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Hernandez R, Garcia-Rodriguez NS, Arriaga MA, Perez R, Bala AA, Leandro AC, Diego VP, Almeida M, Parsons JG, Manusov EG, Galan JA. The hepatocellular model of fatty liver disease: from current imaging diagnostics to innovative proteomics technologies. Front Med (Lausanne) 2025; 12:1513598. [PMID: 40109726 PMCID: PMC11919916 DOI: 10.3389/fmed.2025.1513598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 02/06/2025] [Indexed: 03/22/2025] Open
Abstract
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a prevalent chronic liver condition characterized by lipid accumulation and inflammation, often progressing to severe liver damage. We aim to review the pathophysiology, diagnostics, and clinical care of MASLD, and review highlights of advances in proteomic technologies. Recent advances in proteomics technologies have improved the identification of novel biomarkers and therapeutic targets, offering insight into the molecular mechanisms underlying MASLD progression. We focus on the application of mass spectrometry-based proteomics including single cell proteomics, proteogenomics, extracellular vesicle (EV-omics), and exposomics for biomarker discovery, emphasizing the potential of blood-based panels for noninvasive diagnosis and personalized medicine. Future research directions are presented to develop targeted therapies and improve clinical outcomes for MASLD patients.
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Affiliation(s)
- Renee Hernandez
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Natasha S Garcia-Rodriguez
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Marco A Arriaga
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Ricardo Perez
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Auwal A Bala
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Ana C Leandro
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Vince P Diego
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Marcio Almeida
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Jason G Parsons
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Eron G Manusov
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Jacob A Galan
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
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Ye J, Lai J, Luo L, Zhou T, Sun Y, Zhong B. Cytokeratin 18 fragment in liver inflammation and fibrosis: Systematic review and meta-analysis. Clin Chim Acta 2025; 569:120147. [PMID: 39832704 DOI: 10.1016/j.cca.2025.120147] [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: 11/04/2024] [Revised: 01/16/2025] [Accepted: 01/17/2025] [Indexed: 01/22/2025]
Abstract
BACKGROUND This meta-analysis aimed to summarize the diagnostic accuracy and cut-off values of cytokeratin (CK) 18 measurements, specifically M30 and M65, as candidate biomarkers for the pathological evaluation of biopsy specimens used to stage liver inflammation and fibrosis in patients with chronic liver diseases. METHODS Databases were searched for studies collected up to January 11th, 2025. Pooled sensitivity, specificity, area under the receiver-operating characteristic curves, and mean cut-off values were calculated using random-effects models regardless of heterogeneity. A meta-regression analysis and subgroup analysis were performed to explore heterogeneity. RESULTS Sixty-three studies comprising 9137 patients were included. The summarized AUROC curve of CK18 M30 for the diagnosis of significant liver inflammation, fibrosis ≥F1, ≥F2, ≥F3, and =F4 according to the METAVIR score system were 0.82, 0.75, 0.78, 0.78 and 0.76, with mean cut-off values of 264.3, 188.0, 276.9, 322.8 and 169.4 U/L. For M65, the summarized AUROC curve for detecting significant liver inflammation, fibrosis ≥F1, ≥F2, and =F4 were 0.79, 0.70, 0.76, 0.64 and 0.72, with mean cut-off values of 541.1, 417.6, 500.1, 424.6 and 674.0 U/L. The subgroup analyses implied that ethnicity may be the primary factor related to heterogeneity in CK18 M30 when applied to detect significant inflammation. Asian patients had values 79.7 U/L higher than those of non-Asian patients (p = 0.0157). CONCLUSIONS CK18 M30 and M65 have clinically meaningful accuracy as alternative diagnostic tools for determining liver inflammation and fibrosis using biopsy specimens of patients with steatotic liver disease or viral hepatitis. REGISTRATION PROSPERO registration number: CRD42022364598.
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Affiliation(s)
- Junzhao Ye
- Department of Gastroenterology The First Affiliated Hospital Sun Yat-sen University No. 58 Zhongshan II Road Yuexiu District Guangzhou China
| | - Jiaming Lai
- Department of Gastroenterology The First Affiliated Hospital Sun Yat-sen University No. 58 Zhongshan II Road Yuexiu District Guangzhou China
| | - Ling Luo
- Department of Gastroenterology The First Affiliated Hospital Sun Yat-sen University No. 58 Zhongshan II Road Yuexiu District Guangzhou China
| | - Ting Zhou
- Department of Gastroenterology The First Affiliated Hospital Sun Yat-sen University No. 58 Zhongshan II Road Yuexiu District Guangzhou China
| | - Yanhong Sun
- Department of Laboratory Medicine The First Affiliated Hospital Sun Yat-sen University No. 58 Zhongshan II Road Yuexiu District Guangzhou China.
| | - Bihui Zhong
- Department of Gastroenterology The First Affiliated Hospital Sun Yat-sen University No. 58 Zhongshan II Road Yuexiu District Guangzhou China.
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Vachliotis ID, Anastasilakis AD, Rafailidis V, Polyzos SA. Osteokines in Nonalcoholic Fatty Liver Disease. Curr Obes Rep 2024; 13:703-723. [PMID: 39225951 DOI: 10.1007/s13679-024-00586-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/21/2024] [Indexed: 09/04/2024]
Abstract
PURPOSE OF REVIEW To critically summarize evidence on the potential role of osteokines in the pathogenesis and progression of nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS There are emerging data supporting that certain osteokines, which are specific bone-derived proteins, may beneficially or adversely affect hepatic metabolism, and their alterations in the setting of osteoporosis or other bone metabolic diseases may possibly contribute to the development and progression of NAFLD. There is evidence showing a potential bidirectional association between NAFLD and bone metabolism, which may imply the existence of a liver-bone axis. In this regard, osteocalcin, osteoprotegerin, bone morphogenic protein 4 (BMP4) and BMP6 appear to have a positive impact on the liver, thus possibly alleviating NAFLD, whereas osteopontin, receptor activator of nuclear factor kappa Β ligand (RANKL), sclerostin, periostin, BMP8B, and fibroblast growth factor 23 (FGF23) appear to have a negative impact on the liver, thus possibly exacerbating NAFLD. The potential implication of osteokines in NAFLD warrants further animal and clinical research in the field that may possibly result in novel therapeutic targets for NAFLD in the future.
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Affiliation(s)
- Ilias D Vachliotis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
| | | | - Vasileios Rafailidis
- Department of Clinical Radiology, AHEPA University Hospital of Thessaloniki, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
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Romeo S, Chan C, Matsukuma K, Corwin MT, Lyo V, Chen S, Wang G, Sarkar S. Positron emission tomography combined with serum biomarkers detects fibrotic MASH. Sci Rep 2024; 14:21939. [PMID: 39304687 DOI: 10.1038/s41598-024-72655-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/06/2024] [Indexed: 09/22/2024] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a rising global disease signaling the urgent need for non-invasive tests (NITs). Recent work demonstrated that dynamic 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) imaging can identify MASH by measuring liver glucose transport rate, K1, and liver CT attenuation. By combining dynamic PET/CT with the serum-based fibrosis-4 (FIB-4) test, we were able to better distinguish clinical MASH from fibrotic subtypes, enabling determination of the core tenets of MASH: steatosis, inflammation, and fibrosis. Future studies using FDG-PET technology can further enable concomitant prediction of MASH severity and extrahepatic comorbidities such as cardiovascular disease.
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Affiliation(s)
- Sean Romeo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California, Davis, CA, USA
| | - Connie Chan
- School of Medicine, University of California, Davis, CA, USA
| | - Karen Matsukuma
- Department of Pathology and Laboratory Medicine, University of California, Davis, CA, USA
| | - Michael T Corwin
- Department of Radiology, University of California, Davis, CA, USA
| | - Victoria Lyo
- Department of Surgery, University of California, Davis, CA, USA
| | - Shuai Chen
- Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, CA, USA
| | - Guobao Wang
- Department of Radiology, University of California, Davis, CA, USA
| | - Souvik Sarkar
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California, Davis, CA, USA.
- Department of Radiology, University of California, Davis, CA, USA.
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Huang Y, Wang X, Sun L. The gut-liver axis calibrates PEDF production for ISC homeostasis. BIOPHYSICS REPORTS 2024; 10:175-177. [PMID: 39027319 PMCID: PMC11252237 DOI: 10.52601/bpr.2024.240904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 04/03/2024] [Indexed: 07/20/2024] Open
Affiliation(s)
- Ying Huang
- State Key Laboratory of Female Fertility Promotion, Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China
| | - Xinran Wang
- State Key Laboratory of Female Fertility Promotion, Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China
| | - Lulu Sun
- State Key Laboratory of Female Fertility Promotion, Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China
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Bahijri S, Eldakhakhny B, Enani S, Ajabnoor G, Al-Mowallad AS, Alsheikh L, Alhozali A, Alamoudi AA, Borai A, Tuomilehto J. Fibroblast Growth Factor 21: A More Effective Biomarker Than Free Fatty Acids and Other Insulin Sensitivity Measures for Predicting Non-alcoholic Fatty Liver Disease in Saudi Arabian Type 2 Diabetes Patients. Cureus 2023; 15:e50524. [PMID: 38222178 PMCID: PMC10787595 DOI: 10.7759/cureus.50524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/14/2023] [Indexed: 01/16/2024] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is more prevalent among individuals with type 2 diabetes (T2DM), elevating their risk of cardiovascular diseases (CVDs) and premature mortality. There is a need to modify treatment strategies to prevent or delay these adverse outcomes. Currently, there are no sensitive or specific biomarkers for predicting NAFLD in Saudi T2DM patients. Therefore, we aimed to explore the possibility of using fibroblast growth factor 21 (FGF-21), free fatty acids (FFAs), homeostatic model assessment for insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI) as possible markers. Methodology In this study, a total of 67 T2DM patients were recruited. NAFLD was detected by ultrasonography in 28 patients. Plasma glucose, FFAs, FGF-21, and serum insulin were measured in fasting blood samples. HOMA-IR and QUICKI were calculated. The means of the two groups with and without NAFLD were statistically compared. The receiver operating characteristics (ROC) curve and the area under the curve (AUC) were used to assess the ability to identify NAFLD. Results The mean levels of FGF-21 and HOMA-IR were significantly higher and that of QUICKI was significantly lower in patients with NAFLD than in those without (p < 0.001, p = 0.023, and p = 0.018, respectively). FGF-21 had the highest AUC to identify NAFLD (AUC = 0.981, 95% confidence interval = 0.954-1, P < 0.001). The AUCs for HOMA-IR, QUICKI, and FFA were <0.7. The highest sensitivity, specificity, positive likelihood ratio, and the lowest negative likelihood ratio were found when FGF-21 was used to predict NAFLD. Conclusions FGF-21 may be used as a biomarker to predict NAFLD in people with T2DM due to its high sensitivity and specificity compared to the other markers.
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Affiliation(s)
- Suhad Bahijri
- Department of Clinical Biochemistry, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
- Saudi Diabetes Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, SAU
- Food, Nutrition and Lifestyle Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, SAU
| | - Basmah Eldakhakhny
- Department of Clinical Biochemistry, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
- Saudi Diabetes Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, SAU
- Food, Nutrition and Lifestyle Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, SAU
| | - Sumia Enani
- Department of Food and Nutrition, Faculty of Human Sciences and Design, King Abdulaziz University, Jeddah, SAU
- Saudi Diabetes Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, SAU
- Food, Nutrition and Lifestyle Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, SAU
| | - Ghada Ajabnoor
- Department of Clinical Biochemistry, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
- Saudi Diabetes Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, SAU
- Food, Nutrition and Lifestyle Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, SAU
| | - Alaa S Al-Mowallad
- Department of Clinical Biochemistry, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
| | - Lubna Alsheikh
- Department of Biochemistry, King Abdulaziz University, Jeddah, SAU
| | - Amani Alhozali
- Department of Internal Medicine, King Abdulaziz University Hospital, Jeddah, SAU
| | - Aliaa A Alamoudi
- Department of Clinical Biochemistry, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
- Saudi Diabetes Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, SAU
| | - Anwar Borai
- King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU
- Saudi Diabetes Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, SAU
| | - Jaakko Tuomilehto
- Department of Public Health, University of Helsinki, Helsinki, FIN
- Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, FIN
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Tarasova LV, Tsyganova YV. Early diagnosis of non-alcoholic fatty liver disease: the role of biomarkers and complex indices of non-alcoholic fatty liver steatosis. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2023:27-36. [DOI: 10.31146/1682-8658-ecg-216-8-27-36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Metabolic syndrome is a series of pathologies united by a similar pathogenesis, the end of which, most often, is cardiovascular accidents, which are leaders among the causes of death in the population around the world. Non-alcoholic fatty liver disease (NAFLD) is the hepatic equivalent of the metabolic syndrome, registered earlier than all other equivalents, on the rights of the liver as a first-line energy depot. At the same time, according to multicenter studies, 95% of people with NAFLD (any stage) are not diagnosed with the disease. Clarification of additional risk factors for NAFLD and the presence of a specific biomarker of non-alcoholic liver steatosis would make it possible to stop the vicious cascade of metabolic processes, which in the future can lead to a significant increase in the life expectancy of the population. The potentially high role of Secreted Frizzled Related Protein-4 (SFRP4) adipokine in the early diagnosis of NAFLD is known. The aim of the study was to optimize the early diagnosis of non-alcoholic fatty liver disease using modern indices and biomarkers. Materials and methods. The work was carried out at the Department of Faculty and Hospital Therapy of the Chuvash State University named after I. N. Ulyanov” in the period from 2016 to 2020. This study included several stages: first of all, a retrospective analysis of 1150 outpatient records of patients from several medical organizations of the Chuvash Republic for the period 2016-2018 was carried out. to form two study groups: experimental and control. At the second stage, as a result of applying the exclusion criteria, 162 people remained in the experiment: 110 from the experimental group, 52 from the control group. The subjects of both groups were compared by gender and age, the age range of the subjects varied from 18 to 80 years old with an average value of 48.3 years. Further, the patients undergo a detailed examination, according to the presented plan: Collection of complaints, medical history, objective examination. Laboratory studies (general and biochemical blood tests, lipidogram, assessment of the level of serum adipokine SFRP4). Instrumental studies (ultrasound of the OBP, TE (SAR), ESP with elastometry). Evaluation of the most informative complex indices for the early diagnosis of NAFLD: MI, IVO indices, HSI, FLD-I. Further, all the necessary statistical processing and analysis of the obtained data were performed (Microsoft Office Excel 2016, StatTech v. 2.8.8 (developer - Stattech LLC, Russia)). Results. Accessible (not requiring the use of additional time and material costs) NAFLD indices with the highest sensitivity rates (99.1% and 98.2%, respectively) were MI and IVO. A noticeable direct correlation was traced between MI (p=0.640), moderate - between the IVO (p=0.398) and the elastographically determined index of non-alcoholic liver steatosis. High sensitivity and specificity of skin manifestations (xanthoma, xanthelasma - 69.6% and 89.7% and seborrheic dermatitis - 82.0% and 71.4%) were found in relation to early manifestations of NAFLD. From anthropometric indicators: the CW/CF index has a pronounced (ρ=0.643), CW - moderate (ρ=0.238), and BMI - a weak direct (ρ=0.223) correlation with the elastographically determined index of non-alcoholic liver steatosis. Adipokine SFRP4 correlates (ρ=0.841) with early manifestations of hepatic steatosis in patients, as determined by TE in CAP mode.
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Stiglund N, Hagström H, Stål P, Cornillet M, Björkström NK. Dysregulated peripheral proteome reveals NASH-specific signatures identifying patient subgroups with distinct liver biology. Front Immunol 2023; 14:1186097. [PMID: 37342340 PMCID: PMC10277514 DOI: 10.3389/fimmu.2023.1186097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/22/2023] [Indexed: 06/22/2023] Open
Abstract
Background and aims Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. The prognosis may vary from simple steatosis to more severe outcomes such as nonalcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. The understanding of the biological processes leading to NASH is limited and non-invasive diagnostic tools are lacking. Methods The peripheral immunoproteome in biopsy-proven NAFL (n=35) and NASH patients (n=35) compared to matched, normal-weight healthy controls (n=15) was studied using a proximity extension assay, combined with spatial and single cell hepatic transcriptome analysis. Results We identified 13 inflammatory serum proteins that, independent of comorbidities and fibrosis stage, distinguished NASH from NAFL. Analysis of co-expression patterns and biological networks further revealed NASH-specific biological perturbations indicative of temporal dysregulation of IL-4/-13, -10, -18, and non-canonical NF-kβ signaling. Of the identified inflammatory serum proteins, IL-18 and EN-RAGE as well as ST1A1 mapped to hepatic macrophages and periportal hepatocytes, respectively, at the single cell level. The signature of inflammatory serum proteins further permitted identification of biologically distinct subgroups of NASH patients. Conclusion NASH patients have a distinct inflammatory serum protein signature, which can be mapped to the liver parenchyma, disease pathogenesis, and identifies subgroups of NASH patients with altered liver biology.
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Affiliation(s)
- Natalie Stiglund
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Hannes Hagström
- Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Per Stål
- Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Martin Cornillet
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Niklas K. Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Vachliotis ID, Polyzos SA. Osteoprotegerin/Receptor Activator of Nuclear Factor-Kappa B Ligand/Receptor Activator of Nuclear Factor-Kappa B Axis in Obesity, Type 2 Diabetes Mellitus, and Nonalcoholic Fatty Liver Disease. Curr Obes Rep 2023:10.1007/s13679-023-00505-4. [PMID: 37208545 DOI: 10.1007/s13679-023-00505-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 05/21/2023]
Abstract
PURPOSE OF REVIEW To summarize evidence on the potential involvement of the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B (NF-κΒ) ligand (RANKL)/receptor activator of NF-κΒ (RANK) axis in the pathogenesis of metabolic diseases. RECENT FINDINGS The OPG-RANKL-RANK axis, which has been originally involved in bone remodeling and osteoporosis, is now recognized as a potential contributor in the pathogenesis of obesity and its associated comorbidities, i.e., type 2 diabetes mellitus and nonalcoholic fatty liver disease. Besides bone, OPG and RANKL are also produced in adipose tissue and may be involved in the inflammatory process associated with obesity. Metabolically healthy obesity has been associated with lower circulating OPG concentrations, possibly representing a counteracting mechanism, while elevated serum OPG levels may reflect an increased risk of metabolic dysfunction or cardiovascular disease. OPG and RANKL have been also proposed as potential regulators of glucose metabolism and are potentially involved in the pathogenesis of type 2 diabetes mellitus. In clinical terms, type 2 diabetes mellitus has been consistently associated with increased serum OPG concentrations. With regard to nonalcoholic fatty liver disease, experimental data suggest a potential contribution of OPG and RANKL in hepatic steatosis, inflammation, and fibrosis; however, most clinical studies showed reduction in serum concentrations of OPG and RANKL. The emerging contribution of the OPG-RANKL-RANK axis to the pathogenesis of obesity and its associated comorbidities warrants further investigation by mechanistic studies and may have potential diagnostic and therapeutic implications.
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Affiliation(s)
- Ilias D Vachliotis
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece.
- Second Department of Internal Medicine, 424 General Military Hospital, Thessaloniki, 56429, Greece.
| | - Stergios A Polyzos
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
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Golabi P, Shah D, Younossi ZM. How to Identify Advanced Nonalcoholic Fatty Liver Disease in the Primary Care Setting. Semin Liver Dis 2023; 43:142-148. [PMID: 37414024 DOI: 10.1055/s-0043-1770984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects 30 to 40% of the population globally and is increasingly considered the most common liver disease. Patients with type 2 diabetes, obesity, and cardiovascular diseases are at especially increased risk for NAFLD. Although most patients with NAFLD do not have progressive liver disease, some patients progress to cirrhosis, liver cancer, and liver mortality. Given the sheer number of patients with NAFLD, the burden of disease is enormous. Despite this large and increasing burden, identification of NAFLD patients at risk for progressive liver disease in the primary care and diabetology practice settings remains highly suboptimal. In this review, our aim is to summarize a stepwise approach to risk stratify patients with NAFLD which should help practitioners in their management of patients with NAFLD.
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Affiliation(s)
- Pegah Golabi
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Virginia
- Department of Medicine, Center for Liver Disease, Inova Fairfax Medical Campus, Falls Church, Virginia
- Inova Medicine, Inova Health System, Falls Church, Virginia
| | - Dipam Shah
- Department of Medicine, Center for Liver Disease, Inova Fairfax Medical Campus, Falls Church, Virginia
| | - Zobair M Younossi
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Virginia
- Department of Medicine, Center for Liver Disease, Inova Fairfax Medical Campus, Falls Church, Virginia
- Inova Medicine, Inova Health System, Falls Church, Virginia
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Osteoprotegerin deficiency aggravates methionine-choline-deficient diet-induced nonalcoholic steatohepatitis in mice. Sci Rep 2023; 13:3194. [PMID: 36823220 PMCID: PMC9950492 DOI: 10.1038/s41598-023-30001-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 02/14/2023] [Indexed: 02/25/2023] Open
Abstract
Clinical studies have shown that osteoprotegerin (OPG) is reduced in patients with nonalcoholic steatohepatitis (NASH), but the underlying mechanisms are unclear. The current study focuses on the role of OPG in the NASH pathogenesis. OPG knockout mice and wild-type control mice fed a methionine choline-deficient diet (MCD) for 4 weeks resulted in an animal model of NASH. Measurement of triglycerides (TG) in serum and liver to assess steatosis. Hematoxylin eosin (HE), Sirius Red and Masson staining were used to assess the liver damage. Transcriptome sequencing analysis, qPCR and western blot were to analyze changes in lipid metabolism and inflammation-related indicators in the liver. In vivo knockout of OPG resulted in a reduction of TG levels in the liver and a significant increase in serum ALT and AST. The expression of inflammatory factors and fibrosis genes was significantly upregulated in the livers of OPG knockout mice. Transcriptome sequencing analysis showed that OPG knockout significantly enhanced MCD diet-induced activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Mechanistically, OPG may inhibit MAPK signaling pathway activity by upregulating the expression of dual specificity phosphatase 14 (DUSP14), thereby reducing inflammatory injury. OPG could regulate the activity of the MAPK signaling pathway via DUSP14, thus regulating the expression of some inflammatory factors in NASH, it may be a promising target for the treatment of NASH.
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Raptis DD, Mantzoros CS, Polyzos SA. Fibroblast Growth Factor-21 as a Potential Therapeutic Target of Nonalcoholic Fatty Liver Disease. Ther Clin Risk Manag 2023; 19:77-96. [PMID: 36713291 PMCID: PMC9879042 DOI: 10.2147/tcrm.s352008] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 12/22/2022] [Indexed: 01/23/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease without any approved treatment to-date despite intensive research efforts by researchers and pharmaceutical industry. Fibroblast growth factor (FGF)-21 has been gaining increasing attention as a possible contributing factor and thus therapeutic target for obesity-related metabolic disorders, including NAFLD, mainly due to its effects on lipid and carbohydrate metabolism. Most animal and human observational studies have shown higher FGF-21 concentrations in NAFLD than non-NAFLD, implying that FGF-21 may be increased to counteract hepatic steatosis and inflammation. However, although Mendelian Randomization studies have revealed that variations of FGF-21 levels within the physiological range may have effects in hyperlipidemia and possibly nonalcoholic steatohepatitis, they also indicate that FGF-21, in physiological concentrations, may fail to reverse NAFLD and may not be able to control obesity and other diseases, indicating a state of FGF-21 resistance or insensitivity that could not respond to administration of FGF-21 in supraphysiological concentrations. Interventional studies with FGF-21 analogs (eg, pegbelfermin, efruxifermin, BOS-580) in humans have provided some favorable results in Phase 1 and Phase 2 studies. However, the definite effect of FGF-21 on NAFLD may be clarified after the completion of the ongoing clinical trials with paired liver biopsies and histological endpoints. The aim of this review is to critically summarize experimental and clinical data of FGF-21 in NAFLD, in an attempt to highlight existing knowledge and areas of uncertainty, and subsequently, to focus on the potential therapeutic effects of FGF-21 and its analogs in NAFLD.
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Affiliation(s)
- Dimitrios D Raptis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece,Second Department of Internal Medicine, 424 General Military Hospital, Thessaloniki, Greece
| | - Christos S Mantzoros
- Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA,Department of Internal Medicine, Boston VA Healthcare System, Harvard Medical School, Boston, MA, 02115, USA
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece,Correspondence: Stergios A Polyzos, First Laboratory of Pharmacology, School of Medicine, Campus of Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece, Tel +30 2310 999316, Email
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Exploring the Validity of Available Markers and Indices in the Diagnosis of Nonalcoholic Fatty Liver Disease (NAFLD) in People with Type 2 Diabetes in Saudi Arabia. Diseases 2023; 11:diseases11010010. [PMID: 36648875 PMCID: PMC9887592 DOI: 10.3390/diseases11010010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/12/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is common among Saudi patients with type 2 diabetes (T2DM). However, recommended clinical procedures to detect it are unavailable in many locations. Therefore, better and more available diagnostic biomarkers for NAFLD are needed. Various serum parameters were suggested, and algorithms that employ routine measurements in clinical practice have been developed for the prediction of fat stores in the liver in different populations. However, no such studies have been conducted on Saudis. We aimed to compare selected biochemical markers and calculated indices in T2DM patients diagnosed with NAFLD and patients without NAFLD to find the best markers associated with NAFLD. A cross-sectional study was employed to recruit 67 people with T2DM from endocrine outpatient clinics at King Abdul-Aziz University Hospital. NAFLD was detected by ultrasonography in 28 patients. Demographic information, anthropometric, and blood pressure (BP) measurements were taken. Fasting blood samples were obtained to measure glucose, glycated haemoglobin, lipid profile, liver function tests, and highly sensitive C-reactive protein. Fatty liver index, hepatic steatosis index, NAFLD-liver fat score, and triglyceride and glucose index were calculated. Following stepwise forward likelihood ratio regression with independent variables included in one model using binary logistic regression with age and waist circumference (WC) entered as covariates, elevated diastolic BP and low high-density lipoprotein- cholesterol remained significantly associated with NAFLD (p = 0.002 and 0.03, respectively). However, none of the investigated indices could be used to diagnose the disease adequately due to low specificity, even after calculating new cut-off values. Investigating novel markers and adjusting existing equations used to calculate indices to improve sensitivity and specificity in our population is needed.
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Physiological and pathophysiological role of endocrine fibroblast growth factors. POSTEP HIG MED DOSW 2022. [DOI: 10.2478/ahem-2022-0045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
The endocrine subfamily of fibroblast growth factors (FGF) includes three factors: FGF19, FGF21, FGF23. They act on distal tissues through FGF receptors (FGFRs). The FGFR activation requires two cofactors: α- and β-Klotho, which are structurally related single-pass transmembrane proteins. The endocrine FGFs regulate various metabolic processes involved in the regulation of glucose and lipid metabolism as well as bile acid circulation, vitamin D modulation, and phosphate homeostasis. The FGF-FGFR dysregulation is widely implicated in the pathogenesis of various disorders. Significant alterations in plasma FGF concentration are associated with the most prevalent chronic diseases, including dyslipidemia, type 2 diabetes, cardiovascular diseases, obesity, non-alcoholic fatty liver disease, diseases of the biliary tract, chronic kidney disease, inflammatory bowel disease, osteomalacia, various malignancies, and depression. Therefore, the endocrine FGFs may serve as disease predictors or biomarkers, as well as potential therapeutic targets. Currently, numerous analogues and inhibitors of endocrine FGFs are under development for treatment of various disorders, and recently, a human monoclonal antibody against FGF23 has been approved for treatment of X-linked hypophosphatemia. The aim of this review is to summarize the current data on physiological and pathophysiological actions of the endocrine FGF subfamily and recent research concerning the therapeutic potential of the endocrine FGF pathways.
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Cantero I, Abete I, Bullón-Vela V, Crujeiras AB, Casanueva FF, Zulet MA, Martinez JA. Fibroblast growth factor 21 levels and liver inflammatory biomarkers in obese subjects after weight loss. Arch Med Sci 2022; 18:36-44. [PMID: 35154523 PMCID: PMC8826683 DOI: 10.5114/aoms/98948] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 10/14/2018] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Previous studies have hypothesized fibroblast growth factor 21 (FGF-21) as a potential biomarker of the inflammation associated with liver diseases, which is also receiving considerable attention for its potential application concerning the management of obesity and co-morbidities. This study aimed to analyze the response of FGF-21 after a weight loss intervention and the relationships with other putative inflammatory liver biomarkers. MATERIAL AND METHODS Sixty-six obese participants from the RESMENA study were evaluated at baseline and following a 6-month energy restriction treatment. Anthropometric, body composition by DXA, routine laboratory measurements, which included transaminases and γ-glutamyl transferase (GGT) were analyzed by standardized methods. Moreover, FGF-21, M30 fragment (M30) and plasminogen activator inhibitor-1 (PAI-I) were analyzed as recognized liver inflammatory related biomarkers with specific ELISA kits. RESULTS Most measurements related to hepatic damage, inflammation and adiposity status improved at the end of the 6-month nutritional intervention. In addition, ΔFGF-21 shifts showed statistical relationships with changes in ΔM30, ΔGGT and ΔPAI. The reduction of M30 showed significant associations with changes in transaminases. Furthermore, PAI-I changes were associated with ΔM30 and ΔGGT regardless of weight loss. A linear regression model was set up to assess the influence of ΔPAI-I and ΔM30 on the variability of ΔFGF-21 (23.8%) adjusted by weight loss. CONCLUSIONS These results demonstrated interactions of some liver inflammatory mediators, specifically M30 and PAI-I with FGF-21. Thus, more investigation about FGF-21 is required given that this protein could be a biomarker of the obesity-inflammation-liver process.
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Affiliation(s)
- Irene Cantero
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain
- Centre for Nutrition Research, University of Navarra, Pamplona, Spain
| | - Itziar Abete
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain
- Centre for Nutrition Research, University of Navarra, Pamplona, Spain
- CIBER in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Spain
- Navarra Institute for Health Research (IdiSNA), Spain
| | - Vanessa Bullón-Vela
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain
- Centre for Nutrition Research, University of Navarra, Pamplona, Spain
| | - Ana B. Crujeiras
- CIBER in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Spain
- Laboratory of Molecular Endocrinology and Epigenomics in Endocrinology and Nutrition, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela University (USC), Santiago de Compostela, Spain
| | - Felipe F. Casanueva
- CIBER in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Spain
- Laboratory of Molecular Endocrinology and Epigenomics in Endocrinology and Nutrition, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela University (USC), Santiago de Compostela, Spain
| | - M. Angeles Zulet
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain
- Centre for Nutrition Research, University of Navarra, Pamplona, Spain
- CIBER in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Spain
- Navarra Institute for Health Research (IdiSNA), Spain
| | - J. Alfredo Martinez
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain
- Centre for Nutrition Research, University of Navarra, Pamplona, Spain
- CIBER in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Spain
- Navarra Institute for Health Research (IdiSNA), Spain
- IMDEA Food, Madrid, Spain
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Sak JJ, Prystupa A, Kiciński P, Luchowska-Kocot D, Kurys-Denis E, Bis-Wencel H. Leukocyte cell-derived chemotaxin-2 and fibroblast growth factor 21 in alcohol-induced liver cirrhosis. World J Hepatol 2021; 13:2071-2080. [PMID: 35070009 PMCID: PMC8727211 DOI: 10.4254/wjh.v13.i12.2071] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 07/22/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The importance of early diagnosis of alcoholic liver disease underscores the need to seek better and especially non-invasive diagnostic procedures. Leukocyte cell-derived chemotaxin-2 (LECT2) has been widely studied to determine its usefulness in monitoring the course of non-alcoholic fatty liver disease but not for alcoholic liver cirrhosis (ALC).
AIM To determine the concentration of LECT2 in the blood serum of patients in relation to progressive stages of ALC, its relation to fibroblast growth factor 1 (FGF-1) and FGF-21, and to examine the possible wider use of LECT2 in diagnosing ALC.
METHODS A retrospective case-control study was conducted with 69 ALC cases and 17 controls with no ALC. Subjects were recruited from the region of Lublin (eastern Poland). Liver cirrhosis was diagnosed based on clinical features, history of heavy alcohol consumption, laboratory tests, and abdominal ultrasonography. The degree of ALC was evaluated according to Pugh-Child criteria (the Pugh-Child score). Blood was drawn and, after centrifugation, serum was collected for analysis. LECT2, FGF-1, and FGF-21 were determined using enzyme-linked immunosorbent assay kits.
RESULTS The LECT2 Levels in the control group were 18.99 ± 5.36 ng/mL. In the study groups, they declined with the progression of cirrhosis to 11.06 ± 6.47 ng/mL in one group and to 8.06 ± 5.74 ng/mL in the other (P < 0.0001). Multiple comparison tests confirmed the statistically significant differences in LECT2 Levels between the control group and both test groups (P = 0.006 and P < 0.0001). FGF-21 Levels were 44.27 ± 64.19 pg/mL in the first test group, 45.4 ± 51.69 pg/mL in the second (P = 0.008), and 13.52 ± 7.51 pg/mL in the control group. The difference between the control group and the second test group was statistically significant (P = 0.007).
CONCLUSION We suggest that LECT2 may be a non-invasive diagnostic factor for alcohol-induced liver cirrhosis. The usefulness of LECT2 for non-invasive monitoring of alcohol-induced liver cirrhosis was indirectly confirmed by the multiple regression model developed on the basis of our statistical analysis.
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Affiliation(s)
- Jarosław Jerzy Sak
- Chair and Department of Humanities and Social Medicine, Medical University of Lublin, Lublin 20-093, Poland
| | - Andrzej Prystupa
- Department of Internal Medicine, Medical University of Lublin, Lublin 20-081, Poland
| | - Paweł Kiciński
- Department of Experimental Hematooncology, Medical University of Lublin, Lublin 20-080, Poland
| | | | - Ewa Kurys-Denis
- The Second Department of Radiology, Medical University of Lublin, Lublin 20-081, Poland
| | - Hanna Bis-Wencel
- Department of Microbiology and Reproductive Biology, University of Life Sciences in Lublin, Lublin 20-950, Poland
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Kim TH, Hong DG, Yang YM. Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism. Biomedicines 2021; 9:biomedicines9121903. [PMID: 34944728 PMCID: PMC8698516 DOI: 10.3390/biomedicines9121903] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/12/2021] [Accepted: 12/12/2021] [Indexed: 12/16/2022] Open
Abstract
The liver plays a key role in maintaining energy homeostasis by sensing and responding to changes in nutrient status under various metabolic conditions. Recently highlighted as a major endocrine organ, the contribution of the liver to systemic glucose and lipid metabolism is primarily attributed to signaling crosstalk between multiple organs via hepatic hormones, cytokines, and hepatokines. Hepatokines are hormone-like proteins secreted by hepatocytes, and a number of these have been associated with extra-hepatic metabolic regulation. Mounting evidence has revealed that the secretory profiles of hepatokines are significantly altered in non-alcoholic fatty liver disease (NAFLD), the most common hepatic manifestation, which frequently precedes other metabolic disorders, including insulin resistance and type 2 diabetes. Therefore, deciphering the mechanism of hepatokine-mediated inter-organ communication is essential for understanding the complex metabolic network between tissues, as well as for the identification of novel diagnostic and/or therapeutic targets in metabolic disease. In this review, we describe the hepatokine-driven inter-organ crosstalk in the context of liver pathophysiology, with a particular focus on NAFLD progression. Moreover, we summarize key hepatokines and their molecular mechanisms of metabolic control in non-hepatic tissues, discussing their potential as novel biomarkers and therapeutic targets in the treatment of metabolic diseases.
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Affiliation(s)
- Tae Hyun Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women’s University, Seoul 04310, Korea;
| | - Dong-Gyun Hong
- Department of Pharmacy, Kangwon National University, Chuncheon 24341, Korea;
- KNU Researcher Training Program for Developing Anti-Viral Innovative Drugs, Kangwon National University, Chuncheon 24341, Korea
| | - Yoon Mee Yang
- Department of Pharmacy, Kangwon National University, Chuncheon 24341, Korea;
- KNU Researcher Training Program for Developing Anti-Viral Innovative Drugs, Kangwon National University, Chuncheon 24341, Korea
- Correspondence: ; Tel.: +82-33-250-6909
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18
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Alternative Method for HDL and Exosome Isolation with Small Serum Volumes and Their Characterizations. SEPARATIONS 2021. [DOI: 10.3390/separations8110204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
High-density lipoprotein (HDL) and exosomes are promising sources of biomarkers. However, the limited sample volume and access to the ultracentrifuge equipment are still an issue during HDL and exosome isolation. This study aimed to isolate HDL and exosomes using an ultracentrifugation-free method with various small serum volumes. HDL was isolated from 200 µL (HDL200) and 500 µL (HDL500) of sera. Three different volumes: 50 µL (Exo50), 100 µL (Exo100), and 250 µL (Exo250) were used for exosome isolation. HDL and exosomes were isolated using commercial kits with the modified method and characterized by multiple approaches. The HDL levels of HDL200 and HDL500 were not significantly different (p > 0.05), with percent recoveries of >90%. HDL200 and HDL500 had the same protein pattern with a biochemical similarity of 99.60 ± 0.10%. The particle sizes of Exo50, Exo100, and Exo250 were in the expected range. All isolated exosomes exhibited a similar protein pattern with a biochemical similarity of >99%. In conclusion, two different serum volumes (200 and 500 µL) and three different serum volumes (50, 100, and 250 µL) can be employed for HDL and exosome isolation, respectively. The possibility of HDL and exosome isolation with small volumes will accelerate biomarker discoveries with various molecular diagnostic approaches.
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Kim H, Lee DS, An TH, Park HJ, Kim WK, Bae KH, Oh KJ. Metabolic Spectrum of Liver Failure in Type 2 Diabetes and Obesity: From NAFLD to NASH to HCC. Int J Mol Sci 2021; 22:ijms22094495. [PMID: 33925827 PMCID: PMC8123490 DOI: 10.3390/ijms22094495] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver disease is the spectrum of liver damage ranging from simple steatosis called as nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC). Clinically, NAFLD and type 2 diabetes coexist. Type 2 diabetes contributes to biological processes driving the severity of NAFLD, the primary cause for development of chronic liver diseases. In the last 20 years, the rate of non-viral NAFLD/NASH-derived HCC has been increasing rapidly. As there are currently no suitable drugs for treatment of NAFLD and NASH, a class of thiazolidinediones (TZDs) drugs for the treatment of type 2 diabetes is sometimes used to improve liver failure despite the risk of side effects. Therefore, diagnosis, prevention, and treatment of the development and progression of NAFLD and NASH are important issues. In this review, we will discuss the pathogenesis of NAFLD/NASH and NAFLD/NASH-derived HCC and the current promising pharmacological therapies of NAFLD/NASH. Further, we will provide insights into "adipose-derived adipokines" and "liver-derived hepatokines" as diagnostic and therapeutic targets from NAFLD to HCC.
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Affiliation(s)
- Hyunmi Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
| | - Da Som Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
| | - Tae Hyeon An
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
| | - Hyun-Ju Park
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
| | - Won Kon Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
- Correspondence: (K.-H.B.); (K.-J.O.); Tel.: +82-42-860-4268 (K.-H.B.); +82-42-879-8265 (K.-J.O.)
| | - Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
- Correspondence: (K.-H.B.); (K.-J.O.); Tel.: +82-42-860-4268 (K.-H.B.); +82-42-879-8265 (K.-J.O.)
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20
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Kucukoglu O, Sowa JP, Mazzolini GD, Syn WK, Canbay A. Hepatokines and adipokines in NASH-related hepatocellular carcinoma. J Hepatol 2021; 74:442-457. [PMID: 33161047 DOI: 10.1016/j.jhep.2020.10.030] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 10/26/2020] [Accepted: 10/28/2020] [Indexed: 12/12/2022]
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing in industrialised societies; this is likely secondary to the increasing burden of non-alcoholic fatty liver disease (NAFLD), its progressive form non-alcoholic steatohepatitis (NASH), and the metabolic syndrome. Cumulative studies suggest that NAFLD-related HCC may also develop in non-cirrhotic livers. However, prognosis and survival do not differ between NAFLD- or virus-associated HCC. Thus, research has increasingly focused on NAFLD-related risk factors to better understand the biology of hepatocarcinogenesis and to develop new diagnostic, preventive, and therapeutic strategies. One important aspect thereof is the role of hepatokines and adipokines in NAFLD/NASH-related HCC. In this review, we compile current data supporting the use of hepatokines and adipokines as potential markers of disease progression in NAFLD or as early markers of NAFLD-related HCC. While much work must be done to elucidate the mechanisms and interactions underlying alterations to hepatokines and adipokines, current data support the possible utility of these factors - in particular, angiopoietin-like proteins, fibroblast growth factors, and apelin - for detection or even as therapeutic targets in NAFLD-related HCC.
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Affiliation(s)
- Ozlem Kucukoglu
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Jan-Peter Sowa
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany
| | - Guillermo Daniel Mazzolini
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina; Liver Unit, Hospital Universitario Austral, Universidad Austral, Argentina
| | - Wing-Kin Syn
- Section of Gastroenterology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA; Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC, USA; Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country UPV/EHU, 48940 Leioa, Vizcaya, Spain
| | - Ali Canbay
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany.
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21
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Ipsen DH, Tveden-Nyborg P. Extracellular Vesicles as Drivers of Non-Alcoholic Fatty Liver Disease: Small Particles with Big Impact. Biomedicines 2021; 9:biomedicines9010093. [PMID: 33477873 PMCID: PMC7832840 DOI: 10.3390/biomedicines9010093] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/07/2021] [Accepted: 01/16/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming the leading chronic liver disease, negatively affecting the lives of millions of patients worldwide. The complex pathogenesis involves crosstalk between multiple cellular networks, but how the intricate communication between these cells drives disease progression remains to be further elucidated. Furthermore, the disease is not limited to the liver and includes the reprogramming of distant cell populations in different organs. Extracellular vesicles (EVs) have gained increased attention as mediators of cellular communication. EVs carry specific cargos that can act as disease-specific signals both locally and systemically. Focusing on NAFLD advancing to steatohepatitis (NASH), this review provides an update on current experimental and clinical findings of the potential role of EVs in hepatic inflammation and fibrosis, the main contributors to progressive NASH. Particular attention is placed on the characteristics of EV cargos and potential specificity to disease stages, with putative value as disease markers and treatment targets for future investigations.
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22
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Cai F, Zhao Y, Chen Q, Hu Y, Su S, Lu Y. Serum Cytokine Analysis Reveals Predictors of Progression from Chronic Hepatitis B to Liver Cirrhosis. Folia Biol (Praha) 2021; 67:28-36. [PMID: 34273264 DOI: 10.14712/fb2021067010028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Hepatitis B virus (HBV) infection is more likely to develop into chronic and persistent infection in China, which is the main cause of chronic liver disease. We examined the cytokine profiles of chronic hepatitis B (CHB) and CHB-caused liver cirrhosis (LC) to look for the predictor of progression from CHB to LC. Serum samples of 15 healthy controls (HC), 15 CHB patients and 15 LC patients were collected to detect the profiles of 48 cytokines by multiplex biometric ELISA-based immunoassay. Partial least squares discriminant analysis (PLS-DA) and random forest were used to analyse significant cytokines, which were further validated by ELISA using an independent cohort of 60 CHB patients, 60 LC patients and 35 HC samples. There were 18 differentially expressed cytokines of CHB and LC. Three cytokines were identified by PLS-DA and random forest, including interleukin (IL)-9, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-2 receptor subunit α (IL-2Rα), which displayed significant changes in serum levels. Differentially expressed cytokine networks between HC, CHB and LC also indicated particular cytokine co-expression network patterns of CHB and LC. The receiver-operator characteristic (ROC) analysis demonstrated that IL-9, GM-CSF, IL-2Rα and their logistic regression panel are potential predictors that significantly differentiate CHB from LC (P < 0.001) and CHB from Child class A LC (P < 0.001). The three cytokines and the panel showed significant correlation with the Child-Pugh score. IL-9, GM-CSF, IL-2Rα and their logistic panel may be predictors for monitoring the progression of CHB to LC.
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Affiliation(s)
- F Cai
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Y Zhao
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Q Chen
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Y Hu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - S Su
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Y Lu
- Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Adams LA, Chan WK. Noninvasive Tests in the Assessment of NASH and NAFLD Fibrosis: Now and Into the Future. Semin Liver Dis 2020; 40:331-338. [PMID: 32526784 DOI: 10.1055/s-0040-1713006] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Noninvasive serum and imaging methods offer accessible, accurate, and safe assessment of fibrosis severity in nonalcoholic fatty liver disease. In contrast, current serum and imaging methods for the prediction of nonalcoholic steatohepatitis are not sufficiently accurate for routine clinical use. Serum fibrosis markers that incorporate direct measures of fibrogenesis (for example, hyaluronic acid) or fibrinolysis are generally more accurate than biomarkers not incorporating direct measures of fibrogenesis. Elastography methods are more accurate than serum markers for fibrosis assessment and particularly for the determination of cirrhosis, but have a significant failure and/or unreliability rate in obese individuals. To overcome this, combining serum and elastography methods in a sequential manner minimizes indeterminate results and maintains accuracy. The accuracy of current noninvasive methods for monitoring fibrosis response to treatment are limited; however, new tools derived from "omic" methodologies offer promise for the future.
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Affiliation(s)
- Leon A Adams
- Medical School, Faculty of Medicine and Health Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.,Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
| | - Wah-Kheong Chan
- Department of Medicine, Gastroenterology and Hepatology Unit, University of Malaysia, Kuala Lumpur, Malaysia
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24
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Accumulation of 8-hydroxydeoxyguanosine, L-arginine and Glucose Metabolites by Liver Tumor Cells Are the Important Characteristic Features of Metabolic Syndrome and Non-Alcoholic Steatohepatitis-Associated Hepatocarcinogenesis. Int J Mol Sci 2020; 21:ijms21207746. [PMID: 33092030 PMCID: PMC7594076 DOI: 10.3390/ijms21207746] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/22/2020] [Accepted: 10/16/2020] [Indexed: 02/07/2023] Open
Abstract
To uncover mechanisms and explore novel biomarkers of obesity, type 2 diabetes (T2DM) and nonalcoholic steatohepatitis (NASH)-associated hepatocarcinogenesis, cellular and molecular alterations in the liver, and hepatocellular carcinomas (HCCs) were investigated in NASH model 60-week-old Tsumura, Suzuki, Obese Diabetic (TSOD) mice and NASH HCC patients. Markedly elevated lipid deposition, inflammation, fibrosis, and peroxisome proliferation in the liver, preneoplastic lesions, and HCCs of TSOD mice were accompanied by accumulation of polysaccharides in the cellular cytoplasm and nuclei and increase of oxidative DNA damage marker, 8-hydroxydeoxyguanosine (8-OHdG) formation in the liver and altered foci. Metabolomics of TSOD mice HCCs demonstrated significant elevation of the concentration of amino acid L-arginine, phosphocreatine, S-adenosylmethionine/S-adenosylhomocysteine ratio, adenylate, and guanylate energy charges in coordination with tremendous rise of glucose metabolites, mostly fructose 1,6-diphosphate. L-arginine accumulation in HCCs was associated with significant under-expression of arginase 1 (ARG1), suppression of the urea cycle, methionine and putrescine degradation pathways, activation of Ser and Thr kinase Akt AKT, phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinase 1/2 (ERK1/2) kinases, β-catenin, mammalian target of rapamycin (mTOR), and cell proliferation. Furthermore, clinicopathological analysis in 20 metabolic syndrome/NASH and 80 HCV-positive HCC patients demonstrated significant correlation of negative ARG1 expression with poor tumor differentiation, higher pathological stage, and significant decrease of survival in metabolic syndrome/NASH-associated HCC patients, thus indicating that ARG1 could become a potential marker for NASH HCC. From these results, formation of oxidative stress and 8-OHdG in the DNA and elevation of glucose metabolites and L-arginine due to ARG1 suppression in mice liver cells are the important characteristics of T2DM/NASH-associated hepatocarcinogenesis, which may take part in activating oxidative stress resistance, synthesis of phosphocreatine, cell signaling, methylation, and proliferation.
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Nikseresht M, Azarmehr N, Arya A, Alipoor B, Fadaei R, Khalvati B, Abidi H, Doustimotlagh AH. Circulating mRNA and plasma levels of osteoprotegerin and receptor activator of NF-κB ligand in nonalcoholic fatty liver disease. Biotechnol Appl Biochem 2020; 68:1243-1249. [PMID: 33010062 DOI: 10.1002/bab.2047] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 09/30/2020] [Indexed: 01/13/2023]
Abstract
Pathogenesis of the beginning and progression of nonalcoholic fatty liver disease (NAFLD) has not been clarified exactly. The osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) axis seems to play an imperative function in the onset and progression of this disease. The goal of the present study was to investigate the peripheral blood mononuclear cell (PBMC) expression and plasma levels of RANKL and OPG cytokines in NAFLD patients and compare them with healthy group. Plasma levels of OPG and RANKL were determined with ELISA kits in 57 men with NAFLD and 25 healthy men as controls. Biochemical and anthropometric parameters tests were also evaluated in the study groups. RANKL and OPG mRNA contents were evaluated by quantitative RT-PCR. OPG contents were markedly decreased in NAFLD patients as compared with healthy patients [1.43 (1.05-5.45)] versus [2.94 (1.76-4.73)] ng/mL; P = 0.007). The levels of RANKL were significantly reduced in NAFLD patients [74.00 (56.26-203.52) ng/mL] than in healthy patients [119.37 (83.71-150.13) ng/mL]; (P = 0.03). Also, OPG and RANKL gene expression were significantly decreased in NAFLD patients in comparison with the control group (P < 0.05). Moreover, receiver operating characteristic curve indicated that OPG may have a good capability to discriminate between NAFLD patients and normal individuals. A positive correlation was observed between OPG and RANKL in plasma sample (r = 0.495) (P = 0.000). Decreased plasma levels and gene expression of RANKL and OPG cytokines in NAFLD patients indicate that there is a relationship between these cytokines and the pathology of NAFLD disease. Confirmation of this association as well as the mechanism and role of these cytokines in NAFLD require further studies.
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Affiliation(s)
- Mohsen Nikseresht
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Nahid Azarmehr
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Arash Arya
- Internal medicine Department, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Behnam Alipoor
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Reza Fadaei
- Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Bahman Khalvati
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Hassan Abidi
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Amir Hossein Doustimotlagh
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.,Department of Clinical Biochemistry, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
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26
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Tariq S, Tariq S, Hussain S, Baig M. Association of serum osteoprotegerin with severity of chronic liver disease in female patients: A potential biomarker. Pak J Med Sci 2020; 36:1325-1329. [PMID: 32968402 PMCID: PMC7501019 DOI: 10.12669/pjms.36.6.2678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Objective To determine the association of serum osteoprotegerin (OPG) with the severity of chronic liver disease in female patients. Methods This case-control study was conducted in Madina Teaching Hospital from 2019-2020.An institutional review board of University Medical and Dental College, The University of Faisalabad gave the approval to conduct the study. Only female patients of age group 40 to 60 years having CLD were included in this study. Total 80 participants were enrolled after fulfilling the inclusion and exclusion criteria. Serum OPG levels were measured by enzyme linked immunosorbant assay (ELISA) supplied by ELAB Sciences, USA. The severity of disease was assessed by Child-Pugh classification. Results OPG levels were significantly different between the three Child-Pugh classes. OPG levels were significantly high in class C indicating increased level of this cytokine in CLD as compared to class A (p = <0.05). There was a positive association of OPG with splenomegaly (OR = 2.10, p = <0.001), hepatomegaly (OR = 4.41, (p = <0.05), skin pigmentation (OR = 2.06, p = <0.05), malena (OR = 1.87, p = <0.05) and prolonged bleeding (OR = 1.86, p = <0.05). Conclusion The levels of serum Osteoprotegerin is increased in severe form of chronic liver disease (Class C) of Child-Pughs classification as compared to mild (Class A) and moderate (Class B) forms of Child-Pughs classification.
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Affiliation(s)
- Saba Tariq
- Saba Tariq, MBBS, M.Phil. Associate Professor of Pharmacology, University Medical & Dental College, University of Faisalabad, Pakistan, Research Scholar, Pharmacology, University of Health Sciences, Lahore, Pakistan
| | - Sundus Tariq
- Sundus Tariq, MBBS, M.Phil. Associate Professor of Physiology, University Medical & Dental College, Faisalabad, Pakistan. Research Scholar, Physiology, University of Health Sciences, Lahore, Pakistan
| | - Shaista Hussain
- Shaista Hussain, MBBS. House Officer, Allied Hospital Faisalabad, Faisalabad, Pakistan
| | - Mukhtiar Baig
- Prof. Mukhtiar Baig, MBBS, M.Phil., PhD. Department of Clinical Biochemistry, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah- 21589, KSA
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27
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Pillai SS, Lakhani HV, Zehra M, Wang J, Dilip A, Puri N, O’Hanlon K, Sodhi K. Predicting Nonalcoholic Fatty Liver Disease through a Panel of Plasma Biomarkers and MicroRNAs in Female West Virginia Population. Int J Mol Sci 2020; 21:ijms21186698. [PMID: 32933141 PMCID: PMC7554851 DOI: 10.3390/ijms21186698] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 09/04/2020] [Accepted: 09/11/2020] [Indexed: 02/07/2023] Open
Abstract
(1) Background: Nonalcoholic fatty liver disease (NAFLD) is primarily characterized by the presence of fatty liver, hepatic inflammation and fibrogenesis eventually leading to nonalcoholic steatohepatitis (NASH) or cirrhosis. Obesity and diabetes are common risk factors associated with the development and progression of NAFLD, with one of the highest prevalence of these diseased conditions in the West Virginia population. Currently, the diagnosis of NAFLD is limited to radiologic studies and biopsies, which are not cost-effective and highly invasive. Hence, this study aimed to develop a panel and assess the progressive levels of circulatory biomarkers and miRNA expression in patients at risk for progression to NASH to allow early intervention strategies. (2) Methods: In total, 62 female patients were enrolled and blood samples were collected after 8–10 h of fasting. Computed tomography was performed on abdomen/pelvis following IV contrast administration. The patients were divided into the following groups: Healthy subjects with normal BMI and normal fasting blood glucose (Control, n = 20), Obese with high BMI and normal fasting blood glucose (Obese, n = 20) and Obese with high fasting blood glucose (Obese + DM, n = 22). Based on findings from CT, another subset was created from Obese + DM group with patients who showed signs of fatty liver infiltration (Obese + DM(FI), n = 10). ELISA was performed for measurement of plasma biomarkers and RT-PCR was performed for circulating miRNA expression. (3) Results: Our results show significantly increased levels of plasma IL-6, Leptin and FABP-1, while significantly decreased level of adiponectin in Obese, Obese + DM and Obese + DM(FI) group, as compared to healthy controls. The level of CK-18 was significantly increased in Obese + DM(FI) group as compared to control. Subsequently, the expression of miR-122, miR-34a, miR-375, miR-16 and miR-21 was significantly increased in Obese + DM and Obese + DM(FI) group as compared to healthy control. Our results also show distinct correlation of IL-6, FABP-1 and adiponectin levels with the expression of miRNAs in relation to the extent of NAFLD progression. (4) Conclusion: Our results support the clinical application of these biomarkers and miRNAs in monitoring the progression of NAFLD, suggesting a more advanced diagnostic potential of this panel than conventional methods. This panel may provide an appropriate method for early prognosis and management of NAFLD and subsequent adverse hepatic pathophysiology, potentially reducing the disease burden on the West Virginia population.
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Affiliation(s)
- Sneha S. Pillai
- Departments of Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA; (S.S.P.); (H.V.L.); (M.Z.); (J.W.); (A.D.)
| | - Hari Vishal Lakhani
- Departments of Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA; (S.S.P.); (H.V.L.); (M.Z.); (J.W.); (A.D.)
| | - Mishghan Zehra
- Departments of Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA; (S.S.P.); (H.V.L.); (M.Z.); (J.W.); (A.D.)
| | - Jiayan Wang
- Departments of Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA; (S.S.P.); (H.V.L.); (M.Z.); (J.W.); (A.D.)
| | - Anum Dilip
- Departments of Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA; (S.S.P.); (H.V.L.); (M.Z.); (J.W.); (A.D.)
| | - Nitin Puri
- Departments of Biomedical Sciences and Medical Education, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA;
| | - Kathleen O’Hanlon
- Departments of Family Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA;
| | - Komal Sodhi
- Departments of Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA; (S.S.P.); (H.V.L.); (M.Z.); (J.W.); (A.D.)
- Correspondence: ; Tel.: +1-(304)-691-1704; Fax: +1-(914)-347-4956
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28
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Lee J, Vali Y, Boursier J, Duffin K, Verheij J, Brosnan MJ, Zwinderman K, Anstee QM, Bossuyt PM, Zafarmand MH. Accuracy of cytokeratin 18 (M30 and M65) in detecting non-alcoholic steatohepatitis and fibrosis: A systematic review and meta-analysis. PLoS One 2020; 15:e0238717. [PMID: 32915852 PMCID: PMC7485872 DOI: 10.1371/journal.pone.0238717] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/22/2020] [Indexed: 12/16/2022] Open
Abstract
Introduction Association between elevated cytokeratin 18 (CK-18) levels and hepatocyte death has made circulating CK-18 a candidate biomarker to differentiate non-alcoholic fatty liver from non-alcoholic steatohepatitis (NASH). Yet studies produced variable diagnostic performance. We aimed to provide summary estimates with increased precision for the accuracy of CK-18 (M30, M65) in detecting NASH and fibrosis among non-alcoholic fatty liver disease (NAFLD) adults. Methods We searched five databases to retrieve studies evaluating CK-18 against a liver biopsy in NAFLD adults. Reference screening, data extraction and quality assessment (QUADAS-2) were independently conducted by two authors. Meta-analyses were performed for five groups based on the CK-18 antigens and target conditions, using one of two methods: linear mixed-effects multiple thresholds model or bivariate logit-normal random-effects model. Results We included 41 studies, with data on 5,815 participants. A wide range of disease prevalence was observed. No study reported a pre-defined cut-off. Thirty of 41 studies provided sufficient data for inclusion in any of the meta-analyses. Summary AUC [95% CI] were: 0.75 [0.69–0.82] (M30) and 0.82 [0.69–0.91] (M65) for NASH; 0.73 [0.57–0.85] (M30) for fibrotic NASH; 0.68 (M30) for significant (F2-4) fibrosis; and 0.75 (M30) for advanced (F3-4) fibrosis. Thirteen studies used CK-18 as a component of a multimarker model. Conclusions For M30 we found lower diagnostic accuracy to detect NASH compared to previous meta-analyses, indicating a limited ability to act as a stand-alone test, with better performance for M65. Additional external validation studies are needed to obtain credible estimates of the diagnostic accuracy of multimarker models.
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Affiliation(s)
- Jenny Lee
- Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- * E-mail:
| | - Yasaman Vali
- Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Jérôme Boursier
- Hepato-Gastroenterology Department, Angers University Hospital, Angers, France
- HIFIH Laboratory, UPRES EA3859, Angers University, Angers, France
| | - Kevin Duffin
- Lilly Research Laboratories, Eli Lilly and Company Ltd (LLY), Indianapolis, IN, United States of America
| | - Joanne Verheij
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - M. Julia Brosnan
- Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, United States of America
| | - Koos Zwinderman
- Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Quentin M. Anstee
- The Newcastle Liver Research Group, Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Patrick M. Bossuyt
- Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Mohammad Hadi Zafarmand
- Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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29
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Adhyatmika A, Beljaars L, Putri KSS, Habibie H, Boorsma CE, Reker-Smit C, Luangmonkong T, Guney B, Haak A, Mangnus KA, Post E, Poelstra K, Ravnskjaer K, Olinga P, Melgert BN. Osteoprotegerin is More than a Possible Serum Marker in Liver Fibrosis: A Study into its Function in Human and Murine Liver. Pharmaceutics 2020; 12:pharmaceutics12050471. [PMID: 32455750 PMCID: PMC7284440 DOI: 10.3390/pharmaceutics12050471] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 05/19/2020] [Accepted: 05/19/2020] [Indexed: 12/17/2022] Open
Abstract
Osteoprotegerin (OPG) serum levels are associated with liver fibrogenesis and have been proposed as a biomarker for diagnosis. However, the source and role of OPG in liver fibrosis are unknown, as is the question of whether OPG expression responds to treatment. Therefore, we aimed to elucidate the fibrotic regulation of OPG production and its possible function in human and mouse livers. OPG levels were significantly higher in lysates of human and mouse fibrotic livers compared to healthy livers. Hepatic OPG expression localized in cirrhotic collagenous bands in and around myofibroblasts. Single cell sequencing of murine liver cells showed hepatic stellate cells (HSC) to be the main producers of OPG in healthy livers. Using mouse precision-cut liver slices, we found OPG production induced by transforming growth factor β1 (TGFβ1) stimulation. Moreover, OPG itself stimulated expression of genes associated with fibrogenesis in liver slices through TGFβ1, suggesting profibrotic activity of OPG. Resolution of fibrosis in mice was associated with decreased production of OPG compared to ongoing fibrosis. OPG may stimulate fibrogenesis through TGFβ1 and is associated with the degree of fibrogenesis. It should therefore be investigated further as a possible drug target for liver fibrosis or biomarker for treatment success of novel antifibrotics.
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Affiliation(s)
- Adhyatmika Adhyatmika
- Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands; (A.A.); (C.E.B.); (C.R.-S.); (B.G.); (A.H.); (K.A.M.); (E.P.); (K.P.)
- Department of Pharmaceutics, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Leonie Beljaars
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands; (L.B.); (K.S.S.P.); (T.L.); (P.O.)
| | - Kurnia S. S. Putri
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands; (L.B.); (K.S.S.P.); (T.L.); (P.O.)
- Faculty of Pharmacy, University of Indonesia, Depok 16424, Indonesia
| | - Habibie Habibie
- Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands;
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia
- Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
| | - Carian E. Boorsma
- Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands; (A.A.); (C.E.B.); (C.R.-S.); (B.G.); (A.H.); (K.A.M.); (E.P.); (K.P.)
| | - Catharina Reker-Smit
- Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands; (A.A.); (C.E.B.); (C.R.-S.); (B.G.); (A.H.); (K.A.M.); (E.P.); (K.P.)
| | - Theerut Luangmonkong
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands; (L.B.); (K.S.S.P.); (T.L.); (P.O.)
- Faculty of Pharmacy, Mahidol University, Bangkok 73170, Thailand
| | - Burak Guney
- Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands; (A.A.); (C.E.B.); (C.R.-S.); (B.G.); (A.H.); (K.A.M.); (E.P.); (K.P.)
| | - Axel Haak
- Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands; (A.A.); (C.E.B.); (C.R.-S.); (B.G.); (A.H.); (K.A.M.); (E.P.); (K.P.)
| | - Keri A. Mangnus
- Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands; (A.A.); (C.E.B.); (C.R.-S.); (B.G.); (A.H.); (K.A.M.); (E.P.); (K.P.)
| | - Eduard Post
- Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands; (A.A.); (C.E.B.); (C.R.-S.); (B.G.); (A.H.); (K.A.M.); (E.P.); (K.P.)
| | - Klaas Poelstra
- Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands; (A.A.); (C.E.B.); (C.R.-S.); (B.G.); (A.H.); (K.A.M.); (E.P.); (K.P.)
| | - Kim Ravnskjaer
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 M Odense M, Denmark;
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands; (L.B.); (K.S.S.P.); (T.L.); (P.O.)
| | - Barbro N. Melgert
- Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands;
- Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
- Correspondence:
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30
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Okamoto K, Koda M, Okamoto T, Onoyama T, Miyoshi K, Kishina M, Matono T, Kato J, Tokunaga S, Sugihara T, Hiramatsu A, Hyogo H, Tobita H, Sato S, Kawanaka M, Hara Y, Hino K, Chayama K, Murawaki Y, Isomoto H. Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease. PLoS One 2020; 15:e0219412. [PMID: 32106257 PMCID: PMC7046274 DOI: 10.1371/journal.pone.0219412] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 02/10/2020] [Indexed: 12/15/2022] Open
Abstract
Introduction Non-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker. Methods Eighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control. One patient was excluded due to low RT-PCR signal. Results Compared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, low-density-lipoprotein cholesterol and non-high-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism–related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379. Conclusions Serum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.
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Affiliation(s)
- Kinya Okamoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
- * E-mail:
| | - Masahiko Koda
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Toshiaki Okamoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Takumi Onoyama
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Kenichi Miyoshi
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Manabu Kishina
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Tomomitsu Matono
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Jun Kato
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Shiho Tokunaga
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Takaaki Sugihara
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Hepatology, JA Hiroshima General Hospital, Hatsukaichi, Hiroshima, Japan
| | - Hiroshi Tobita
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Shuichi Sato
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama, Okayama, Japan
| | - Yuichi Hara
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan
| | - Yoshikazu Murawaki
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Hajime Isomoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
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Ocker M. Fibroblast growth factor signaling in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: Paving the way to hepatocellular carcinoma. World J Gastroenterol 2020; 26:279-290. [PMID: 31988589 PMCID: PMC6969880 DOI: 10.3748/wjg.v26.i3.279] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/17/2019] [Accepted: 01/01/2020] [Indexed: 02/06/2023] Open
Abstract
Metabolic disorders are increasingly leading to non-alcoholic fatty liver disease, subsequent steatohepatitis, cirrhosis and hepatocellular carcinoma. Fibroblast growth factors and their receptors play an important role in maintaining metabolic homeostasis also in the liver and disorders in signaling have been identified to contribute to those pathophysiologic conditions leading to hepatic lipid accumulation and chronic inflammation. While specific and well tolerated inhibitors of fibroblast growth factor receptor activity are currently developed for (non-liver) cancer therapy, treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis is still limited. Fibroblast growth factor-mimicking or restoring approaches have recently evolved as a novel therapeutic option and the impact of such interactions with the fibroblast growth factor receptor signaling network during non-alcoholic fatty liver disease/non-alcoholic steatohepatitis development is reviewed here.
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Affiliation(s)
- Matthias Ocker
- Department of Gastroenterology (CBF), Charité University Medicine Berlin, Berlin 10117, Germany
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32
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Shiha G, Mousa N. Noninvasive Biomarkers for Liver Fibrosis. LIVER DISEASES 2020:427-441. [DOI: 10.1007/978-3-030-24432-3_36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
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Tucker B, Li H, Long X, Rye KA, Ong KL. Fibroblast growth factor 21 in non-alcoholic fatty liver disease. Metabolism 2019; 101:153994. [PMID: 31672443 DOI: 10.1016/j.metabol.2019.153994] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/25/2019] [Accepted: 10/04/2019] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies ranging from uncomplicated hepatic fat accumulation to a state of lobular inflammation and hepatocyte ballooning, known as non-alcoholic steatohepatitis (NASH). Currently, there are no reliable biomarkers or effective therapeutic options established for NAFLD. Nevertheless, there are several molecular targets in the pipeline, of which fibroblast growth factor 21 (FGF21) is one. FGF21 is secreted primarily from liver and has a plethora of metabolic functions. Pre-clinical and epidemiological studies indicate a relationship between circulating FGF21 levels and hepatic fat content in both mice and humans. Moreover, animal studies have clearly shown that aberrant FGF21 signalling is a key pathological step in the development and progression of NAFLD. A recent Phase II clinical trial demonstrated that administration of an FGF21 analogue significantly reduced hepatic fat in subjects with NASH. As such, FGF21 provides a novel target for future biomarker and therapeutic studies. This review appraises preclinical data to outline the current understanding of FGF21 function in both normal hepatic function and NAFLD. Epidemiological evidence is explored to delineate the relationship between circulating FGF21 levels and NAFLD in humans. Finally, we review the therapeutic effects of FGF21 in the treatment of NAFLD.
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Affiliation(s)
- Bradley Tucker
- Lipid Research Group, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia
| | - Huating Li
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center of Diabetes, Shanghai, China.
| | - Xiaoxue Long
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center of Diabetes, Shanghai, China
| | - Kerry-Anne Rye
- Lipid Research Group, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia
| | - Kwok Leung Ong
- Lipid Research Group, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia.
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Watt MJ, Miotto PM, De Nardo W, Montgomery MK. The Liver as an Endocrine Organ-Linking NAFLD and Insulin Resistance. Endocr Rev 2019; 40:1367-1393. [PMID: 31098621 DOI: 10.1210/er.2019-00034] [Citation(s) in RCA: 380] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/04/2019] [Indexed: 02/06/2023]
Abstract
The liver is a dynamic organ that plays critical roles in many physiological processes, including the regulation of systemic glucose and lipid metabolism. Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. Through the use of advanced mass spectrometry "omics" approaches and detailed experimentation in cells, mice, and humans, we now understand that the liver secretes a wide array of proteins, metabolites, and noncoding RNAs (miRNAs) and that many of these secreted factors exert powerful effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the rapidly evolving field of "hepatokine" biology with a particular focus on delineating previously unappreciated communication between the liver and other tissues in the body. We describe the NAFLD-induced changes in secretion of liver proteins, lipids, other metabolites, and miRNAs, and how these molecules alter metabolism in liver, muscle, adipose tissue, and pancreas to induce insulin resistance. We also synthesize the limited information that indicates that extracellular vesicles, and in particular exosomes, may be an important mechanism for intertissue communication in normal physiology and in promoting metabolic dysregulation in NAFLD.
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Affiliation(s)
- Matthew J Watt
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
| | - Paula M Miotto
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
| | - William De Nardo
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
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Faienza MF, D'Amato G, Chiarito M, Colaianni G, Colucci S, Grano M, Corbo F, Brunetti G. Mechanisms Involved in Childhood Obesity-Related Bone Fragility. Front Endocrinol (Lausanne) 2019; 10:269. [PMID: 31130918 PMCID: PMC6509993 DOI: 10.3389/fendo.2019.00269] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 04/11/2019] [Indexed: 01/11/2023] Open
Abstract
Childhood obesity is one of the major health problems in western countries. The excessive accumulation of adipose tissue causes inflammation, oxidative stress, apoptosis, and mitochondrial dysfunctions. Thus, obesity leads to the development of severe co-morbidities including type 2 diabetes mellitus, liver steatosis, cardiovascular, and neurodegenerative diseases which can develop early in life. Furthermore, obese children have low bone mineral density and a greater risk of osteoporosis and fractures. The knowledge about the interplay bone tissue and between adipose is still growing, although recent findings suggest that adipose tissue activity on bone can be fat-depot specific. Obesity is associated to a low-grade inflammation that alters the expression of adiponectin, leptin, IL-6, Monocyte Chemotactic Protein 1 (MCP1), TRAIL, LIGHT/TNFSF14, OPG, and TNFα. These molecules can affect bone metabolism, thus resulting in osteoporosis. The purpose of this review was to deepen the cellular mechanisms by which obesity may facilitate osteoporosis and bone fractures.
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Affiliation(s)
- Maria Felicia Faienza
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
| | | | - Mariangela Chiarito
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
| | - Graziana Colaianni
- Department of Emergency and Organ Transplantation, Section of Human Anatomy and Histology, University of Bari, Bari, Italy
| | - Silvia Colucci
- Department of Basic and Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari Aldo Moro, Bari, Italy
| | - Maria Grano
- Department of Emergency and Organ Transplantation, Section of Human Anatomy and Histology, University of Bari, Bari, Italy
| | - Filomena Corbo
- Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari, Italy
| | - Giacomina Brunetti
- Department of Basic and Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari Aldo Moro, Bari, Italy
- *Correspondence: Giacomina Brunetti
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36
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Cantero I, Elorz M, Abete I, Marin BA, Herrero JI, Monreal JI, Benito A, Quiroga J, Martínez A, Huarte MP, Uriz-Otano JI, Tur JA, Kearney J, Martinez JA, Zulet MA. Ultrasound/Elastography techniques, lipidomic and blood markers compared to Magnetic Resonance Imaging in non-alcoholic fatty liver disease adults. Int J Med Sci 2019; 16:75-83. [PMID: 30662331 PMCID: PMC6332481 DOI: 10.7150/ijms.28044] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 10/18/2018] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) may progress to steatohepatitis, cirrhosis and complicated hepatocellular carcinoma with defined differential symptoms and manifestations. OBJECTIVE To evaluate the fatty liver status by several validated approaches and to compare imaging techniques, lipidomic and routine blood markers with magnetic resonance imaging in adults subjects with non-alcoholic fatty liver disease. MATERIALS AND METHODS A total of 127 overweight/obese with NAFLD, were parallelly assessed by Magnetic Resonance Imaging (MRI), ultrasonography, transient elastography and a validated metabolomic designed test to diagnose NAFLD in this cross-sectional study. Body composition (DXA), hepatic related biochemical measurements as well as the Fatty Liver Index (FLI) were evaluated. This study was registered as FLiO: Fatty Liver in Obesity study; NCT03183193. RESULTS The subjects with more severe liver disease were found to have worse metabolic parameters. Positive associations between MRI with inflammatory and insulin biomarkers were found. A linear regression model including ALT, RBP4 and HOMA-IR was able to explain 40.9% of the variability in fat content by MRI. In ROC analyses a combination panel formed of ALT, HOMA-IR and RBP4 followed by ultrasonography, ALT and metabolomic test showed the major predictive ability (77.3%, 74.6%, 74.3% and 71.1%, respectively) for liver fat content. CONCLUSIONS A panel combination including routine blood markers linked to insulin resistance showed highest associations with MRI considered as a gold standard for determining liver fat content. This combination of tests can facilitate the diagnosis of early stages of non-alcoholic liver disease thereby avoiding other invasive and expensive methods.
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Affiliation(s)
- Irene Cantero
- Department of Nutrition, Food Science and Physiology. Centre for Nutrition Research. School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
| | - Mariana Elorz
- Department of Radiology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Itziar Abete
- Department of Nutrition, Food Science and Physiology. Centre for Nutrition Research. School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.,CIBERobn, Physiopathology of Obesity and Nutrition. Instituto de Salud Carlos III. Madrid, Spain
| | - Bertha Araceli Marin
- Department of Nutrition, Food Science and Physiology. Centre for Nutrition Research. School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
| | - Jose Ignacio Herrero
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.,Liver Unit, Clinica Universidad de Navarra, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Jose Ignacio Monreal
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.,Clinical Chemistry Department, Clínica Universidad de Navarra, Pamplona, Spain
| | - Alberto Benito
- Department of Radiology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Jorge Quiroga
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.,Department of Internal Medicine, Clínica Universidad de Navarra, Pamplona, Navarra, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Ana Martínez
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.,Department of Gastroenterology, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Mª Pilar Huarte
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.,Department of Gastroenterology, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Juan Isidro Uriz-Otano
- Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.,Department of Gastroenterology, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Josep Antoni Tur
- CIBERobn, Physiopathology of Obesity and Nutrition. Instituto de Salud Carlos III. Madrid, Spain.,Research Group on Community Nutrition and Oxidative Stress. University of Balearic Islands. Palma de Mallorca. Spain
| | - John Kearney
- School of Biological Sciences, Dublin Institute of Technology, Dublin, Republic of Ireland
| | - J Alfredo Martinez
- Department of Nutrition, Food Science and Physiology. Centre for Nutrition Research. School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.,CIBERobn, Physiopathology of Obesity and Nutrition. Instituto de Salud Carlos III. Madrid, Spain.,Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.,IMDEA FOOD. Madrid
| | - M Angeles Zulet
- Department of Nutrition, Food Science and Physiology. Centre for Nutrition Research. School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.,CIBERobn, Physiopathology of Obesity and Nutrition. Instituto de Salud Carlos III. Madrid, Spain.,Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
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Adak M, Das D, Niyogi S, Nagalakshmi C, Ray D, Chakrabarti P. Inflammasome activation in Kupffer cells confers a protective response in nonalcoholic steatohepatitis through pigment epithelium-derived factor expression. FASEB J 2018; 32:fj201800190. [PMID: 29897812 DOI: 10.1096/fj.201800190] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
Hepatocellular death or ballooning distinguishes the transition of simple steatosis to irreversible nonalcoholic steatohepatitis (NASH). However, the molecular mechanism of hepatocellular apoptosis in NASH is largely unclear, and discovery of endogenous mediators that could prevent or inhibit cell death is thereby critical in intercepting NASH progression. Here, we identified pigment epithelium-derived factor (PEDF), a secreted, moonlighting hepatokine as 1 hepatoprotective agent in mice with diet-induced NASH. Hepatic PEDF expression is induced by IL-1β, which is derived from inflammasome activation in liver-resident Kupffer cells, an effect that is negatively regulated by TNF-α and predominantly secreted by monocyte-derived, recruited, hepatic macrophages. Mechanistically, reciprocal and opposing roles for IL-1β and TNF-α in PEDF expression are mediated by differential activation of NF-κB. Although augmented TNF-α production leads to temporal reduction of PEDF expression in NASH, PEDF conversely abrogates TNF-α-mediated hepatocyte death by modulating the extrinsic apoptosis pathway. Thus, our study highlights PEDF as a functionally important hepatokine in NASH progression by linking inflammasome activation and hepatocellular death.-Adak, M., Das, D., Niyogi, S., Nagalakshmi, C., Ray, D., Chakrabarti, P. Inflammasome activation in Kupffer cells confers a protective response in nonalcoholic steatohepatitis through pigment epithelium-derived factor expression.
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Affiliation(s)
- Moumita Adak
- Division of Cell Biology and Physiology, Council of Scientific and Industrial Research (CSIR), Indian Institute of Chemical Biology, Kolkata, India
| | - Debajyoti Das
- Division of Cell Biology and Physiology, Council of Scientific and Industrial Research (CSIR), Indian Institute of Chemical Biology, Kolkata, India
| | - Sougata Niyogi
- Division of Cell Biology and Physiology, Council of Scientific and Industrial Research (CSIR), Indian Institute of Chemical Biology, Kolkata, India
| | - Challa Nagalakshmi
- National Institute of Pharmaceutical Education and Research, Kolkata, India
| | - Dipika Ray
- Division of Cell Biology and Physiology, Council of Scientific and Industrial Research (CSIR), Indian Institute of Chemical Biology, Kolkata, India
| | - Partha Chakrabarti
- Division of Cell Biology and Physiology, Council of Scientific and Industrial Research (CSIR), Indian Institute of Chemical Biology, Kolkata, India
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Verhaegh P, Bavalia R, Winkens B, Masclee A, Jonkers D, Koek G. Noninvasive Tests Do Not Accurately Differentiate Nonalcoholic Steatohepatitis From Simple Steatosis: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2018; 16:837-861. [PMID: 28838784 DOI: 10.1016/j.cgh.2017.08.024] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 08/15/2017] [Accepted: 08/16/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease is a rapidly increasing health problem. Liver biopsy analysis is the most sensitive test to differentiate between nonalcoholic steatohepatitis (NASH) and simple steatosis (SS), but noninvasive methods are needed. We performed a systematic review and meta-analysis of noninvasive tests for differentiating NASH from SS, focusing on blood markers. METHODS We performed a systematic search of the PubMed, Medline and Embase (1990-2016) databases using defined keywords, limited to full-text papers in English and human adults, and identified 2608 articles. Two independent reviewers screened the articles and identified 122 eligible articles that used liver biopsy as reference standard. If at least 2 studies were available, pooled sensitivity (sensp) and specificity (specp) values were determined using the Meta-Analysis Package for R (metafor). RESULTS In the 122 studies analyzed, 219 different blood markers (107 single markers and 112 scoring systems) were identified to differentiate NASH from simple steatosis, and 22 other diagnostic tests were studied. Markers identified related to several pathophysiological mechanisms. The markers analyzed in the largest proportions of studies were alanine aminotransferase (sensp, 63.5% and specp, 74.4%) within routine biochemical tests, adiponectin (sensp, 72.0% and specp, 75.7%) within inflammatory markers, CK18-M30 (sensp, 68.4% and specp, 74.2%) within markers of cell death or proliferation and homeostatic model assessment of insulin resistance (sensp, 69.0% and specp, 72.7%) within the metabolic markers. Two scoring systems could also be pooled: the NASH test (differentiated NASH from borderline NASH plus simple steatosis with 22.9% sensp and 95.3% specp) and the GlycoNASH test (67.1% sensp and 63.8% specp). CONCLUSION In the meta-analysis, we found no test to differentiate NASH from SS with a high level of pooled sensitivity and specificity (≥80%). However, some blood markers, when included in scoring systems in single studies, identified patients with NASH with ≥80% sensitivity and specificity. Replication studies and more standardized study designs are urgently needed. At present, no marker or scoring system can be recommended for use in clinical practice to differentiate NASH from simple steatosis.
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Affiliation(s)
- Pauline Verhaegh
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Roisin Bavalia
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Bjorn Winkens
- Department of Methodology and Statistic, School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, the Netherlands
| | - Ad Masclee
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Daisy Jonkers
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Ger Koek
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands.
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Pacifico L, Andreoli GM, D’Avanzo M, De Mitri D, Pierimarchi P. Role of osteoprotegerin/receptor activator of nuclear factor kappa B/receptor activator of nuclear factor kappa B ligand axis in nonalcoholic fatty liver disease. World J Gastroenterol 2018; 24:2073-2082. [PMID: 29785076 PMCID: PMC5960813 DOI: 10.3748/wjg.v24.i19.2073] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/03/2018] [Accepted: 05/11/2018] [Indexed: 02/06/2023] Open
Abstract
Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease (NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with fatty liver display features of metabolic syndrome (MetS), like insulin resistance (IR), glucose intolerance, hypertension and dyslipidemia. Recently, epidemiological studies have linked obesity, MetS, and NAFLD to decreased bone mineral density and osteoporosis, highlighting an intricate interplay among bone, adipose tissue, and liver. Osteoprotegerin (OPG), an important symbol of the receptor activator of nuclear factor-B ligand/receptor activator of nuclear factor kappa B/OPG system activation, typically considered for its role in bone metabolism, may also play critical roles in the initiation and perpetuation of obesity-related comorbidities. Clinical data have indicated that OPG concentrations are associated with hypertension, left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and severity of liver damage in chronic hepatitis C. Nonetheless, the relationship between circulating OPG and IR as a key feature of MetS as well as between OPG and NAFLD remains uncertain. Thus, the aims of the present review are to provide the existent knowledge on these associations and to discuss briefly the underlying mechanisms linking OPG and NAFLD.
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Affiliation(s)
- Lucia Pacifico
- Policlinico Umberto I Hospital, Sapienza University of Rome, Rome 00161, Italy
| | - Gian Marco Andreoli
- Policlinico Umberto I Hospital, Sapienza University of Rome, Rome 00161, Italy
| | - Miriam D’Avanzo
- Policlinico Umberto I Hospital, Sapienza University of Rome, Rome 00161, Italy
| | - Delia De Mitri
- Policlinico Umberto I Hospital, Sapienza University of Rome, Rome 00161, Italy
| | - Pasquale Pierimarchi
- Institute of Translational Pharmacology, National Research Council, Rome 00083, Italy
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40
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Mayo R, Crespo J, Martínez-Arranz I, Banales JM, Arias M, Mincholé I, Aller de la Fuente R, Jimenez-Agüero R, Alonso C, de Luis DA, Vitek L, Stritesky J, Caballería J, Romero-Gómez M, Martín-Duce A, Mugüerza Huguet JM, Busteros-Moraza JI, Idowu MO, Castro A, Martínez-Chantar ML, Ortiz P, Bruha R, Lu SC, Bedossa P, Noureddin M, Sanyal AJ, Mato JM. Metabolomic-based noninvasive serum test to diagnose nonalcoholic steatohepatitis: Results from discovery and validation cohorts. Hepatol Commun 2018; 2:807-820. [PMID: 30027139 PMCID: PMC6049064 DOI: 10.1002/hep4.1188] [Citation(s) in RCA: 116] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 03/15/2018] [Accepted: 03/15/2018] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease worldwide and includes a broad spectrum of histologic phenotypes, ranging from simple hepatic steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). While liver biopsy is the reference gold standard for NAFLD diagnosis and staging, it has limitations due to its sampling variability, invasive nature, and high cost. Thus, there is a need for noninvasive biomarkers that are robust, reliable, and cost effective. In this study, we measured 540 lipids and amino acids in serum samples from biopsy‐proven subjects with normal liver (NL), NAFL, and NASH. Using logistic regression analysis, we identified two panels of triglycerides that could first discriminate between NAFLD and NL and second between NASH and NAFL. These noninvasive tests were compared to blinded histology as a reference standard. We performed these tests in an original cohort of 467 patients with NAFLD (90 NL, 246 NAFL, and 131 NASH) that was subsequently validated in a separate cohort of 192 patients (7 NL, 109 NAFL, 76 NASH). The diagnostic performances of the validated tests showed an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.88 ± 0.05, 0.94, and 0.57, respectively, for the discrimination between NAFLD and NL and 0.79 ± 0.04, 0.70, and 0.81, respectively, for the discrimination between NASH and NAFL. When the analysis was performed excluding patients with glucose levels >136 mg/dL, the area under the receiver operating characteristic curve for the discrimination between NASH and NAFL increased to 0.81 ± 0.04 with sensitivity and specificity of 0.73 and 0.80, respectively. Conclusion: The assessed noninvasive lipidomic serum tests distinguish between NAFLD and NL and between NASH and NAFL with high accuracy. (Hepatology Communications 2018;2:807‐820)
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Affiliation(s)
- Rebeca Mayo
- OWL Metabolomics Bizkaia Technology Park Derio Spain
| | - Javier Crespo
- Department of Digestive Disease Marqués de Valdecilla University Hospital, Cantabaria University Research Institute Marqués de Valdecilla (IDIVAL) Santander Spain
| | | | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute Donostia University Hospital, University of the Basque Country (UPV-EHU) CIBERehd, IKERBASQUE Donostia Spain
| | - Mayte Arias
- Department of Digestive Disease Marqués de Valdecilla University Hospital, Cantabaria University Research Institute Marqués de Valdecilla (IDIVAL) Santander Spain
| | | | - Rocío Aller de la Fuente
- Department of Digestive Disease, Clinic University Hospital University of Valladolid Valladolid Spain
| | - Raúl Jimenez-Agüero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute Donostia University Hospital, University of the Basque Country (UPV-EHU) CIBERehd, IKERBASQUE Donostia Spain
| | | | - Daniel A de Luis
- Center of Investigation of Endocrinology and Clinical Nutrition, Medicine School and Department of Endocrinology and Nutrition, Clinic University Hospital University of Valladolid Valladolid Spain
| | - Libor Vitek
- Faculty General Hospital and the First Faculty of Medicine Charles University Prague Czech Republic
| | - Jan Stritesky
- Faculty General Hospital and the First Faculty of Medicine Charles University Prague Czech Republic
| | - Joan Caballería
- Liver Unit, Hospital Clinic, CIBERehd IDIBAPS Barcelona Spain
| | - Manuel Romero-Gómez
- Unit for the Clinical Management of Digestive Diseases and CIBERehd Valme University Hospital Seville Spain
| | - Antonio Martín-Duce
- Faculty of Medicine and Health Science University Hospital Príncipe de Asturias, Alcalá University Madrid Spain
| | | | | | - Michael O Idowu
- Division of Surgical Pathology, Department of Pathology Virginia Commonwealth University Medical Center Richmond VA United States
| | | | | | - Pablo Ortiz
- OWL Metabolomics Bizkaia Technology Park Derio Spain
| | - Radan Bruha
- Faculty General Hospital and the First Faculty of Medicine Charles University Prague Czech Republic
| | - Shelly C Lu
- Division of Digestive and Liver Diseases Cedars-Sinai Medical Center Los Angeles CA United States
| | - Pierre Bedossa
- Department of Pathology University Hospitals Paris Nord Val de Seine, Beaujon, Hauts-de-Seine Clichy France
| | - Mazen Noureddin
- Division of Digestive and Liver Diseases Cedars-Sinai Medical Center Los Angeles CA United States
| | - Arun J Sanyal
- Division of Gastroenterology and Hepatology Virginia Commonwealth University Medical Center Richmond VA United States
| | - José M Mato
- CIC bioGUNE, CIBERehd Bizkaia Technology Park Derio Bizkaia Spain
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Qiu Y, Wang S, Wan T, Ye M, Jiang R, Pei L, Yang L. Blood-based novel biomarkers for nonalcoholic steatohepatitis. Biomark Med 2018; 12:501-515. [PMID: 29712439 DOI: 10.2217/bmm-2017-0361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Nonalcoholic fatty liver disease has become a social health challenge of global concern. The term nonalcoholic steatohepatitis (NASH) is a more severe condition than simple steatosis and distinguishing NASH from nonalcoholic fatty liver disease is particularly important. Liver biopsy remains a gold standard in diagnosing NASH. Meanwhile, radiological techniques such as ultrasonography and MRI are also applied widely. However, the invasive and expensive examination is not suitable for screening, and there is a great need for reliable and appropriate biomarkers to screen patients for NASH. Based on the current studies of blood-based novel biomarkers, we attempt to summarize the latest findings on biomarkers for NASH, including blood biomarkers encompassing proteins, lipids and miRNAs; the correlation between extracellular vesicles and NASH; and treatment strategies for NASH.
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Affiliation(s)
- Yun Qiu
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
| | - Sufan Wang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
| | - Ting Wan
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
| | - Mingtong Ye
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
| | - Rui Jiang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
| | - Lei Pei
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
| | - Lili Yang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.,Guangdong Provincial Key Laboratory of Food, Nutrition & Health, Guangzhou, Guangdong 510080, PR China
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Del Ben M, Overi D, Polimeni L, Carpino G, Labbadia G, Baratta F, Pastori D, Noce V, Gaudio E, Angelico F, Mancone C. Overexpression of the Vitronectin V10 Subunit in Patients with Nonalcoholic Steatohepatitis: Implications for Noninvasive Diagnosis of NASH. Int J Mol Sci 2018; 19:ijms19020603. [PMID: 29463024 PMCID: PMC5855825 DOI: 10.3390/ijms19020603] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 02/13/2018] [Accepted: 02/16/2018] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the critical stage of nonalcoholic fatty liver disease (NAFLD). The persistence of necroinflammatory lesions and fibrogenesis in NASH is the leading cause of liver cirrhosis and, ultimately, hepatocellular carcinoma. To date, the histological examination of liver biopsies, albeit invasive, remains the means to distinguish NASH from simple steatosis (NAFL). Therefore, a noninvasive diagnosis by serum biomarkers is eagerly needed. Here, by a proteomic approach, we analysed the soluble low-molecular-weight protein fragments flushed out from the liver tissue of NAFL and NASH patients. On the basis of the assumption that steatohepatitis leads to the remodelling of the liver extracellular matrix (ECM), NASH-specific fragments were in silico analysed for their involvement in the ECM molecular composition. The 10 kDa C-terminal fragment of the ECM protein vitronectin (VTN) was then selected as a promising circulating biomarker in discriminating NASH. The analysis of sera of patients provided these major findings: the circulating VTN fragment (i) is overexpressed in NASH patients and positively correlates with the NASH activity score (NAS); (ii) originates from the disulfide bond reduction between the V10 and the V65 subunits. In conclusion, V10 determination in the serum could represent a reliable tool for the noninvasive discrimination of NASH from simple steatosis.
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Affiliation(s)
- Maria Del Ben
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy.
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy.
| | - Licia Polimeni
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy.
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Piazza Lauro De Bosis 6, 00135 Rome, Italy.
| | - Giancarlo Labbadia
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy.
| | - Francesco Baratta
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy.
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy.
| | - Daniele Pastori
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy.
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy.
| | - Valeria Noce
- Department of Cellular Biotechnologies and Haematology, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy.
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy.
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy.
| | - Carmine Mancone
- Department of Cellular Biotechnologies and Haematology, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy.
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Nallagangula KS, Nagaraj SK, Venkataswamy L, Chandrappa M. Liver fibrosis: a compilation on the biomarkers status and their significance during disease progression. Future Sci OA 2018; 4:FSO250. [PMID: 29255622 PMCID: PMC5729599 DOI: 10.4155/fsoa-2017-0083] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 09/06/2017] [Indexed: 02/08/2023] Open
Abstract
Liver fibrosis occurs in response to different etiologies of chronic liver injury. Diagnosing degree of liver fibrosis is a crucial step in evaluation of severity of the disease. An invasive liver biopsy is the gold standard method associated with pain and complications. Biomarkers to detect liver fibrosis include direct markers of extracellular matrix turnover and indirect markers as a reflection of liver dysfunction. Although a single marker may not be useful for successful management, a mathematical equation combining tests might be effective. The main purpose of this review is to understand the diagnostic accuracy of biomarkers and scoring systems for liver fibrosis. Advances in -omics approach have generated clinically significant biomarker candidates for liver fibrosis that need further evaluation.
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Affiliation(s)
| | - Shashidhar Kurpad Nagaraj
- Department of Biochemistry, Sri Devaraj Urs Medical College, SDUAHER, Tamaka, Kolar, Karnataka, India
| | - Lakshmaiah Venkataswamy
- Department of Medicine, Sri Devaraj Urs MedicalCollege, SDUAHER, Tamaka, Kolar, Karnataka, India
| | - Muninarayana Chandrappa
- Department of Community Medicine, Sri DevarajUrs Medical College, SDUAHER, Tamaka, Kolar, Karnataka, India
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Braun LR, Feldpausch MN, Czerwonka N, Torriani M, Grinspoon SK, Stanley TL. Fibroblast growth factor 21 decreases after liver fat reduction via growth hormone augmentation. Growth Horm IGF Res 2017; 37:1-6. [PMID: 29031905 PMCID: PMC5705434 DOI: 10.1016/j.ghir.2017.10.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 08/31/2017] [Accepted: 10/06/2017] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Fibroblast growth factor 21 (FGF21) ameliorates steatohepatitis but is increased in humans with fatty liver, potentially due to compensatory mechanisms and/or FGF21 resistance. Further, animal models suggest that GH increases serum FGF21. Tesamorelin, a growth hormone releasing hormone agonist, reduces liver fat in HIV-infected individuals. The objectives of this study were to investigate changes in FGF21 during tesamorelin treatment, to elucide the interplay between FGF21, GH augmentation, and liver fat reduction in humans. METHODS 50 HIV-infected men and women with increased abdominal adiposity participated in this randomized, placebo-controlled trial of tesamorelin, 2mg vs. identical placebo daily for six months. Fasting laboratory measures, liver fat by 1H-magnetic resonance spectroscopy, and visceral adipose tissue (VAT) by computed tomography were obtained. Euglycemic hyperinsulinemic clamp was performed in a randomly selected subset. RESULTS At baseline, serum log10 FGF21 was significantly associated with log10 liver fat (r=0.32, p=0.03). Log10 FGF21 tended to decrease in the tesamorelin group compared to placebo (p=0.06). Among the entire cohort, reductions in FGF21 were significantly associated with reductions in liver fat (ρ=0.41, p=0.01), log10 gamma glutamyl tran speptidase (GGT, r=0.40, p=0.009), and FIB4 index (r=0.37, p=0.02). CONCLUSIONS In HIV-infected individuals, FGF21 is significantly positively associated with liver fat. FGF21 decreases in association with reductions in liver fat, GGT, and FIB4, suggesting that FGF21 is upregulated in the context of steatosis and steatohepatitis and is reduced when these conditions improve. Moreover, these data suggest that tesamorelin improves liver fat via pathways other than increasing serum FGF21. TRIAL REGISTRATION clinicaltrials.govNCT01263717.
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Affiliation(s)
- Laurie R Braun
- Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Meghan N Feldpausch
- Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Natalia Czerwonka
- Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Martin Torriani
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Steven K Grinspoon
- Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Takara L Stanley
- Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
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Xu B, Shen T, Chen L, Xia J, Zhang C, Wang H, Yu M, Lei T. The Effect of Sitagliptin on Lipid Metabolism of Fatty Liver Mice and Related Mechanisms. Med Sci Monit 2017; 23:1363-1370. [PMID: 28315901 PMCID: PMC5370388 DOI: 10.12659/msm.900033] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background In clinics, patients with type 2 diabetes complicated with non-alcoholic fatty liver disease (NAFLD) have been shown to receive significant improvements in blood glucose levels, lipid levels, and liver function after sitagliptin treatment, although the mechanism of drug action remains poorly understood. This study investigated the possible mechanism of sitagliptin on lipid metabolism of NAFLD mice. Material/Methods Male C57/BL6 mice were induced for NAFLD via 16 weeks of a high-fat diet, and were treated with 15 mg/kg/day sitagliptin for 16 consecutive weeks. Blood lipid levels were measured and samples were stained with hematoxylin and eosin (H&E) and oil red staining for liver pathology and lipid deposition. Serum levels of fibroblast growth factor (FGF)-9 and FGF-21 were quantified by enzyme-linked immunosorbent assay (ELISA). Peroxisome proliferator-activated receptor (PPAR)-α, and cAMP reactive element binding homolog (CREBH) were measured by Western blotting, while fatty acid synthase and carnitine palmitoyltransferase 1 (CPT1) mRNA levels were assayed by RT-PCR. Results Compared to the control group, the NAFLD model mice had liver fatty disease, lower serum FGF-21 and FGF-19 levels, elevated serum lipid levels, depressed PPAR-α, CREBH, and CPT1 expression, and enhanced FAS expression (p<0.05). Sitagliptin treatment depressed blood lipid levels, increased serum FGF-21 and FGF-19 levels, PPAR-α, CREBH, and CPT1 expression, and suppressed FAS expression (p<0.05). Conclusions Sitagliptin can protect liver tissue and modulate lipid metabolism in NAFLD mice via elevating FGF-21 and FGF-19, upregulating liver PPAR-α and CREBH levels, and mediating expression levels of key enzymes for lipid metabolism.
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Affiliation(s)
- Bilin Xu
- Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
| | - Tian Shen
- Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
| | - Lin Chen
- Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
| | - Juan Xia
- Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
| | - Cuiping Zhang
- Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
| | - Hongping Wang
- Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
| | - Ming Yu
- Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
| | - Tao Lei
- Department of Endocrinology, Puto Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China (mainland)
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Diagnostic Value of CK-18, FGF-21, and Related Biomarker Panel in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2017; 2017:9729107. [PMID: 28326329 PMCID: PMC5343245 DOI: 10.1155/2017/9729107] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Accepted: 01/19/2017] [Indexed: 12/17/2022]
Abstract
Liver biopsy still remains the gold standard for diagnosing nonalcoholic steatohepatitis (NASH), but with limitations. There is an urgent need to develop noninvasive tests that accurately distinguish NASH from simple steatosis. The purpose of this meta-analysis was to evaluate the diagnostic value of serum biomarkers including cytokeratin 18 (CK-18), fibroblast growth factor 21 (FGF-21), and combined biomarker panel (CBP) in the diagnosis of NAFLD, especially NASH. A total of 25 studies met the inclusion criteria. Pooled sensitivity and specificity values for chosen serum markers for diagnosing NASH are as follows: CK-18 (M30), 0.75 and 0.77; CK-18 (M65), 0.71 and 0.77; FGF-21, 0.62 and 0.78; and CBP, 0.92 and 0.85. CBP demonstrated better accuracy with higher sensitivity and specificity than those tested individually. Furthermore, the AUROC of CBP was 0.94 (95% CI, 0.92-0.96), compared to CK-18 or FGF-21 assay, which showed the most significant ability to distinguish NASH from simple steatosis. The results suggest that increased circulating CK-18 and FGF-21 are associated with NASH and may be used for initial assessment, but not enough. Importantly, CBP is potentially used as accurate diagnostic tools for NASH. Further prospective designed studies are warranted to confirm our findings.
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Erol M, Bostan Gayret O, Tekin Nacaroglu H, Yigit O, Zengi O, Salih Akkurt M, Tasdemir M. Association of Osteoprotegerin with Obesity, Insulin Resistance and Non-Alcoholic Fatty Liver Disease in Children. IRANIAN RED CRESCENT MEDICAL JOURNAL 2016; 18:e41873. [PMID: 28203453 PMCID: PMC5294423 DOI: 10.5812/ircmj.41873] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 09/28/2016] [Accepted: 10/24/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Osteoprotegerin (OPG) is a member of the tumor necrosis factor superfamily. Reduced OPG levels are related to obesity, insulin resistance, and non-alcoholic fatty liver disease (NAFLD). OBJECTIVES The aim of this study was to evaluate the relationship between OPG levels, obesity, insulin resistance, and NAFLD in pediatric patients. METHODS This was a prospective, cross-sectional, controlled study that was conducted in the department of pediatrics at Bagcilar training and research hospital in Istanbul, Turkey, between April and August 2015. The study was performed on 107 children with obesity and 37 controls aged 5 - 17 years. In the obese subset, 62 patients had NAFLD. Homeostatic model assessment-insulin resistance (HOMA-IR) was used to calculate insulin resistance. Insulin resistance was defined as a HOMA-IR value greater than 2.5. Plasma OPG levels were measured using enzyme-linked immunosorbent assays. NAFLD was diagnosed by hepatic ultrasound. RESULTS The mean age was 11.25 ± 3.38 years in the patient group and 10.41 ± 3.15 years in the control group. The OPG level in the obese group with the mean of 55.20 ± 24.55 pg/mL (median = 48.81 pg/mL) was significantly lower than that in the control group with the mean of 70.78 ± 33.41 pg/mL (median = 64.57 pg/mL) (P = 0.0001). The optimal cut-off point (sensitivity, specificity) of the OPG level for the diagnosis of obesity was ≤ 46, 19 pg/mL. According to logistic regression analysis, fasting insulin (P = 0.036) and OPG (P = 0.01) levels were most affected by obesity. In the obese patients, who had HOMA-IR < 2.5, the mean level of OPG was 58.91 ± 6.88729 pg/mL (median = 49.55). In the obese patients, who had HOMA-IR ≥ 2.5, the mean level of OPG was 54.19 ± 22.21 pg/mL (median = 48.47). No significant correlations were found between OPG and HOMA-IR (P = 0.791). No statistically significant difference was observed in the mean OPG between patients with hepatosteatosis (mean = 54.55 ± 25.01 pg/mL) (median = 49.46) and those without the disease (56.30 ± 24.02 pg/mL) (mean = 48.34) (P = 0.089). CONCLUSIONS We confirmed that serum OPG concentrations reduce in obese children. However, no correlation was identified between OPG and insulin resistance. OPG levels are not meaningful in the diagnosis of NAFLD in children with obesity.
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Affiliation(s)
- Meltem Erol
- Bagcilar Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey
- Corresponding Author: Meltem Erol, Bagcilar Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey. Tel: +90-2124404000-1344, Fax: +90-2124404242, E-mail:
| | - Ozlem Bostan Gayret
- Bagcilar Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey
| | - Hikmet Tekin Nacaroglu
- Bagcilar Training and Research Hospital, Department of Pediatric Allergy, Istanbul, Turkey
| | - Ozgul Yigit
- Bagcilar Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey
| | - Oguzhan Zengi
- Bagcilar Training and Research Hospital, Department of Biochemistry, Istanbul, Turkey
| | - Mehmet Salih Akkurt
- Bagcilar Training and Research Hospital, Department of Radiology, Istanbul, Turkey
| | - Mehmet Tasdemir
- Department of Pediatric Nephology, Koc University Hospital, Istanbul, Turkey
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Golabi P, Sayiner M, Fazel Y, Koenig A, Henry L, Younossi ZM. Current complications and challenges in nonalcoholic steatohepatitis screening and diagnosis. Expert Rev Gastroenterol Hepatol 2016; 10:63-71. [PMID: 26469309 DOI: 10.1586/17474124.2016.1099433] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) can lead to complications such as liver failure, cirrhosis and hepatocellular carcinoma. The diagnostic gold standard for NASH is liver biopsy; however, other noninvasive methods have been developed. In this article, the authors evaluate current methods in NASH screening and diagnosis. Routine radiologic modalities were found to detect hepatic steatosis accurately, but were unable to establish the diagnosis of NASH or stage of fibrosis. Newly developed elastography based techniques seem promising to estimate liver fibrosis. Other noninvasive tests such as FibroTest, ELF, Hepascore, FIB-4, NFS, FLI and ION (biochemical panels) have AUROCs ranging between 0.80-0.98 for detecting advanced fibrosis but lack specificity for detecting mild fibrosis. Noninvasive tools, especially elastography, identify NASH associated advanced fibrosis potentially reducing liver biopsies. More research is needed to validate the clinical utility of these tests.
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Affiliation(s)
- Pegah Golabi
- a Betty and Guy Beatty Center for Integrated Research , Inova Health System , Falls Church , VA , USA
| | - Mehmet Sayiner
- a Betty and Guy Beatty Center for Integrated Research , Inova Health System , Falls Church , VA , USA
| | - Yousef Fazel
- a Betty and Guy Beatty Center for Integrated Research , Inova Health System , Falls Church , VA , USA
| | - Aaron Koenig
- a Betty and Guy Beatty Center for Integrated Research , Inova Health System , Falls Church , VA , USA
| | - Linda Henry
- a Betty and Guy Beatty Center for Integrated Research , Inova Health System , Falls Church , VA , USA
| | - Zobair M Younossi
- a Betty and Guy Beatty Center for Integrated Research , Inova Health System , Falls Church , VA , USA.,b Center for Liver Disease, Department of Medicine , Inova Fairfax Hospital , Falls Church , VA , USA
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Li Z, Feng S, Zhou L, Liu S, Cheng J. NS5ATP6 modulates intracellular triglyceride content through FGF21 and independently of SIRT1 and SREBP1. Biochem Biophys Res Commun 2016; 475:133-9. [PMID: 27179781 DOI: 10.1016/j.bbrc.2016.05.056] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 05/10/2016] [Indexed: 02/07/2023]
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is rising strikingly in Western countries and China. The molecular biological mechanism of NAFLD remains unclear, with no effective therapies developed so far. Fibroblast growth factor 21 (FGF21) is a recently discovered hormone, with safe lipid lowering effects. FGF21 analogs are being developed for clinical application. Here we demonstrated that a novel gene, NS5ATP6, modulated intracellular triglyceride (TG) content independently of sirtuin1 (SIRT1) and sterol regulatory element binding protein 1 (SREBP1) in HepG2 cells. Interestingly, NS5ATP6 regulated FGF21 expression both at the mRNA and protein levels. The modulatory effects of NS5ATP6 on intracellular TG content depended upon FGF21. Further studies revealed that NS5ATP6 decreased the promoter activity of FGF21. In addition, NS5ATP6 regulated the expression of miR-577, which directly targeted and regulated FGF21. Therefore, miR-577 might be involved in NS5ATP6 regulation of FGF21 at the post-transcriptional level. In conclusion, NS5ATP6 regulates the intracellular TG level via FGF21, and independently of SIRT1 and SREBP1.
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Affiliation(s)
- Zhongshu Li
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
| | - Shenghu Feng
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Ditan Hospital, Teaching Hospital of Peking University, Beijing 100015, China
| | - Li Zhou
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Ditan Hospital, Teaching Hospital of Peking University, Beijing 100015, China
| | - Shunai Liu
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China.
| | - Jun Cheng
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China.
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50
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Niu Y, Zhang W, Yang Z, Li X, Fang W, Zhang H, Wang S, Zhou H, Fan J, Qin L, Su Q. Plasma osteoprotegerin levels are inversely associated with nonalcoholic fatty liver disease in patients with type 2 diabetes: A case-control study in China. Metabolism 2016; 65:475-81. [PMID: 26975539 DOI: 10.1016/j.metabol.2015.12.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Revised: 12/02/2015] [Accepted: 12/12/2015] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor (TNF) receptor superfamily, is a decoy receptor for the receptor activator of nucleus factor-κB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG has an effect on systemic insulin sensitivity and glucose homeostasis. The objective of this study was to evaluate the relationship between plasma osteoprotegerin (OPG) levels and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes. MATERIALS/METHODS A case-control study was performed with 746 patients with type 2 diabetes. Of the study population, 367 patients had B-mode ultrasound-proven NAFLD and 379 were controls. The plasma OPG levels were measured using ELISA methods. NAFLD was diagnosed by hepatic ultrasound after the exclusion of alcohol abuse and other liver diseases. RESULTS The OPG levels were significantly decreased in patients with NAFLD (2.3±1.1μg/L vs. 2.8±1.3μg/L, p=3.75×10(5)) compared to controls. Pearson correlation analysis showed that the OPG levels were associated with age and systolic blood pressure (both p<0.05). The participants in the lowest OPG quartile had a significantly increased risk for NAFLD (OR=3.49, 95% CI 1.86-6.94) after adjusting for potential cofounders. CONCLUSIONS The plasma OPG level is negatively associated with NAFLD independent of potential cofounders.
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Affiliation(s)
- Yixin Niu
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Weiwei Zhang
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhen Yang
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Xiaoyong Li
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wenjun Fang
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hongmei Zhang
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Suijun Wang
- Department of Endocrinology, Clinical Geriatric Medicine, Henan Provincial People's Hospital, Zhengzhou, China
| | - Houguang Zhou
- Department of Geriatrics, Huashan Hospital Affiliated to Fudan University, Shanghai, China
| | - Jiangao Fan
- Department of Gastroenterology, Shanghai Key Laboratory of Children's Digestion and Nutrition, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Li Qin
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qing Su
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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