Mário Reis Alvares-da-Silva
- Division of Gastroenterology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Flair José Carrilho
- Department of Gastroenterology (LIM-07/ 37), University of São Paulo School of Medicine, São Paulo, Brazil
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Venâncio A F Alves
- Department of Pathology (LIM-14), University of São Paulo School of Medicine, São Paulo, Brazil
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Yao J, Yu Y, Nyberg SL. Induced Pluripotent Stem Cells for the Treatment of Liver Diseases: Novel Concepts. Cells Tissues Organs 2022; 211:368-384. [PMID: 32615573 PMCID: PMC7775900 DOI: 10.1159/000508182] [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: 02/25/2020] [Accepted: 04/24/2020] [Indexed: 01/03/2023] Open
Abstract
Millions of people worldwide with incurable liver disease die because of inadequate treatment options and limited availability of donor organs for liver transplantation. Regenerative medicine as an innovative approach to repairing and replacing cells, tissues, and organs is undergoing a major revolution due to the unprecedented need for organs for patients around the world. Induced pluripotent stem cells (iPSCs) have been widely studied in the field of liver regeneration and are considered to be the most promising candidate therapies. This review will conclude the current state of efforts to derive human iPSCs for potential use in the modeling and treatment of liver disease.
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Affiliation(s)
- Jia Yao
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA.,Clinical Research and Project Management Office, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yue Yu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation; Nanjing, China
| | - Scott L. Nyberg
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA.,Corresponding Author: Scott L. Nyberg, William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA, Tel: Rochester, MN 55905, USA, Fax: (507) 284-2511,
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Albadawy R, Agwa SHA, Khairy E, Saad M, El Touchy N, Othman M, El Kassas M, Matboli M. Circulatory Endothelin 1-Regulating RNAs Panel: Promising Biomarkers for Non-Invasive NAFLD/NASH Diagnosis and Stratification: Clinical and Molecular Pilot Study. Genes (Basel) 2021; 12:1813. [PMID: 34828420 PMCID: PMC8619934 DOI: 10.3390/genes12111813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/12/2021] [Accepted: 11/16/2021] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the major seeds of liver cirrhosis and hepatocellular carcinoma. There is no convenient reliable non-invasive early diagnostic tool available for NAFLD/NASH diagnosis and stratification. Recently, the role of cytosolic sensor, stimulator of interferon genes (STING) signaling pathway in pathogenesis of nonalcoholic steatohepatitis (NASH) has been evidenced in research. We have selected EDN1/TNF/MAPK3/EP300/hsa-miR-6888-5p/lncRNA RABGAP1L-DT-206 RNA panel from bioinformatics microarrays databases related to STING pathway and NAFLD/NASH pathogenesis. We have used reverse-transcriptase real-time polymerase chain reaction to assess the expression of the serum RNAs panel in NAFLD/NASH without suspicion of advanced fibrosis, NAFLD/with NASH patients with suspicion of advanced fibrosis and controls. Additionally, we have assessed the diagnostic performance of the Ribonucleic acid (RNA) panel. We have detected upregulation of the EDN1 regulating RNAs panel expression in NAFLD/NASH cases compared to healthy controls. We concluded that this circulatory RNA panel could enable us to discriminate NAFLD/NASH cases from controls, and also NAFLD/NASH cases (F1, F2) from advanced fibrosis stages (F3, F4).
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Affiliation(s)
- Reda Albadawy
- Gastroentrology, Hepatology & Infectious Disease Department, Faculty of Medicine, Benha University, Benha 13736, Egypt;
| | - Sara H. A. Agwa
- Clinical Pathology Department, Molecular Genomics Unit of Medical Ain Shams Research Institute, School of Medicine, Ain Shams University, Cairo 11566, Egypt;
| | - Eman Khairy
- Medicinal Biochemistry and Molecular Biology Department, Ain Shams University School of Medicine, Cairo 11566, Egypt;
| | - Maha Saad
- Biochemistry Department, Faculty of Medicine, Modern University for Technology and Information, Cairo 12055, Egypt;
| | - Naglaa El Touchy
- Gastroentrology, Hepatology & Infectious Disease Department, Faculty of Medicine, Benha University, Benha 13736, Egypt;
| | - Mohamed Othman
- Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Mohamed El Kassas
- Endemic Medicine and Hepato-Gastroenterology Department, Faculty of Medicine, Helwan University, Helwan 11792, Egypt;
| | - Marwa Matboli
- Medicinal Biochemistry and Molecular Biology Department, Ain Shams University School of Medicine, Cairo 11566, Egypt;
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11
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Wruck W, Graffmann N, Spitzhorn LS, Adjaye J. Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Acquire Rejuvenation and Reduced Heterogeneity. Front Cell Dev Biol 2021; 9:717772. [PMID: 34604216 PMCID: PMC8481886 DOI: 10.3389/fcell.2021.717772] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/17/2021] [Indexed: 12/20/2022] Open
Abstract
Despite the uniform selection criteria for the isolation of human mesenchymal stem cells (MSCs), considerable heterogeneity exists which reflects the distinct tissue origins and differences between individuals with respect to their genetic background and age. This heterogeneity is manifested by the variabilities seen in the transcriptomes, proteomes, secretomes, and epigenomes of tissue-specific MSCs. Here, we review literature on different aspects of MSC heterogeneity including the role of epigenetics and the impact of MSC heterogeneity on therapies. We then combine this with a meta-analysis of transcriptome data from distinct MSC subpopulations derived from bone marrow, adipose tissue, cruciate, tonsil, kidney, umbilical cord, fetus, and induced pluripotent stem cells derived MSCs (iMSCs). Beyond that, we investigate transcriptome differences between tissue-specific MSCs and pluripotent stem cells. Our meta-analysis of numerous MSC-related data sets revealed markers and associated biological processes characterizing the heterogeneity and the common features of MSCs from various tissues. We found that this heterogeneity is mainly related to the origin of the MSCs and infer that microenvironment and epigenetics are key drivers. The epigenomes of MSCs alter with age and this has a profound impact on their differentiation capabilities. Epigenetic modifications of MSCs are propagated during cell divisions and manifest in differentiated cells, thus contributing to diseased or healthy phenotypes of the respective tissue. An approach used to reduce heterogeneity caused by age- and tissue-related epigenetic and microenvironmental patterns is the iMSC concept: iMSCs are MSCs generated from induced pluripotent stem cells (iPSCs). During iMSC generation epigenetic and chromatin remodeling result in a gene expression pattern associated with rejuvenation thus allowing to overcome age-related shortcomings (e.g., limited differentiation and proliferation capacity). The importance of the iMSC concept is underlined by multiple clinical trials. In conclusion, we propose the use of rejuvenated iMSCs to bypass tissue- and age-related heterogeneity which are associated with native MSCs.
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Affiliation(s)
- Wasco Wruck
- Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Nina Graffmann
- Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Lucas-Sebastian Spitzhorn
- Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - James Adjaye
- Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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12
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Zheng J, Wu H, Zhang Z, Yao S. Dynamic co-expression modular network analysis in nonalcoholic fatty liver disease. Hereditas 2021; 158:31. [PMID: 34419146 PMCID: PMC8380347 DOI: 10.1186/s41065-021-00196-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 08/04/2021] [Indexed: 12/13/2022] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting people’s health worldwide. Exploring the potential biomarkers and dynamic networks during NAFLD progression is urgently important. Material and methods Differentially expressed genes (DEGs) in obesity, NAFL and NASH were screened from GSE126848 and GSE130970, respectively. Gene set enrichment analysis of DEGs was conducted to reveal the Gene Ontology (GO) biological process in each period. Dynamic molecular networks were constructed by DyNet to illustrate the common and distinct progression of health- or obesity-derived NAFLD. The dynamic co-expression modular analysis was carried out by CEMiTool to elucidate the key modulators, networks, and enriched pathways during NAFLD. Results A total of 453 DEGs were filtered from obesity, NAFL and NASH periods. Function annotation showed that health-NAFLD sequence was mainly associated with dysfunction of metabolic syndrome pathways, while obesity-NAFLD sequence exhibited dysregulation of Cell cycle and Cellular senescence pathways. Nine nodes including COL3A1, CXCL9, CYCS, CXCL10, THY1, COL1A2, SAA1, CDKN1A, and JUN in the dynamic networks were commonly identified in health- and obesity-derived NAFLD. Moreover, CYCS, whose role is unknown in NAFLD, possessed the highest correlation with NAFLD activity score, lobular inflammation grade, and the cytological ballooning grade. Dynamic co-expression modular analysis showed that module 4 was activated in NAFL and NASH, while module 3 was inhibited at NAFLD stages. Module 3 was negatively correlated with CXCL10, and module 4 was positively correlated with COL1A2 and THY1. Conclusion Dynamic network analysis and dynamic gene co-expression modular analysis identified a nine-gene signature as the potential key regulator in NAFLD progression, which provided comprehensive regulatory mechanisms underlying NAFLD progression. Supplementary Information The online version contains supplementary material available at 10.1186/s41065-021-00196-8.
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Affiliation(s)
- Jing Zheng
- Department of Pharmacy, Zhejiang Medical & Health Group Hangzhou Hospital, No.1 Banshan Road, Kangjian nong, Hangzhou, 310022, China
| | - Huizhong Wu
- Department of Pharmacy, Zhejiang Quhua Hospital, Quzhou, 324002, China
| | - Zhiying Zhang
- Department of Pharmacy, Hangzhou Jianggan District People's Hospital, Hangzhou, 310016, China
| | - Songqiang Yao
- Department of Pharmacy, Zhejiang Medical & Health Group Hangzhou Hospital, No.1 Banshan Road, Kangjian nong, Hangzhou, 310022, China.
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13
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Li L, Li SH, Jiang JP, Liu C, Ji LL. Investigating pharmacological mechanisms of andrographolide on non-alcoholic steatohepatitis (NASH): A bioinformatics approach of network pharmacology. CHINESE HERBAL MEDICINES 2021; 13:342-350. [PMID: 36118934 PMCID: PMC9476713 DOI: 10.1016/j.chmed.2021.05.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/19/2020] [Accepted: 10/25/2020] [Indexed: 12/12/2022] Open
Abstract
Objective To investigate the mechanisms of andrographolide against non-alcoholic steatohepatitis (NASH) based on network pharmacology, so as to provide a reference for further study of andrographolide in the treatment of NASH and other metabolic diseases. Methods The methionine- and choline-deficient (MCD) diet-induced NASH mice were treated by administration of andrographolide, and serum transaminase and pathological changes were analyzed. The network pharmacology-based bioinformatic strategy was then used to search the potential targets, construct protein-protein interaction (PPI) network, analyze gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment, and conduct molecular docking to explore the molecular mechanisms. Results The predicted core targets TNF, MAPK8, IL6, IL1B and AKT1 were enriched in non-alcoholic fatty liver disease (NAFLD) signaling pathway and against NASH by regulation of de novo fatty acids synthesis, anti-inflammation and anti-oxidation. Conclusion This work provides a scientific basis for further demonstration of the anti-NASH mechanisms of andrographolide.
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Affiliation(s)
- Lei Li
- Key Laboratory of Quality & Safety Control for Pork, Ministry of Agriculture and Rural, Anhui Key Laboratory of Animal Nutritional Regulation and Health, College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
- Shanghai Key Laboratory of Compound Chinese Medicines, MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Sheng-he Li
- Key Laboratory of Quality & Safety Control for Pork, Ministry of Agriculture and Rural, Anhui Key Laboratory of Animal Nutritional Regulation and Health, College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Jin-peng Jiang
- Key Laboratory of Quality & Safety Control for Pork, Ministry of Agriculture and Rural, Anhui Key Laboratory of Animal Nutritional Regulation and Health, College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Chang Liu
- Key Laboratory of Quality & Safety Control for Pork, Ministry of Agriculture and Rural, Anhui Key Laboratory of Animal Nutritional Regulation and Health, College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Li-li Ji
- Shanghai Key Laboratory of Compound Chinese Medicines, MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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14
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Matboli M, Gadallah SH, Rashed WM, Hasanin AH, Essawy N, Ghanem HM, Eissa S. mRNA-miRNA-lncRNA Regulatory Network in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:6770. [PMID: 34202571 PMCID: PMC8269036 DOI: 10.3390/ijms22136770] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 12/13/2022] Open
Abstract
AIM we aimed to construct a bioinformatics-based co-regulatory network of mRNAs and non coding RNAs (ncRNAs), which is implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), followed by its validation in a NAFLD animal model. MATERIALS AND METHODS The mRNAs-miRNAs-lncRNAs regulatory network involved in NAFLD was retrieved and constructed utilizing bioinformatics tools. Then, we validated this network using an NAFLD animal model, high sucrose and high fat diet (HSHF)-fed rats. Finally, the expression level of the network players was assessed in the liver tissues using reverse transcriptase real-time polymerase chain reaction. RESULTS in-silico constructed network revealed six mRNAs (YAP1, FOXA2, AMOTL2, TEAD2, SMAD4 and NF2), two miRNAs (miR-650 and miR-1205), and two lncRNAs (RPARP-AS1 and SRD5A3-AS1) that play important roles as a co-regulatory network in NAFLD pathogenesis. Moreover, the expression level of these constructed network-players was significantly different between NAFLD and normal control. Conclusion and future perspectives: this study provides new insight into the molecular mechanism of NAFLD pathogenesis and valuable clues for the potential use of the constructed RNA network in effective diagnostic or management strategies of NAFLD.
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Affiliation(s)
- Marwa Matboli
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo 11382, Egypt
| | - Shaimaa H. Gadallah
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo 11382, Egypt; (S.H.G.); (H.M.G.)
| | - Wafaa M. Rashed
- Department of Research, Children’s Cancer Hospital-57357, Cairo 11382, Egypt;
| | - Amany Helmy Hasanin
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11382, Egypt;
| | - Nada Essawy
- Institut Pasteur, CEDEX 15, 75724 Paris, France;
| | - Hala M. Ghanem
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo 11382, Egypt; (S.H.G.); (H.M.G.)
| | - Sanaa Eissa
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo 11382, Egypt
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15
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Zhang H, Niu Q, Liang K, Li X, Jiang J, Bian C. Effect of LncPVT1/miR-20a-5p on Lipid Metabolism and Insulin Resistance in NAFLD. Diabetes Metab Syndr Obes 2021; 14:4599-4608. [PMID: 34848984 PMCID: PMC8627263 DOI: 10.2147/dmso.s338097] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/02/2021] [Indexed: 12/20/2022] Open
Abstract
PURPOSE Nonalcoholic fatty liver disease (NAFLD) is closely related to lipid metabolism and insulin resistance. The current research mainly attempted to verify the clinical value of LncRNA plasmacytoma variant translocation 1 (PVT1), and whether microRNA regulates lipid metabolism and insulin resistance to participate in NAFLD. PATIENTS AND METHODS 81 patients with NAFLD and 78 healthy individuals were enrolled in this study. In addition, C57BL/6 mice were fed a high-fat diet to establish NAFLD model in vivo. Serum PVT1 and miR-20a-5p expression in NAFLD patients and mice were assessed by RT-qPCR. ROC curves determine the diagnostic value of PVT1 and miR-20a-5p. NAFLD mice were subjected to IPGTT to detect changes in insulin sensitivity, and the common indicators of lipid metabolism and insulin resistance were also evaluated. Dual-luciferase reporter assay verified the regulation mechanism of PVT1 and miR-20a-5p. RESULTS PVT1 was upregulated in NAFLD patients and mice, while miR-20a-5p was decreased. Their expression trends were similar in patients with HOMA-IR ≥2.5. What's more, miR-20a-5p, FBG, ALT, and HOMA-IR were independently correlated with PVT1. And PVT1 and miR-20a-5p show high clinical diagnostic value. Bodyweight, insulin sensitivity, lipid metabolism inductors were increased in NAFLD mice, but these increases were attenuated by PVT1 elimination. Finally, miR-20a-5p might function as the possible miRNA target of PVT1 via the binding sites at 3'-UTR and negatively regulated by it. CONCLUSION PVT1 and miR-20a-5p are potential clinical biomarkers of NAFLD, and PVT1 promotes the occurrence of NAFLD by regulating insulin sensitivity and lipid metabolism, which may be achieved by targeting miR-20a-5p.
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Affiliation(s)
- Han Zhang
- Department of Liver Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
| | - Qinghui Niu
- Department of Liver Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
- Correspondence: Qinghui Niu Department of Liver Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, Shandong, 266100, People’s Republic of ChinaTel +86-0532-82915998 Email
| | - Kun Liang
- Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
| | - Xuesen Li
- Department of Spine Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
| | - Jing Jiang
- Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
| | - Cheng Bian
- Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
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GC-TOF-MS-Based Metabolomics Analyses of Liver and Intestinal Contents in the Overfed vs. Normally-Fed Geese. Animals (Basel) 2020; 10:ani10122375. [PMID: 33322323 PMCID: PMC7763799 DOI: 10.3390/ani10122375] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Non-alcoholic fatty liver disease has been considered as one of the most important causes of liver disease, and it is a threat to human and animal health worldwide. Interestingly, goose fatty liver can reach 8–10 times the weight of normal liver with no overt pathological symptoms, suggesting that there are some protective mechanisms. Scientists have indicated that gut microbiota participate in the formation of non-alcoholic fatty liver disease in human and mammalian animals. However, it is unclear whether gut microbiota and their metabolites contribute to goose fatty liver. The aim of the present study was to investigate the metabolomic analyses of liver and intestinal contents in overfed vs. normally fed geese. The results showed that the formation of goose fatty liver is accompanied by obvious changes in the metabolic profiles of liver and intestinal contents. The intestinal metabolites can affect the formation of goose fatty liver by affecting the metabolisms of glucose and fatty acid, oxidative stress, and inflammatory reactions. These findings provide a basis for future work addressing the relationship between intestinal metabolites and the development of non-alcoholic fatty liver disease. Abstract No overt pathological symptoms are observed in the goose liver with severe steatosis, suggesting that geese may host unique protective mechanisms. Gas chromatography time-of-flight mass spectrometry-based metabolomics analyses of liver and intestinal contents in overfed vs. normally fed geese (26 geese in each treatment) were investigated. We found that overfeeding significantly changed the metabolic profiles of liver and intestinal contents. The differential metabolites mainly belong to fatty acids, amino acids, organic acids, and amines. The differential metabolites were involved in glycolysis/gluconeogenesis, glycerolipid metabolism, the pentose phosphate pathway, fatty acid degradation, the sphingolipid signaling pathway, and the biosynthesis of unsaturated fatty acids. Moreover, we determined the biological effects of arachidonic acid (ARA) and tetrahydrocorticosterone (TD) in goose primary hepatocytes and intestinal cells. Data showed that the mRNA expression of arachidonate 5-lipoxygenase (ALOX5) in goose primary intestinal cells was significantly induced by 0.50 mM ARA treatment. Cytochrome P-450 27A1 (CYP27A1) mRNA expression was significantly inhibited in goose primary hepatocytes by 1 µM TD treatment. In conclusion, the formation of goose fatty liver is accompanied by significant changes in the metabolic profiles of liver and intestinal contents, and the changes are closely related to the metabolisms of glucose and fatty acids, oxidative stress, and inflammatory reactions.
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Larsen LE, Smith MA, Abbey D, Korn A, Reeskamp LF, Hand NJ, Holleboom AG. Hepatocyte-like cells derived from induced pluripotent stem cells: A versatile tool to understand lipid disorders. Atherosclerosis 2020; 303:8-14. [PMID: 32460140 DOI: 10.1016/j.atherosclerosis.2020.03.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 02/19/2020] [Accepted: 03/18/2020] [Indexed: 12/12/2022]
Abstract
Dyslipidemias are strongly linked to the development of atherosclerotic cardiovascular disease. Most dyslipidemias find their origin in the liver. In recent years, the differentiation of induced pluripotent stem cells (iPSCs) into hepatocyte-like cells has provided a versatile platform for the functional study of various dyslipidemias, both rare genetic dyslipidemia as well as common lipid disorders associated with insulin resistance or non-alcoholic fatty liver disease. In addition, iPSC-derived hepatocytes can serve as a cell model for developing novel lipid lowering therapies and have the potential of regenerative medicine. This review provides an overview of these developments.
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Affiliation(s)
- Lars E Larsen
- Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
| | - Mikhaila A Smith
- Departments of Genetics and Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
| | - Deepti Abbey
- Departments of Genetics and Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
| | - Amber Korn
- Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
| | - Laurens F Reeskamp
- Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
| | - Nicholas J Hand
- Departments of Genetics and Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.
| | - Adriaan G Holleboom
- Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
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18
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Drug-Induced Steatosis and Steatohepatitis: The Search for Novel Serum Biomarkers Among Potential Biomarkers for Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. Drug Saf 2020; 42:701-711. [PMID: 30762163 DOI: 10.1007/s40264-018-00790-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Drug-induced steatosis (DIS) and drug-induced steatohepatitis (DISH) are two of several types of drug-induced liver injury (DILI). They can be caused by various drugs and may present as acute, potentially lethal disorders or as chronic slowly progressive liver injury. Despite the fact that they are distinct disorders, the slow progressive forms of DIS and DISH are often confused with or misdiagnosed as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), which are much more common and, by definition, not caused by drugs. Currently the only way to identify DIS is via imaging studies or a liver biopsy, while DISH can be identified only through liver biopsy. In addition, diagnosis of either DIS or DISH requires an exhaustive clinical evaluation and comprehensive causality assessment to rule out other possible causes and determine the association with the suspected drug. Furthermore, it is difficult, using existing methods, to monitor the progression of DIS and DISH and to determine the underlying mechanism. Therefore, there is a great unmet need for non-invasive biomarkers that will be able to identify the development of DIS or DISH during drug development and to monitor for progression or regression of the disorder during treatment or following drug discontinuation. Recent developments in the fields of NAFLD and NASH have introduced several novel biomarkers that show promise for the diagnosis, monitoring, and severity assessment of these common diseases. Given the significant overlap in possible underlying mechanisms and histological pattern between NAFLD/NASH and DIS/DISH, these postulated NAFLD and NASH biomarkers may have a potential application to DIS and DISH. This article reviews the existing medical literature and other publically available information pertaining to novel serum biomarkers for NAFLD and NASH, and explores the concurrent identification of these biomarkers for DIS and DISH.
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Chen B, Zheng YM, Zhang MQ, Han Y, Zhang JP, Hu CQ. Microarray Expression Profiling and Raman Spectroscopy Reveal Anti-Fatty Liver Action of Berberine in a Diet-Induced Larval Zebrafish Model. Front Pharmacol 2020; 10:1504. [PMID: 31969822 PMCID: PMC6960226 DOI: 10.3389/fphar.2019.01504] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/20/2019] [Indexed: 12/14/2022] Open
Abstract
Background: The prevalence of non-alcohol fatty liver disease (NAFLD) is increasing in children and adolescents who are mostly resulted from overfeeding. Previous studies demonstrate that berberine (BBR), a compound derived from plant, has beneficial effects on NAFLD in adults but poorly understood in the pediatric population. This study employed a larval zebrafish model to mimic the therapeutic effects of BBR in the pediatric population and the mechanisms underlying its hepatoprotection. Methods: High-cholesterol diet (HCD)-fed zebrafish exposed to BBR at doses of 0, 1, 5, and 25 μM. After the larvae were treated with BBR for 10 days, its effect on hepatic steatosis was evaluated. We introduced Raman imaging and three-dimensional (3D) molecular imaging to detect changes in the biochemical composition and reactive oxygen species (ROS) levels of zebrafish liver. Gene expression microarray was performed to identify differentially expressed genes (DEGs) followed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and functional category analysis. Results: BBR (5 and 25 μM) administration prevented HCD-induced liver lipid accumulation in larval zebrafish. The result was further confirmed by the pathological observation. Raman mapping indicated that the biochemical composition in the liver of BBR-treated group shifted to the control. The quantitative analysis of 3D imaging showed that the ROS level was significantly decreased in the liver of BBR-treated larvae. In the livers of the BBR group, we found 468 DEGs, including 172 genes with upregulated expression and 296 genes with downregulated expression. Besides, GO enrichment, KEGG pathway, and functional category analysis showed that various processes related to glucolipid metabolism, immune response, DNA damage and repair, and iron were significantly enriched with DEGs. The expression levels of the crucial genes from the functional analysis were also confirmed by quantitative PCR (qPCR). Conclusion: BBR can significantly improve hepatic steatosis in HCD-fed zebrafish larvae. Its mechanisms might be associated with the regulation of lipid metabolism, oxidative stress, and iron homeostasis. Raman imaging in larval zebrafish might become a useful tool for drug evaluation. Mainly, the gene expression profiles provide molecular information for BBR on the prevention and treatment of pediatric NAFLD.
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Affiliation(s)
- Bo Chen
- Key Laboratory of Biotechnology of Antibiotics, The National Health Commission (NHC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yang-Min Zheng
- Key Laboratory of Biotechnology of Antibiotics, The National Health Commission (NHC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Miao-Qing Zhang
- Key Laboratory of Biotechnology of Antibiotics, The National Health Commission (NHC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Postdoctoral Scientific Research Workstation, China Resources Sanjiu Medical & Pharmaceutical Co., Ltd., Shenzhen, China.,Postdoctoral Mobile Research Station, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Ying Han
- National Institutes for Food and Drug Control, Graduate School of Peking Union Medical College, Beijing, China
| | - Jing-Pu Zhang
- Key Laboratory of Biotechnology of Antibiotics, The National Health Commission (NHC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Chang-Qin Hu
- National Institutes for Food and Drug Control, Graduate School of Peking Union Medical College, Beijing, China
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Stefano JT, de Mello Malta F, de Campos PB, Andrade PF, Paranaguá-Vezzozo DC, Carrilho FJ, Oliveira CP. HCC in Patients with NAFLD/NASH. NAFLD AND NASH 2020:191-203. [DOI: 10.1007/978-3-030-37173-9_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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21
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Gan M, Shen L, Fan Y, Tan Y, Zheng T, Tang G, Niu L, Zhao Y, Chen L, Jiang D, Li X, Zhang S, Zhu L. MicroRNA-451 and Genistein Ameliorate Nonalcoholic Steatohepatitis in Mice. Int J Mol Sci 2019; 20:E6084. [PMID: 31816816 PMCID: PMC6928943 DOI: 10.3390/ijms20236084] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 11/13/2019] [Accepted: 11/22/2019] [Indexed: 01/18/2023] Open
Abstract
Effective, targeted therapy for chronic liver disease nonalcoholic steatohepatitis (NASH) is imminent. MicroRNAs (miRNAs) are a potential therapeutic target, and natural products that regulate miRNA expression may be a safe and effective treatment strategy for liver disease. Here, we investigated the functional role of miR-451 and the therapeutic effects of genistein in the NASH mouse model. MiR-451 was downregulated in various types of liver inflammation, and subsequent experiments showed that miR-451 regulates liver inflammation via IL1β. Genistein is a phytoestrogen with anti-inflammatory and anti-oxidant effects. Interestingly, we found that the anti-inflammatory effects of genistein were related to miR-451 and was partially antagonized by the miR-451 inhibitor. MiR-451 overexpression or genistein treatment inhibited IL1β expression and inflammation. Taken together, this study shows that miR-451 has a protective effect on hepatic inflammation, and genistein can be used as a natural promoter of miR-451 to ameliorate NASH.
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Affiliation(s)
- Mailin Gan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Linyuan Shen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Yuan Fan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Ya Tan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
- Institute of Animal Husbandry and Veterinary, Guizhou Academy of Agricultural Science, Guiyang 550005, China
| | - Ting Zheng
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Guoqing Tang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Lili Niu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Ye Zhao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Lei Chen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Dongmei Jiang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Xuewei Li
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Shunhua Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Li Zhu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
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Klieser E, Mayr C, Kiesslich T, Wissniowski T, Fazio PD, Neureiter D, Ocker M. The Crosstalk of miRNA and Oxidative Stress in the Liver: From Physiology to Pathology and Clinical Implications. Int J Mol Sci 2019; 20:5266. [PMID: 31652839 PMCID: PMC6862076 DOI: 10.3390/ijms20215266] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/14/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023] Open
Abstract
The liver is the central metabolic organ of mammals. In humans, most diseases of the liver are primarily caused by an unhealthy lifestyle-high fat diet, drug and alcohol consumption- or due to infections and exposure to toxic substances like aflatoxin or other environmental factors. All these noxae cause changes in the metabolism of functional cells in the liver. In this literature review we focus on the changes at the miRNA level, the formation and impact of reactive oxygen species and the crosstalk between those factors. Both, miRNAs and oxidative stress are involved in the multifactorial development and progression of acute and chronic liver diseases, as well as in viral hepatitis and carcinogenesis, by influencing numerous signaling and metabolic pathways. Furthermore, expression patterns of miRNAs and antioxidants can be used for biomonitoring the course of disease and show potential to serve as possible therapeutic targets.
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Affiliation(s)
- Eckhard Klieser
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Christian Mayr
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Tobias Kiesslich
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Till Wissniowski
- Department of Gastroenterology and Endocrinology, Philipps University Marburg, 35043 Marburg, Germany.
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany.
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Matthias Ocker
- Translational Medicine Oncology, Bayer AG, 13353 Berlin, Germany.
- Department of Gastroenterology CBF, Charité University Medicine Berlin, 12200 Berlin, Germany.
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23
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Gene Expression Predicts Histological Severity and Reveals Distinct Molecular Profiles of Nonalcoholic Fatty Liver Disease. Sci Rep 2019; 9:12541. [PMID: 31467298 PMCID: PMC6715650 DOI: 10.1038/s41598-019-48746-5] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 07/29/2019] [Indexed: 12/15/2022] Open
Abstract
The heterogeneity of biological processes driving the severity of nonalcoholic fatty liver disease (NAFLD) as reflected in the transcriptome and the relationship between the pathways involved are not well established. Well-defined associations between gene expression profiles and disease progression would benefit efforts to develop novel therapies and to understand disease heterogeneity. We analyzed hepatic gene expression in controls and a cohort with the full histological spectrum of NAFLD. Protein-protein interaction and gene set variation analysis revealed distinct sets of coordinately regulated genes and pathways whose expression progressively change over the course of the disease. The progressive nature of these changes enabled us to develop a framework for calculating a disease progression score for individual genes. We show that, in aggregate, these scores correlate strongly with histological measures of disease progression and can thus themselves serve as a proxy for severity. Furthermore, we demonstrate that the expression levels of a small number of genes (~20) can be used to infer disease severity. Finally, we show that patient subgroups can be distinguished by the relative distribution of gene-level scores in specific gene sets. While future work is required to identify the specific disease characteristics that correspond to patient clusters identified on this basis, this work provides a general framework for the use of high-content molecular profiling to identify NAFLD patient subgroups.
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Zhang DY, Zhu L, Liu HN, Tseng YJ, Weng SQ, Liu TT, Dong L, Shen XZ. The protective effect and mechanism of the FXR agonist obeticholic acid via targeting gut microbiota in non-alcoholic fatty liver disease. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:2249-2270. [PMID: 31308634 PMCID: PMC6617567 DOI: 10.2147/dddt.s207277] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 06/02/2019] [Indexed: 12/25/2022]
Abstract
Background: It is reported that various diseases such as non-alcoholic fatty liver disease (NAFLD) are associated with imbalance of microbiome. And FXR has been well investigated in liver diseases. Purpose: The objective of this study was to identify the role of farnesoid X receptor agonist obeticholic acid via targeting gut microbiota in NAFLD. Patients and methods: Male C57BL/6 mice were fed either a normal-chow diet or a high-fat diet (HFD). Obeticholic acid(30mg/(kg·d)) and/or a combination of antibiotics were administered orally by gavage to mice for 12 weeks. Gut microbiota profiles were established through 16S rRNA amplicon sequencing. The effects of obeticholic acid on liver inflammation, the gut barrier, endotoxemia, gut microbiome and composition of the bile acid were also investigated. Results: Obeticholic acid treatment can significantly improve obesity, circulation metabolism disorders, liver inflammation and fibrosis, and intestinal barrier damage caused by HFD. Removal of normal commensal bacteria can weaken the effect of obeticholic acid. The gut microbial structure was changed, and abundance of Blautia was increased significantly after treated with obeticholic acid. After obeticholic acid treatment, the concentration of taurine-bound bile acid caused by HFD was reduced in the liver. Conclusion: Taken together, these data suggest that obeticholic acid has aprotective effect on NAFLD via changing the components of gut microbiota, specifically increasing the abundance of Blautia.
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Affiliation(s)
- Dan-Ying Zhang
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai 200032, People's Republic of China
| | - Lin Zhu
- Department of Geriatrics, Zhongshan Hospital of Fudan University, Shanghai 200032, People's Republic of China
| | - Hai-Ning Liu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai 200032, People's Republic of China
| | - Yu-Jen Tseng
- Department of Gastroenterology, Huashan Hospital of Fudan University, Shanghai 200040, People's Republic of China
| | - Shu-Qiang Weng
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai 200032, People's Republic of China
| | - Tao-Tao Liu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai 200032, People's Republic of China
| | - Ling Dong
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai 200032, People's Republic of China
| | - Xi-Zhong Shen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai 200032, People's Republic of China.,Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, People's Republic of China
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25
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Ni M, Zhang B, Zhao J, Feng Q, Peng J, Hu Y, Zhao Y. Biological mechanisms and related natural modulators of liver X receptor in nonalcoholic fatty liver disease. Biomed Pharmacother 2019; 113:108778. [PMID: 30897538 DOI: 10.1016/j.biopha.2019.108778] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 03/11/2019] [Accepted: 03/13/2019] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming a worldwide health problem, but no approved medical treatment exists so far. Nuclear receptors are one of the drug targets for nonalcoholic steatohepatitis (NASH). Among them, liver X receptor (LXR) has been studied in recent years in tumors, metabolic diseases and inflammatory diseases, but its physiological and pharmacological effects in the treatment of NASH are controversial. Activation of LXR has the potential to modulate cholesterol homeostasis, induce anti-inflammatory effects and increase insulin sensitivity, but liver lipid deposition and hypertriglyceridemia are also increased. Inhibition of liver LXR transcriptional activity in the context of NAFLD can effectively alleviate hepatic steatosis, inflammation, and fibrosis but elevates the risk of potential cardiovascular disease. The contradictory pharmacodynamic effects of LXR in the treatment of NASH increase the difficulty of developing targeted drugs. Moreover, natural compounds play an important part in drug development, and in recent years, some natural compounds have been reported to treat NAFLD by acting on LXR or LXR pathways with fewer adverse reactions, presenting a promising therapeutic prospect. In this review, we discuss the mechanisms of LXR in NASH and summarize the natural products reported to modulate NAFLD via LXR or the LXR pathway, offering an alternative approach for LXR-related drug development in NAFLD.
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Affiliation(s)
- Mingzhu Ni
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Binbin Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jianan Zhao
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qin Feng
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai Key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jinghua Peng
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai Key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yiyang Hu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai Key laboratory of Traditional Chinese Medicine, Shanghai 201203, China; E-Institute of Shanghai Municipal Education Commission, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Yu Zhao
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai Key laboratory of Traditional Chinese Medicine, Shanghai 201203, China.
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Sulaiman SA, Muhsin NIA, Jamal R. Regulatory Non-coding RNAs Network in Non-alcoholic Fatty Liver Disease. Front Physiol 2019; 10:279. [PMID: 30941061 PMCID: PMC6433939 DOI: 10.3389/fphys.2019.00279] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 03/04/2019] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) spectrum comprises simple steatosis and non-alcoholic steatohepatitis (NASH) that can lead to fibrosis and cirrhosis. The patients usually have no history of excessive alcohol consumption and other etiologies that can cause fatty liver. Understanding of the pathophysiology of NAFLD has revealed that non-coding RNAs (ncRNAs) play significant roles in modulating the disease susceptibility, pathogenesis and progression. Currently, the ncRNAs are grouped according to their sizes and their regulatory or housekeeping functions. Each of these ncRNAs has a wide range of involvement in the regulation of the genes and biological pathways. Here, we briefly review the current literature the regulatory ncRNAs in NAFLD pathogenesis and progression, mainly the microRNAs, long non-coding RNAs and circular RNAs. We also discuss the co-regulatory functions and interactions between these ncRNAs in modulating the disease pathogenesis. Elucidation of ncRNAs in NAFLD may facilitate the identification of early diagnostic biomarkers and development of therapeutic strategies for NAFLD.
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Affiliation(s)
- Siti Aishah Sulaiman
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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27
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Wu J, Shao H, Zhang J, Ying Y, Cheng Y, Zhao D, Dou X, Lv H, Li S, Liu F, Ling P. Mussel polysaccharide α-D-glucan (MP-A) protects against non-alcoholic fatty liver disease via maintaining the homeostasis of gut microbiota and regulating related gut-liver axis signaling pathways. Int J Biol Macromol 2019; 130:68-78. [PMID: 30797009 DOI: 10.1016/j.ijbiomac.2019.02.097] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 02/09/2019] [Accepted: 02/15/2019] [Indexed: 12/14/2022]
Abstract
We isolated and characterized a Mussel polysaccharide, α-D-glucan (MP-A), from Mytilus coruscus earlier. In this work, the pharmacological activity and mechanisms of MP-A as an oral supplement for non-alcoholic fatty liver disease (NAFLD) were explored. High fat diet (HFD) was utilized to induce NAFLD in Sprague Dawley male rats and MP-A (0.6 g/kg) was supplemented for 4 weeks. The results showed that MP-A supplementation reduced blood lipid levels, intrahepatic lipid accumulation and NAFLD activity score in HFD-fed rats. Additionally, the analysis of 16S rDNA sequencing on gut microbiota samples revealed that HFD could induce microbial dysbiosis. However, MP-A supplementation could remodel gut microbiota structure, inhibit LPS-TLR4-NF-κB pathway activation, and restrain subsequent inflammation factors secretion. Furthermore, MP-A regulated the lipid metabolism by promoting the production of short chain fatty acids and suppressing PPAR γ and SREBP-1c expression. Our results support that MP-A can prevent against NAFLD and act as an oral supplementation for hepatoprotection via modulating gut microbiota and related gut-liver axis signaling pathways.
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Affiliation(s)
- Jixu Wu
- School of Pharmaceutical Sciences, Shandong University, Jinan 250101, China; Shandong Academy of Pharmaceutical Sciences, Key Laboratory of Biopharmaceuticals, Engineering Laboratory of Polysaccharide Drugs, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Jinan 250101, China
| | - Huarong Shao
- Shandong Academy of Pharmaceutical Sciences, Key Laboratory of Biopharmaceuticals, Engineering Laboratory of Polysaccharide Drugs, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Jinan 250101, China.
| | - Jinhua Zhang
- Shandong Academy of Pharmaceutical Sciences, Key Laboratory of Biopharmaceuticals, Engineering Laboratory of Polysaccharide Drugs, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Jinan 250101, China
| | - Yong Ying
- Shandong Academy of Pharmaceutical Sciences, Key Laboratory of Biopharmaceuticals, Engineering Laboratory of Polysaccharide Drugs, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Jinan 250101, China
| | - Yanling Cheng
- Shandong Academy of Pharmaceutical Sciences, Key Laboratory of Biopharmaceuticals, Engineering Laboratory of Polysaccharide Drugs, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Jinan 250101, China
| | - Dan Zhao
- Shandong Academy of Pharmaceutical Sciences, Key Laboratory of Biopharmaceuticals, Engineering Laboratory of Polysaccharide Drugs, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Jinan 250101, China
| | - Xixi Dou
- Shandong Freda Pharmaceutical Group Company, Jinan 250101, China
| | - Huimin Lv
- Shandong Academy of Pharmaceutical Sciences, Key Laboratory of Biopharmaceuticals, Engineering Laboratory of Polysaccharide Drugs, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Jinan 250101, China
| | - Shuaiguang Li
- School of Pharmaceutical Sciences, Shandong University, Jinan 250101, China; Shandong Academy of Pharmaceutical Sciences, Key Laboratory of Biopharmaceuticals, Engineering Laboratory of Polysaccharide Drugs, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Jinan 250101, China
| | - Fei Liu
- School of Pharmaceutical Sciences, Shandong University, Jinan 250101, China; Shandong Academy of Pharmaceutical Sciences, Key Laboratory of Biopharmaceuticals, Engineering Laboratory of Polysaccharide Drugs, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Jinan 250101, China.
| | - Peixue Ling
- School of Pharmaceutical Sciences, Shandong University, Jinan 250101, China; Shandong Academy of Pharmaceutical Sciences, Key Laboratory of Biopharmaceuticals, Engineering Laboratory of Polysaccharide Drugs, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Jinan 250101, China; Shandong Freda Pharmaceutical Group Company, Jinan 250101, China.
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28
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Šeda O, Cahová M, Míková I, Šedová L, Daňková H, Heczková M, Brátová M, Ďásková N, Erhartová D, Čapek V, Chylíková B, Trunečka P. Hepatic Gene Expression Profiles Differentiate Steatotic and Non-steatotic Grafts in Liver Transplant Recipients. Front Endocrinol (Lausanne) 2019; 10:270. [PMID: 31114547 PMCID: PMC6502969 DOI: 10.3389/fendo.2019.00270] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/11/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Liver transplantation leads to non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in up to 40% of graft recipients. The aim of our study was to assess transcriptomic profiles of liver grafts and to contrast the hepatic gene expression between the patients after transplantation with vs. without graft steatosis. Methods: Total RNA was isolated from liver graft biopsies of 91 recipients. Clinical characteristics were compared between steatotic (n = 48) and control (n = 43) samples. Their transcriptomic profiles were assessed using Affymetrix HuGene 2.1 ST Array Strips processed in Affymetrix GeneAtlas. Data were analyzed using Partek Genomics Suite 6.6 and Ingenuity Pathway Analysis. Results: The individuals with hepatic steatosis showed higher indices of obesity including weight, waist circumference or BMI but the two groups were comparable in measures of insulin sensitivity and cholesterol concentrations. We have identified 747 transcripts (326 upregulated and 421 downregulated in steatotic samples compared to controls) significantly differentially expressed between grafts with vs. those without steatosis. Among the most downregulated genes in steatotic samples were P4HA1, IGF1, or fetuin B while the most upregulated were PLIN1 and ME1. Most influential upstream regulators included HNF1A, RXRA, and FXR. The metabolic pathways dysregulated in steatotic liver grafts comprised blood coagulation, bile acid synthesis and transport, cell redox homeostasis, lipid and cholesterol metabolism, epithelial adherence junction signaling, amino acid metabolism, AMPK and glucagon signaling, transmethylation reactions, and inflammation-related pathways. The derived mechanistic network underlying major transcriptome differences between steatotic samples and controls featured PPARA and SERPINE1 as main nodes. Conclusions: While there is a certain overlap between the results of the current study and published transcriptomic profiles of non-transplanted livers with steatosis, we have identified discrete characteristics of the non-alcoholic fatty liver disease in liver grafts potentially utilizable for the establishment of predictive signature.
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Affiliation(s)
- Ondrej Šeda
- First Faculty of Medicine, The General University Hospital, Institute of Biology and Medical Genetics, Charles University, Prague, Czechia
| | - Monika Cahová
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
- *Correspondence: Monika Cahová
| | - Irena Míková
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Lucie Šedová
- First Faculty of Medicine, The General University Hospital, Institute of Biology and Medical Genetics, Charles University, Prague, Czechia
| | - Helena Daňková
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Marie Heczková
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Miriam Brátová
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Nikola Ďásková
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Denisa Erhartová
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Václav Čapek
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Blanka Chylíková
- First Faculty of Medicine, The General University Hospital, Institute of Biology and Medical Genetics, Charles University, Prague, Czechia
| | - Pavel Trunečka
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czechia
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Grandy R, Tomaz RA, Vallier L. Modeling Disease with Human Inducible Pluripotent Stem Cells. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2018; 14:449-468. [PMID: 30355153 DOI: 10.1146/annurev-pathol-020117-043634] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Understanding the physiopathology of disease remains an essential step in developing novel therapeutics. Although animal models have certainly contributed to advancing this enterprise, their limitation in modeling all the aspects of complex human disorders is one of the major challenges faced by the biomedical research field. Human induced pluripotent stem cells (hiPSCs) derived from patients represent a great opportunity to overcome this deficiency because these cells cover the genetic diversity needed to fully model human diseases. Here, we provide an overview of the history of hiPSC technology and discuss common challenges and approaches that we and others have faced when using hiPSCs to model disease. Our emphasis is on liver disease, and consequently, we review the progress made using this technology to produce functional liver cells in vitro and how these systems are being used to recapitulate a diversity of developmental, metabolic, genetic, and infectious liver disorders.
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Affiliation(s)
- Rodrigo Grandy
- Wellcome and MRC Cambridge Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge CB2 0SZ, United Kingdom; .,Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, United Kingdom
| | - Rute A Tomaz
- Wellcome and MRC Cambridge Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge CB2 0SZ, United Kingdom; .,Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, United Kingdom
| | - Ludovic Vallier
- Wellcome and MRC Cambridge Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge CB2 0SZ, United Kingdom; .,Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, United Kingdom
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30
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Cota-Coronado A, Ramírez-Rodríguez PB, Padilla-Camberos E, Díaz ÉNF, Flores-Fernández JM, Ávila-Gónzalez D, Diaz-Martinez NE. Implications of human induced pluripotent stem cells in metabolic disorders: from drug discovery toward precision medicine. Drug Discov Today 2018; 24:334-341. [PMID: 30292915 DOI: 10.1016/j.drudis.2018.10.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 08/28/2018] [Accepted: 10/01/2018] [Indexed: 12/14/2022]
Abstract
Human induced pluripotent stem cells (hiPSCs) enable in vitro high-throughput pharmacological screening assays of diseased tissue. Together with recent genome-wide association studies (GWAS), hiPSCs enable the identification of key mutations for the development of effective treatments based on precise drugs. In concert with CRISPR/Cas9 systems, hiPSC technology can reveal therapeutic targets in metabolic disorders. The ex vivo CRISPR correction of autologous patient-derived hiPSCs has led to the development of replacement cell therapies, providing better patient prognoses.
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Affiliation(s)
- Agustin Cota-Coronado
- Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico
| | | | - Eduardo Padilla-Camberos
- Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico
| | - éNstor F Díaz
- Departamento de Fisiología y Desarrollo Celular, Instituto Nacional de Perinatología, Ciudad de México, Mexico
| | - Jose M Flores-Fernández
- Department of Biochemistry, University of Alberta, 474 Medical Sciences Building, Edmonton, AB, T6G 2R3, Canada; División de Ingeniería en Industrias Alimentarias e Innovación Agrícola Sustentable, Tecnológico de Estudios Superiores de Villa Guerrero, Carretera Toluca-Ixtapan de la Sal, Km 64.5, La Finca, 61763, Villa Guerrero, Estado de Mexico, Mexico
| | - Daniela Ávila-Gónzalez
- Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico; Departamento de Fisiología y Desarrollo Celular, Instituto Nacional de Perinatología, Ciudad de México, Mexico
| | - N Emmanuel Diaz-Martinez
- Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico.
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Abstract
Induced pluripotent stem cells (iPSCs) and human embryonic stem cells (hESCs) differentiated into hepatocyte-like cells (HLCs) provide a defined and renewable source of cells for drug screening, toxicology and regenerative medicine. We previously reprogrammed human fetal foreskin fibroblast cells (HFF1) into iPSCs employing an episomal plasmid-based integration-free approach, this iPSC-line and the hESC lines H1 and H9 were used to model hepatogenesis in vitro. Biochemical characterisation confirmed glycogen storage, ICG uptake and release, urea and bile acid production, as well as CYP3A4 activity. Microarray-based transcriptome analyses was carried out using RNA isolated from the undifferentiated pluripotent stem cells and subsequent differentiation stages- definitive endoderm (DE) hepatic endoderm (HE) and HLCs. K-means identified 100 distinct clusters, for example, POU5F1/OCT4 marking the undifferentiated stage, SOX17 the DE stage, HNF4α the HE stage, and ALB specific to HLCs, fetal liver and primary human hepatocytes (PHH). This data descriptor describes these datasets which should be useful for gaining new insights into the molecular basis of hepatogenesis and associated gene regulatory networks.
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Kim H, Lee KW, Lee K, Seo S, Park MY, Ahn SW, Hong SK, Yoon KC, Kim HS, Choi Y, Lee HW, Yi NJ, Suh KS. Effect of PNPLA3 I148M polymorphism on histologically proven non-alcoholic fatty liver disease in liver transplant recipients. Hepatol Res 2018; 48:E162-E171. [PMID: 28718984 DOI: 10.1111/hepr.12940] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 07/10/2017] [Accepted: 07/13/2017] [Indexed: 12/13/2022]
Abstract
AIM PNPLA3 I148M polymorphism (rs738409 C>G) is the most important and best-known polymorphism for non-alcoholic fatty liver disease (NAFLD). However, little is known about the effect of this polymorphism on NAFLD after liver transplantation (LT). We aimed to evaluate the association between this polymorphism and post-LT NAFLD. METHODS We designed a prospective case-control study. Among adult recipients who underwent LT between April 2014 and October 2015, those whose whole blood was preoperatively collected for genotyping in both recipients and coupled donors and those who underwent protocol biopsy at 1 year post-LT were enrolled. RESULTS A total of 32 recipients were enrolled. Histologically proven steatosis (≥5%) was present in 28.1% of patients at a mean time of 12.7 ± 2.0 months after LT. Moderate and more severe steatosis (≥33%) was present in 9.4%. One year after LT, steatosis was present in 50.0% of homozygous recipients with the rs738409-G allele. It was present in 27.3% of heterozygous recipients with the rs738409-G allele, and in 9.1% (P = 0.041) of recipients with rs738409-CC. The genotype of the donor was not significantly (P = 0.647) associated with post-LT NAFLD. When both recipient and coupled donor showed heterogeneous or homozygous genotype of the rs738409-G allele, there was significantly more post-LT NAFLD compared to that in others (47.1% vs. 6.7%; P = 0.018). In univariate and multivariate analyses, only the presence of the rs738409-G risk allele in both donor and recipient was a significant risk factor for post-LT NALFD (relative risk, 26.95; P = 0.048). CONCLUSIONS PNPLA3 I148M polymorphism can significantly affect histologically proven NAFLD at 1 year post-LT.
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Affiliation(s)
- Hyeyoung Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kyoungbun Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Sooin Seo
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Min-Young Park
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Sung Woo Ahn
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Suk Kyun Hong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung Chul Yoon
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo-Sin Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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Chen B, Zheng YM, Zhang JP. Comparative Study of Different Diets-Induced NAFLD Models of Zebrafish. Front Endocrinol (Lausanne) 2018; 9:366. [PMID: 30026731 PMCID: PMC6041386 DOI: 10.3389/fendo.2018.00366] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 06/18/2018] [Indexed: 12/23/2022] Open
Abstract
Dietary composition has important impact on nonalcoholic fatty liver disease (NAFLD). The purpose of this study was to explore the relationship between NAFLD and major dietary components using zebrafish larvae fed different diets. Zebrafish larvae fed with high cholesterol (HC), high fructose (HF) and extra feeding (EF) diets for 10 days displayed varying degrees steatosis. The incidence and degree of steatosis were the most severe in the EF group. A HC diet severely promoted lipid deposits in the caudal vein. The triglyceride and glucose contents of zebrafish significantly increased in the HF and EF groups compared with the control group. Moreover, the mRNA expression of oxidative stress gene gpx1a, endoplasmic reticulum stress genes ddit3 and grp78, inflammatory genes tnfa, glucose metabolism genes irs2, glut1 and glut2, and lipid metabolism genes cidec, chrebp, ppara and cpt1a were significantly increased in the HF group. The HC diet was associated with upregulation of grp78, and downregulation of irs2, glut1 and glut2. The mRNA expression of lipogenesis and glucose metabolism associated genes were decreased in the EF group. In addition, the autophagy associated genes atg3, atg5, atg7, and atg12, and protein expression of ATG3 and LC3BII were reduced and P62 were elevated in the HC group. We also performed comparative transcriptome analysis of the four groups. A total of 2,492 differentially expressed genes were identified, and 24 statistically significant pathways were enriched in the diet treatment groups. This study extends our understanding of the relationships between diet ingredients and host factors that contribute to the pathogenesis of NAFLD, which may provide new ideas for the treatment of NAFLD.
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Zhang J, Zhang X, Zhao Y, Lv G. Association Between Urinary Alpha1-Microglobulin Levels and Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study. ANNALS OF NUTRITION AND METABOLISM 2017; 72:30-36. [PMID: 29232673 DOI: 10.1159/000484255] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 10/04/2017] [Indexed: 12/24/2022]
Abstract
BACKGROUND We aimed to explore the association between urinary alpha1-microglobulin (A1M) levels and nonalcoholic fatty liver disease (NAFLD) in a Chinese population. STUDY We performed a cross-sectional study among 2,215 Chinese who attended their annual health examination at First Affiliated Hospital, College of Medicine, Zhejiang University. Urinary A1M-creatinine ratio and other clinical and laboratory parameters were measured. RESULTS A total of 20.9% of subjects fulfilled the diagnostic criteria of NAFLD. NAFLD subjects had significantly higher urinary A1M-creatinine ratios. These levels were positively associated with NAFLD prevalence. The association between A1M-creatinine ratio and NAFLD was independent of hyperglycemia status. Stepwise regression showed that urinary A1M-creatinine ratio was significantly associated with the risk for NAFLD. Urinary A1M-creatinine ratio was an independent factor predicting advanced fibrosis (FIB-4 ≥1.3) in NAFLD patients. CONCLUSIONS Our results showed a significant association between urinary A1M-creatinine ratio and NAFLD.
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Affiliation(s)
- Juanwen Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xuyao Zhang
- Clinical Medicine, Hangzhou Normal University Qianjiang College, Hangzhou, China
| | - Ying Zhao
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Guocai Lv
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Guo M. Cellular senescence and liver disease: Mechanisms and therapeutic strategies. Biomed Pharmacother 2017; 96:1527-1537. [PMID: 29174037 DOI: 10.1016/j.biopha.2017.11.075] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/13/2017] [Accepted: 11/13/2017] [Indexed: 12/12/2022] Open
Abstract
Cellular senescence is a fundamental cell fate caused by several cellular injuries which results in irreversible cell cycle arrest yet remaining metabolically active across all species. Cellular senescence not only can prevent tumor occurrence by inhibiting the proliferation of injured cells, but also can affect the surrounding cells through the senescence-associated secretory phenotype (SASP). Attractively, accumulating evidence shows that cellular senescence is closely related to various liver diseases. Therapeutic opportunities based on targeting senescent cells and the SASP are considered to be potential strategy for liver diseases. However, although research on cell senescence has attracted widespread attention, the overview on detailed mechanism and biological function of cell senescence in liver disease is still largely unknown. The present review summarizes the specific role of cell senescence in various liver diseases, and updates the molecular mechanisms underlying cell senescence. Moreover, the review also explores new strategies for prevention and treatment of liver disease through promoting senescence or counteracting excessive pathological senescence.
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Affiliation(s)
- Mei Guo
- Department of Pathogenic Biology and Immunology of Medical School, Southeast University, Nanjing, Jiangsu, 210009, China.
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García-Hermoso A, Hackney AC, Ramírez-Vélez R. Ideal cardiovascular health predicts lower risk of abnormal liver enzymes levels in the Chilean National Health Survey (2009-2010). PLoS One 2017; 12:e0185908. [PMID: 29049384 PMCID: PMC5648121 DOI: 10.1371/journal.pone.0185908] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 09/21/2017] [Indexed: 12/12/2022] Open
Abstract
High levels of gamma glutamyltransferase (gamma-GT) and alanine aminotransferase (ALT), as well as fatty liver index (FLI) has been associated with higher cardiovascular disease risk factors in adults. The aim of this study was to examine the relationship between gamma-GT, ALT, and fatty liver index FLI levels across a gradient number of ideal cardiovascular health metrics in a representative sample of adults from the Chilean National Health Survey 2009-2010. Data from 1,023 men and 1,449 women (≥ 15 years) from the Chilean Health Survey 2009-2010 were analyzed. Ideal cardiovascular health was defined as meeting ideal levels of the following components: four behaviours (smoking, body mass index, physical activity and diet adherence) and three factors (total cholesterol, blood pressure and fasting glucose). Adults were grouped into three categories according to their number of ideal cardiovascular health metrics: ideal (5-7 metrics), intermediate (3-4 metrics), and poor (0-2 metrics). Blood levels of gamma-GT and ALT were measured and the FLI was calculated. A higher number of ideal cardiovascular health index metric was associated with lower gamma-GT, ALT and FLI (p from trend analysis <0.001). Also, adults meeting at least 3-4 metrics were predicted less likely to have prevalence of abnormal levels of gamma-GT and FLI (p<0.001) compared to adults who met only 0-2 metrics. These findings reinforce the usefulness of the ideal cardiovascular health metrics proposed by the American Heart Association as a tool to identify target subjects and promote cardiovascular health in South-American adults.
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Affiliation(s)
- Antonio García-Hermoso
- Laboratorio de Ciencias de la Actividad Física, el Deporte y la Salud, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, USACH, Santiago, Chile
| | - Anthony C. Hackney
- Endocrine Section-Applied Physiology Laboratory, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Robinson Ramírez-Vélez
- Centro de Estudios para la Medición de la Actividad Física «CEMA». Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá D.C, Colombia
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Suárez M, Boqué N, Del Bas JM, Mayneris-Perxachs J, Arola L, Caimari A. Mediterranean Diet and Multi-Ingredient-Based Interventions for the Management of Non-Alcoholic Fatty Liver Disease. Nutrients 2017; 9:E1052. [PMID: 28937599 PMCID: PMC5691669 DOI: 10.3390/nu9101052] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/01/2017] [Accepted: 09/11/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises a wide spectrum of hepatic disorders, from simple steatosis to hepatic necro-inflammation leading to non-alcoholic steatohepatitis (NASH). Although the prevalence of these multifactorial pathologies is continuously increasing in the population, there is still not an established methodology for their treatment other than weight loss and a change in lifestyle habits, such as a hypocaloric diet and physical exercise. In this framework, there is increasing evidence that several food bioactives and dietary patterns are effective for reversing and preventing the onset of these pathologies. Some studies have claimed that better responses are obtained when treatments are performed under a multifaceted approach, using different bioactive compounds that act against complementary targets. Thus, in this work, current strategies for treating NAFLD and NASH based on multi-ingredient-based supplements or the Mediterranean diet, a dietary pattern rich in bioactive compounds, are reviewed. Furthermore, the usefulness of omics techniques to design effective multi-ingredient nutritional interventions and to predict and monitor their response against these disorders is also discussed.
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Affiliation(s)
- Manuel Suárez
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili (URV), Campus Sescelades, Tarragona 43007, Spain.
| | - Noemí Boqué
- Technological Unit of Nutrition and Health, EURECAT-Technology Centre of Catalonia, Avinguda Universitat 1, Reus 43204, Spain.
| | - Josep M Del Bas
- Technological Unit of Nutrition and Health, EURECAT-Technology Centre of Catalonia, Avinguda Universitat 1, Reus 43204, Spain.
| | - Jordi Mayneris-Perxachs
- Technological Unit of Nutrition and Health, EURECAT-Technology Centre of Catalonia, Avinguda Universitat 1, Reus 43204, Spain.
| | - Lluís Arola
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili (URV), Campus Sescelades, Tarragona 43007, Spain.
- Technological Unit of Nutrition and Health, EURECAT-Technology Centre of Catalonia, Avinguda Universitat 1, Reus 43204, Spain.
| | - Antoni Caimari
- Technological Unit of Nutrition and Health, EURECAT-Technology Centre of Catalonia, Avinguda Universitat 1, Reus 43204, Spain.
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Abstract
Tuberculosis (TC) is very common and significant cause of morbidity and mortality worldwide. Isolated cystic duct lymph node TC cases without involvement of gallbladder are exceedingly rare. It is difficult to diagnose preoperatively because of lack of characteristic signs and symptoms of TC. We report a man aged 45 years who presented with right upper abdominal pain since 1week. It was associated with nausea and postprandial fullness. There was no evidence of jaundice and lymphadenopathy. Abdominal examination showed moderate right upper quadrant tenderness with positive Murphy's sign and splenomegaly but no signs of peritonism. Abdomen ultrasound revealed sludge in gallbladder, dilated pancreatic duct, coarse exotexture of liver, splenomegaly and no lymphadenopathy. He underwent laparoscopic cholecystectomy; histological report showed chronic caseating granulomatous lymphadenitis with Langhans type of giant cells in lymph node near cystic duct with chronic cholecystitis of gallbladder. Standard antituberculosis therapy was given for 12 months.
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Affiliation(s)
- Aamir Ghazanfar
- Department of General Surgery, KRL Hospital, Islamabad, Pakistan
| | - Afifa Asghar
- Department of General Surgery, KRL Hospital, Islamabad, Pakistan
| | | | - Iram Hassan
- Department of General Surgery, KRL Hospital, Islamabad, Pakistan
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Wruck W, Adjaye J. Meta-analysis reveals up-regulation of cholesterol processes in non-alcoholic and down-regulation in alcoholic fatty liver disease. World J Hepatol 2017; 9:443-454. [PMID: 28357032 PMCID: PMC5355767 DOI: 10.4254/wjh.v9.i8.443] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 11/29/2016] [Accepted: 12/13/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To compare transcriptomes of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) in a meta-analysis of liver biopsies. METHODS Employing transcriptome data from patient liver biopsies retrieved from several public repositories we performed a meta-analysis comparing ALD and NAFLD. RESULTS We observed predominating commonalities at the transcriptome level between ALD and NAFLD, most prominently numerous down-regulated metabolic pathways and cytochrome-related pathways and a few up-regulated pathways which include ECM-receptor interaction, phagosome and lysosome. However some pathways were regulated in opposite directions in ALD and NAFLD, for example, glycolysis was down-regulated in ALD and up-regulated in NAFLD. Interestingly, we found rate-limiting genes such as HMGCR, SQLE and CYP7A1 which are associated with cholesterol processes adversely regulated between ALD (down-regulated) and NAFLD (up-regulated). We propose that similar phenotypes in both diseases may be due to a lower level of the enzyme CYP7A1 compared to the cholesterol synthesis enzymes HMGCR and SQLE. Additionally, we provide a compendium of comparative KEGG pathways regulation in ALD and NAFLD. CONCLUSION Our finding of adversely regulated cholesterol processes in ALD and NAFLD draws the focus to regulation of cholesterol secretion into bile. Thus, it will be interesting to further investigate CYP7A1-mediated cholesterol secretion into bile - also as possible drug targets. The list of potential novel biomarkers may assist differential diagnosis of ALD and NAFLD.
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Affiliation(s)
- Wasco Wruck
- Wasco Wruck, James Adjaye, Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - James Adjaye
- Wasco Wruck, James Adjaye, Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University, 40225 Düsseldorf, Germany
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