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Shuai R, He Y, Yang D, Zhang Y, Zhang L. Association between the atherogenic index of plasma and non-alcoholic fatty liver disease in Korean pregnant women: secondary analysis of a prospective cohort study. Front Nutr 2025; 12:1511952. [PMID: 39957769 PMCID: PMC11825326 DOI: 10.3389/fnut.2025.1511952] [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: 10/15/2024] [Accepted: 01/21/2025] [Indexed: 02/18/2025] Open
Abstract
Background Recent studies have shown an association between atherogenic index of plasma (AIP) and nonalcoholic fatty liver disease (NAFLD), but the association in a population of pregnant women remains unclear. Objectives Our study aimed to examine the association between AIP and NAFLD in pregnant Korean women. Methods Our study used publicly available data from Korea, which recruited singleton pregnant women between November 2014 and September 2016 who were at 10-14 weeks of gestation. The presence of NAFLD was diagnosed by liver ultrasound. AIP was calculated as log10 (TG/HDL). Participants were grouped according to AIP tertile: T1 (< 0.16, n = 195), T2 (0.16-0.32, n = 195), and T3 (>0.32, n = 196). Logistic regression models were used to estimate the relationship between AIP and NAFLD. Subgroup and sensitivity analyses were conducted to explore the stability of this relationship. Restricted cubic spline (RCS) curve fitting was employed to investigate potential non-linear associations. Results After excluding data on missing variables, 586 singleton pregnant women were finally included. The subjects included in the study had an average AIP of 0.22 (0.11, 0.37), and NAFLD occurred in 110 (18.8%) pregnant women. We observed a positive linear association between AIP and NAFLD (OR = 1.33, 95% CI: 1.19-1.48), which persisted after adjusting for potential confounders (OR = 1.2, 95% CI: 1.06-1.37). When AIP was used as a categorical variable, after adjusting for covariates, the NAFLD risk was significantly higher in the highest tertile of AIP than in the lowest group (OR = 2.02, 95% CI: 1.11-3.68). Their correlations were stable across subgroups and sensitivity analyses. Conclusion In this secondary analysis of a prospective cohort study of pregnant Korean women, AIP was found to be positively associated with NAFLD. These outcomes might be used to screen for NAFLD in pregnant women.
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Affiliation(s)
- Rong Shuai
- Department of Laboratory Medicine, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| | - Yuxing He
- Department of Laboratory Medicine, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| | - Dongqian Yang
- Department of Laboratory Medicine, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| | - Yingying Zhang
- Department of Laboratory Medicine, Affiliated Wuxi Fifth Hospital of Jiangnan University, Wuxi, China
| | - Li Zhang
- Department of Laboratory Medicine, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
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Lian X, Tang X. Immune infiltration analysis based on pyroptosis-related gene in metabolic dysfunction-associated fatty liver disease. Heliyon 2024; 10:e34348. [PMID: 39145004 PMCID: PMC11320144 DOI: 10.1016/j.heliyon.2024.e34348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 07/06/2024] [Accepted: 07/08/2024] [Indexed: 08/16/2024] Open
Abstract
Introduction Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic disease that can involve pyroptosis. The primary objective of this study was to conduct a thorough and comprehensive analysis the pyroptosis-related genes in MAFLD. Methods We identified pyroptosis-related differentially expressed genes (PRDEGs) in both healthy individuals and MAFLD patients. Using various bioinformatic approaches, we conducted an immune infiltration analysis from multiple perspectives. Results A total of 20 pyroptosis-related LASSO genes were obtained, and 10 hub genes were used to do immune infiltration analysis. The hub genes were utilized in the construction of interaction networks between mRNA-miRNA and mRNA-TF. Immune characteristics analysis revealed multiple immune cell types significantly related to PRDEG expression, particularly genes HSP90AA1, TSLP, CDK9, and BRD4. Conclusion Pyroptosis-related immune infiltration might be a mechanism of MAFLD progression and offers a research direction for potential treatment techniques.
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Affiliation(s)
- Xin Lian
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Xulei Tang
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, 730000, China
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Huang SC, Su TH, Tseng TC, Chen CL, Hsu SJ, Liu CH, Liao SH, Hong CM, Lan TY, Yang HC, Liu CJ, Chen PJ, Kao JH. Metabolic Dysfunction-Associated Steatotic Liver Disease Facilitates Hepatitis B Surface Antigen Seroclearance and Seroconversion. Clin Gastroenterol Hepatol 2024; 22:581-590.e6. [PMID: 37871842 DOI: 10.1016/j.cgh.2023.09.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/22/2023] [Accepted: 09/29/2023] [Indexed: 10/25/2023]
Abstract
BACKGROUND & AIMS Hepatitis B surface antigen (HBsAg) seroclearance is the goal of functional cure for hepatitis B virus (HBV) infection. However, the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on this favorable outcome remains unclear. METHODS Patients with chronic hepatitis B (CHB) were consecutively recruited. MASLD was defined by the newly proposed disease criteria. Cumulative incidences and associated factors of HBsAg seroclearance/seroconversion were compared between the MASLD and non-MASLD groups. RESULTS From 2006 to 2021, 4084 treatment-naive hepatitis B e antigen (HBeAg)-negative CHB patients were included. At baseline, CHB patients with concurrent MASLD (n = 887) had significantly lower levels of HBsAg and HBV DNA than the non-MASLD group (n = 3197). During a median follow-up of 5.0 years, MASLD was associated with a higher likelihood of HBsAg seroclearance (adjusted hazard ratio [aHR], 1.43; 95% confidence interval [CI], 1.10-1.85; P = .007), and the accumulation of individual metabolic dysfunctions additively facilitated HBsAg seroclearance. In addition, a higher rate of HBsAg seroconversion was observed in patients with MASLD versus those without MASLD (aHR, 1.37; 95% CI, 1.00-1.86; P = .049). In sensitivity analysis, patients with intermittent MASLD had an intermediate probability of HBsAg seroclearance. After balancing clinical and virologic profiles by inverse probability of treatment weighting (IPTW), MASLD was still associated with a higher HBsAg seroclearance rate (IPTW-adjusted HR, 1.41; 95% CI, 1.09-1.84; P = .010). CONCLUSIONS In untreated HBeAg-negative CHB patients, concurrent MASLD is associated with higher rates of HBsAg seroclearance and seroconversion. Metabolic dysfunctions have additive effects on the functional cure of CHB.
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Affiliation(s)
- Shang-Chin Huang
- Department of Internal Medicine, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
| | - Tai-Chung Tseng
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Shih-Jer Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Sih-Han Liao
- National Taiwan University Cancer Center, Taipei, Taiwan
| | - Chun-Ming Hong
- Division of Hospital Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Ting-Yuan Lan
- Division of Rheumatology, Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
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Chen HJ, Huang TX, Jiang YX, Chen X, Wang AF. Multifunctional roles of inflammation and its causative factors in primary liver cancer: A literature review. World J Hepatol 2023; 15:1258-1271. [PMID: 38223416 PMCID: PMC10784815 DOI: 10.4254/wjh.v15.i12.1258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 11/06/2023] [Accepted: 11/24/2023] [Indexed: 12/25/2023] Open
Abstract
Primary liver cancer is a severe and complex disease, leading to 800000 global deaths annually. Emerging evidence suggests that inflammation is one of the critical factors in the development of hepatocellular carcinoma (HCC). Patients with viral hepatitis, alcoholic hepatitis, and steatohepatitis symptoms are at higher risk of developing HCC. However, not all inflammatory factors have a pathogenic function in HCC development. The current study describes the process and mechanism of hepatitis development and its progression to HCC, particularly focusing on viral hepatitis, alcoholic hepatitis, and steatohepatitis. Furthermore, the roles of some essential inflammatory cytokines in HCC progression are described in addition to a summary of future research directions.
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Affiliation(s)
- Hong-Jin Chen
- Department of Pharmacology, School of Basic Medical Sciences, Translational Medicine Research Center, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Ting-Xiong Huang
- School of Clinical Medical, Translational Medicine Research Center, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Yu-Xi Jiang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou 325035, Zhejiang Province, China
| | - Xiong Chen
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
- Department of Endocrinology, The People's Hospital of Yuhuan, The Yuhuan Branch of The First Affiliated Hospital of Wenzhou Medical University, Yuhuan 317600, Zhejiang Province, China
| | - Ai-Fang Wang
- Department of Endocrinology, The People's Hospital of Yuhuan, The Yuhuan Branch of The First Affiliated Hospital of Wenzhou Medical University, Yuhuan 317600, Zhejiang Province, China.
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Kholodenko IV, Yarygin KN. Hepatic Macrophages as Targets for the MSC-Based Cell Therapy in Non-Alcoholic Steatohepatitis. Biomedicines 2023; 11:3056. [PMID: 38002056 PMCID: PMC10669188 DOI: 10.3390/biomedicines11113056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a serious public health issue associated with the obesity pandemic. Obesity is the main risk factor for the non-alcoholic fatty liver disease (NAFLD), which progresses to NASH and then to end-stage liver disease. Currently, there are no specific pharmacotherapies of NAFLD/NASH approved by the FDA or other national regulatory bodies and the treatment includes lifestyle adjustment and medicines for improving lipid metabolism, enhancing sensitivity to insulin, balancing oxidation, and counteracting fibrosis. Accordingly, further basic research and development of new therapeutic approaches are greatly needed. Mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles prevent induced hepatocyte death in vitro and attenuate NASH symptoms in animal models of the disease. They interact with hepatocytes directly, but also target other liver cells, including Kupffer cells and macrophages recruited from the blood flow. This review provides an update on the pathogenesis of NAFLD/NASH and the key role of macrophages in the development of the disease. We examine in detail the mechanisms of the cross-talk between the MSCs and the macrophages, which are likely to be among the key targets of MSCs and their derivatives in the course of NAFLD/NASH cell therapy.
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Affiliation(s)
- Irina V. Kholodenko
- Laboratory of Cell Biology, Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia;
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Torosian K, Lal E, Kavanaugh A, Loomba R, Ajmera V, Guma M. Psoriatic disease and non-alcoholic fatty liver disease shared pathogenesis review. Semin Arthritis Rheum 2023; 59:152165. [PMID: 36716599 PMCID: PMC9992353 DOI: 10.1016/j.semarthrit.2023.152165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/03/2022] [Accepted: 01/04/2023] [Indexed: 01/20/2023]
Abstract
Psoriatic disease (PD) and non-alcoholic fatty liver disease (NAFLD) potentially share disease pathways given the numerous inflammatory pathways involved in both diseases and a higher prevalence of NAFLD in PD patients. Metabolic syndrome and obesity are a key link between the two diseases, but even when controlling for this, associations between both diseases are still seen. Therapeutics that impact metabolic or inflammatory pathways may be impactful in both PD and NAFLD. In this review, we describe common inflammatory pathways contributing to both PD and NAFLD and critically review the potential impact of treatments for and on both diseases.
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Affiliation(s)
- Kelly Torosian
- Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Esha Lal
- Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Arthur Kavanaugh
- Department of Rheumatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, USA; Division of Epidemiology, Department of Family and Preventative Medicine, University of California at San Diego, La Jolla, USA
| | - Veeral Ajmera
- Division of Gastroenterology and Hepatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, USA.
| | - Monica Guma
- Department of Rheumatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain; San Diego VA Healthcare Service, San Diego, CA, 92161, USA.
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Liu M, Wang Q, Ji D, Zhou J, Yang J. The Effect of Diammonium Glycyrrhizinate Lipid Ligand on Nonalcoholic Fatty Liver Disease Induced Leukocyte Infiltration in Rat Model. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Objective: To investigate the effects of diammonium glycyrrhizinate lipid ligand (DGLL) on nonalcoholic fatty liver disease (NAFLD)-induced leukocyte infiltration in rat and underlying mechanisms. Methods: Sixty SD rats were randomly distributed into six groups, control
group, NAFLD model group, DGLL (30, 60, 120 mg/kg) treatment group and positive control (biphenyl biester tablets (BDP), 200 mg/kg) group. The expression and activity of myeloperoxidase (MPO) in liver tissues were measured by immunohistochemistry and ELISA, respectively. The expressions of
leukocyte adhesion molecules in whole blood were determined by flow cytometry. The intercellular adhesion molecule-1 (ICAM-1) expressions in liver tissues was detected by western blotting. Results: Compared with NAFLD model groups, the expression and activity of MPO in liver tissues
of DGLL (30, 60, 120 mg/kg) treatment group were all significantly ameliorated by the administration of DGLL (P < 0.05). Meanwhile, the up-regulation of adhesion molecules expressed on monocytes and neutrophils in whole blood, as well as endothelial ICAM-1 expression in NAFLD model
groups were eliminated by DGLL treatment (P < 0.05). Conclusion: DGLL ameliorated leukocyte activation and infiltration in rat liver with NAFLD, which might be related to suppression of adhesion molecules expression on leukocyte and endothelium.
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Affiliation(s)
- Meimei Liu
- Department of Histology and Embryology, Anhui Medical College, Hefei, Anhui Province, 230601, China
| | - Qi Wang
- Department of Histology and Embryology, Anhui Medical College, Hefei, Anhui Province, 230601, China
| | - Dan Ji
- Department of Histology and Embryology, Anhui Medical College, Hefei, Anhui Province, 230601, China
| | - Jin Zhou
- Department of Histology and Embryology, Anhui Medical College, Hefei, Anhui Province, 230601, China
| | - Jun Yang
- Department of Histology and Embryology, Anhui Medical College, Hefei, Anhui Province, 230601, China
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T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:ijms222212190. [PMID: 34830072 PMCID: PMC8623596 DOI: 10.3390/ijms222212190] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/06/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by hepatic accumulation of excess lipids. T cells are commonly classified into various subsets based on their surface markers including T cell receptors, type of antigen presentation and pathophysiological functions. Several studies have implicated various T cell subsets and natural killer (NK) cells in the progression of NAFLD. While NK cells are mainly components of the innate hepatic immune system, the majority of T cell subsets can be part of both the adaptive and innate systems. Several studies have reported that various stages of NAFLD are accompanied by the accumulation of distinct T cell subsets and NK cells with different functions and phenotypes observed usually resulting in proinflammatory effects. More importantly, the overall stimulation of the intrahepatic T cell subsets is directly influenced by the homeostasis of the gut microbiota. Similarly, NK cells have been found to accumulate in the liver in response to pathogens and tumors. In this review, we discussed the nature and pathophysiological roles of T cell subsets including γδ T cells, NKT cells, Mucosal-associated invariant T (MAIT) cells as well as NK cells in NAFLD.
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Wu MC, Meng QH. Current understanding of mesenchymal stem cells in liver diseases. World J Stem Cells 2021; 13:1349-1359. [PMID: 34630867 PMCID: PMC8474713 DOI: 10.4252/wjsc.v13.i9.1349] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 07/01/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Liver diseases caused by various factors have become a significant threat to public health worldwide. Liver transplantation has been considered as the only effective treatment for end-stage liver diseases; however, it is limited by the shortage of donor organs, postoperative complications, long-term immunosuppression, and high cost of treatment. Thus, it is not available for all patients. Recently, mesenchymal stem cells (MSCs) transplantation has been extensively explored for repairing hepatic injury in various liver diseases. MSCs are multipotent adult progenitor cells originated from the embryonic mesoderm, and can be found in mesenchymal tissues including the bone marrow, umbilical cord blood, adipose tissue, liver, lung, and others. Although the precise mechanisms of MSC transplantation remain mysterious, MSCs have been demonstrated to be able to prevent the progression of liver injury and improve liver function. MSCs can self-renew by dividing, migrating to injury sites and differentiating into multiple cell types including hepatocytes. Additionally, MSCs have immune-modulatory properties and release paracrine soluble factors. Indeed, the safety and effectiveness of MSC therapy for liver diseases have been demonstrated in animals. However, pre-clinical and clinical trials are largely required to confirm its safety and efficacy before large scale clinical application. In this review, we will explore the molecular mechanisms underlying therapeutic effects of MSCs on liver diseases. We also summarize clinical advances in MSC-based therapies.
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Affiliation(s)
- Mu-Chen Wu
- Department of Medical Oncology,You An Hospital, Capital Medical University, Beijing 100069, China
| | - Qing-Hua Meng
- Department of Medical Oncology,You An Hospital, Capital Medical University, Beijing 100069, China.
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Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis. Cells 2021; 10:cells10081883. [PMID: 34440652 PMCID: PMC8394311 DOI: 10.3390/cells10081883] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is characterized by different stages varying from benign fat accumulation to non-alcoholic steatohepatitis (NASH) that may progress to cirrhosis and liver cancer. In recent years, a regulatory role of long non-coding RNAs (lncRNAs) in NAFLD has emerged. Therefore, we aimed to characterize the still poorly understood lncRNA contribution to disease progression. Transcriptome analysis in 60 human liver samples with various degrees of NAFLD/NASH was combined with a functional genomics experiment in an in vitro model where we exposed HepG2 cells to free fatty acids (FFA) to induce steatosis, then stimulated them with tumor necrosis factor alpha (TNFα) to mimic inflammation. Bioinformatics analyses provided a functional prediction of novel lncRNAs. We further functionally characterized the involvement of one novel lncRNA in the nuclear-factor-kappa B (NF-κB) signaling pathway by its silencing in Hepatoma G2 (HepG2) cells. We identified 730 protein-coding genes and 18 lncRNAs that responded to FFA/TNFα and associated with human NASH phenotypes with consistent effect direction, with most being linked to inflammation. One novel intergenic lncRNA, designated lncTNF, was 20-fold up-regulated upon TNFα stimulation in HepG2 cells and positively correlated with lobular inflammation in human liver samples. Silencing lncTNF in HepG2 cells reduced NF-κB activity and suppressed expression of the NF-κB target genes A20 and NFKBIA. The lncTNF we identified in the NF-κB signaling pathway may represent a novel target for controlling liver inflammation.
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Heitmann J, Frings VG, Geier A, Goebeler M, Kerstan A. Nicht‐alkoholische Fettlebererkrankung und Psoriasis – besteht ein gemeinsames proinflammatorisches Netzwerk? J Dtsch Dermatol Ges 2021; 19:517-529. [PMID: 33861000 DOI: 10.1111/ddg.14425_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/10/2020] [Indexed: 11/29/2022]
Affiliation(s)
- Johanna Heitmann
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg
| | - Verena G Frings
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg
| | - Andreas Geier
- Schwerpunkt Hepatologie, Medizinische Klinik II, Universitätsklinikum Würzburg
| | - Matthias Goebeler
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg
| | - Andreas Kerstan
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg
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Hatasa M, Yoshida S, Takahashi H, Tanaka K, Kubotsu Y, Ohsugi Y, Katagiri T, Iwata T, Katagiri S. Relationship between NAFLD and Periodontal Disease from the View of Clinical and Basic Research, and Immunological Response. Int J Mol Sci 2021; 22:3728. [PMID: 33918456 PMCID: PMC8038294 DOI: 10.3390/ijms22073728] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/31/2021] [Accepted: 04/01/2021] [Indexed: 12/22/2022] Open
Abstract
Periodontal disease is an inflammatory disease caused by pathogenic oral microorganisms that leads to the destruction of alveolar bone and connective tissues around the teeth. Although many studies have shown that periodontal disease is a risk factor for systemic diseases, such as type 2 diabetes and cardiovascular diseases, the relationship between nonalcoholic fatty liver disease (NAFLD) and periodontal disease has not yet been clarified. Thus, the purpose of this review was to reveal the relationship between NAFLD and periodontal disease based on epidemiological studies, basic research, and immunology. Many cross-sectional and prospective epidemiological studies have indicated that periodontal disease is a risk factor for NAFLD. An in vivo animal model revealed that infection with periodontopathic bacteria accelerates the progression of NAFLD accompanied by enhanced steatosis. Moreover, the detection of periodontopathic bacteria in the liver may demonstrate that the bacteria have a direct impact on NAFLD. Furthermore, Porphyromonas gingivalis lipopolysaccharide induces inflammation and accumulation of intracellular lipids in hepatocytes. Th17 may be a key molecule for explaining the relationship between periodontal disease and NAFLD. In this review, we attempted to establish that oral health is essential for systemic health, especially in patients with NAFLD.
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Affiliation(s)
- Masahiro Hatasa
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
| | - Sumiko Yoshida
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (K.T.); (Y.K.)
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Kenichi Tanaka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (K.T.); (Y.K.)
| | - Yoshihito Kubotsu
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (K.T.); (Y.K.)
| | - Yujin Ohsugi
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
| | - Takaharu Katagiri
- Department of Biochemistry, Toho University School of Medicine, Tokyo 143-8540, Japan;
- Division of Rheumatology, Department of Internal Medicine, Ohashi Medical Center, Tokyo 153-8515, Japan
| | - Takanori Iwata
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
| | - Sayaka Katagiri
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan; (M.H.); (S.Y.); (Y.O.); (T.I.)
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13
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Heitmann J, Frings VG, Geier A, Goebeler M, Kerstan A. Non-alcoholic fatty liver disease and psoriasis - is there a shared proinflammatory network? J Dtsch Dermatol Ges 2021; 19:517-528. [PMID: 33768700 DOI: 10.1111/ddg.14425] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/10/2020] [Indexed: 02/06/2023]
Abstract
Psoriasis is an immune-mediated systemic inflammatory disease that is not limited to the skin but may be associated with arthritis, cardiovascular diseases, metabolic syndrome including diabetes and obesity and, as identified more recently, non-alcoholic fatty liver disease (NAFLD) that occurs in approximately 50 % of all patients with psoriasis. NAFLD is characterized by accumulation of fat in hepatocytes in the absence of excessive alcohol consumption. Over the last two decades, NAFLD has developed to the most common chronic liver disease with an estimated prevalence of 25 % in the Western population. NAFLD ranges from non-inflammatory or bland hepatic steatosis to inflammation of hepatic tissue (non-alcoholic steatohepatitis, NASH) and consecutive liver fibrosis. It is controversial whether the underlying systemic inflammation of psoriasis is contributing to development of NAFLD or if comorbid diseases such as obesity enhance NAFLD development. Recent findings indicate that cytokine-mediated inflammation through TNFα, interleukin (IL)-6 and IL-17 might be the common link between psoriasis and NAFLD. Considering the shared inflammatory pathways, IL-17 pharmacological blockade, which is already well-established for psoriasis, may be a promising strategy to treat both psoriasis and NAFLD. Therefore, early detection of NAFLD and a better understanding of its pathophysiology in the context of the systemic inflammation in psoriasis is important with regard to individualized treatment approaches.
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Affiliation(s)
- Johanna Heitmann
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
| | - Verena G Frings
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
| | - Andreas Geier
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Matthias Goebeler
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
| | - Andreas Kerstan
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
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14
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Heyens LJM, Busschots D, Koek GH, Robaeys G, Francque S. Liver Fibrosis in Non-alcoholic Fatty Liver Disease: From Liver Biopsy to Non-invasive Biomarkers in Diagnosis and Treatment. Front Med (Lausanne) 2021; 8:615978. [PMID: 33937277 PMCID: PMC8079659 DOI: 10.3389/fmed.2021.615978] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 03/22/2021] [Indexed: 12/12/2022] Open
Abstract
An increasing percentage of people have or are at risk to develop non-alcoholic fatty liver disease (NAFLD) worldwide. NAFLD comprises different stadia going from isolated steatosis to non-alcoholic steatohepatitis (NASH). NASH is a chronic state of liver inflammation that leads to the transformation of hepatic stellate cells to myofibroblasts. These cells produce extra-cellular matrix that results in liver fibrosis. In a normal situation, fibrogenesis is a wound healing process that preserves tissue integrity. However, sustained and progressive fibrosis can become pathogenic. This process takes many years and is often asymptomatic. Therefore, patients usually present themselves with end-stage liver disease e.g., liver cirrhosis, decompensated liver disease or even hepatocellular carcinoma. Fibrosis has also been identified as the most important predictor of prognosis in patients with NAFLD. Currently, only a minority of patients with liver fibrosis are identified to be at risk and hence referred for treatment. This is not only because the disease is largely asymptomatic, but also due to the fact that currently liver biopsy is still the golden standard for accurate detection of liver fibrosis. However, performing a liver biopsy harbors some risks and requires resources and expertise, hence is not applicable in every clinical setting and is unsuitable for screening. Consequently, different non-invasive diagnostic tools, mainly based on analysis of blood or other specimens or based on imaging have been developed or are in development. In this review, we will first give an overview of the pathogenic mechanisms of the evolution from isolated steatosis to fibrosis. This serves as the basis for the subsequent discussion of the current and future diagnostic biomarkers and anti-fibrotic drugs.
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Affiliation(s)
- Leen J. M. Heyens
- Faculty of Health and Life Sciences, Hasselt University, Hasselt, Belgium
- School of Nutrition and Translational Research in Metabolism, NUTRIM, Maastricht University, Maastricht, Netherlands
- Department of Gastro-Enterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Belgium
| | - Dana Busschots
- Faculty of Health and Life Sciences, Hasselt University, Hasselt, Belgium
- School of Nutrition and Translational Research in Metabolism, NUTRIM, Maastricht University, Maastricht, Netherlands
| | - Ger H. Koek
- School of Nutrition and Translational Research in Metabolism, NUTRIM, Maastricht University, Maastricht, Netherlands
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Geert Robaeys
- Faculty of Health and Life Sciences, Hasselt University, Hasselt, Belgium
- Department of Gastro-Enterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Belgium
- Department of Gastroenterology and Hepatology, University Hospital Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- *Correspondence: Sven Francque
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15
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Lee CH, Fu Y, Yang SJ, Chi CC. Effects of Omega-3 Polyunsaturated Fatty Acid Supplementation on Non-Alcoholic Fatty Liver: A Systematic Review and Meta-Analysis. Nutrients 2020; 12:nu12092769. [PMID: 32932796 PMCID: PMC7551292 DOI: 10.3390/nu12092769] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/06/2020] [Accepted: 09/08/2020] [Indexed: 02/06/2023] Open
Abstract
(1) Aim: Non-alcoholic fatty liver disease (NAFLD) is a prevalent disease worldwide. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) bear anti-inflammatory action and can ameliorate hyperlipidemia. We wish to appraise the effects of n-3 PUFAs supplement on NAFLD. (2) Methods: We searched CENTRAL, Embase, and MEDLINE on 29 March 2020 for randomized control trials (RCTs) on the effects of n-3 PUFAs supplementation in treating NAFLD. The Cochrane Collaboration's tool was used to assess the risk of bias of included RCTs. (3) Results: We included 22 RCTs with 1366 participants. The risk of bias of included RCTs was generally low or unclear. n-3 PUFAs supplementation significantly reduced liver fat compared with placebo (pooled risk ratio 1.52; 95% confidence interval (CI) 1.09 to 2.13). n-3 PUFAs supplementation also significantly improved the levels of triglyceride, total cholesterol, high-density lipoprotein, and body-mass index, with pooled mean difference and 95% CI being -28.57 (-40.81 to -16.33), -7.82 (-14.86 to -0.79), 3.55 (1.38 to 5.73), and -0.46 (-0.84 to -0.08), respectively. (4) Conclusions: The current evidence supports the effects of n-3 PUFAs supplementation in improving fatty liver. n-3 PUFAs supplementation may also improve blood lipid levels and obesity.
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Affiliation(s)
- Cheng-Han Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan;
| | - Yun Fu
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan;
| | - Shih-Jyun Yang
- Department of Dermatology, Chang Gung Memorial Hospital, Keelung 20401, Taiwan;
| | - Ching-Chi Chi
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Correspondence: ; Tel.: +886-3-328-1200 (ext. 3556)
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16
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Takatani N, Kono Y, Beppu F, Okamatsu-Ogura Y, Yamano Y, Miyashita K, Hosokawa M. Fucoxanthin inhibits hepatic oxidative stress, inflammation, and fibrosis in diet-induced nonalcoholic steatohepatitis model mice. Biochem Biophys Res Commun 2020; 528:305-310. [PMID: 32475638 DOI: 10.1016/j.bbrc.2020.05.050] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 05/06/2020] [Indexed: 12/14/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) is associated with hepatocyte injury, excessive oxidative stress, and chronic inflammation in fatty liver, and can progress to more severe liver diseases, such as cirrhosis and hepatocellular carcinoma. However, currently there are no effective therapies for NASH. Marine carotenoid, fucoxanthin (Fx), abundant in brown seaweeds, has variable biological properties, such as anti-cancer, anti-inflammatory, anti-oxidative and anti-obesity. However, the effect of Fx on the development of NASH has not been explored. We investigated the protective effects of Fx in diet-induced NASH model mice fed choline-deficient L-amino acid-defined high fat diet (CDAHFD). Fx administration significantly attenuated liver weight gain and hepatic fat accumulation, resulting in the alleviation of hepatic injury. Furthermore, the Fx-fed mice, not only exhibited reduced hepatic lipid oxidation, but also decreased mRNA expression levels of inflammation and infiltration-related genes compared to that of the CDAHFD-fed mice. Moreover, fucoxanthinol and amarouciaxanthin A, two Fx metabolites exerted anti-inflammatory effects in the liver via inhibiting the chemokine production in hepatocytes. In case of fibrosis, one of the features of advanced NASH, the expression of fibrogenic factors including activated-hepatic stellate cell marker was significantly decreased in the liver of Fx-fed mice. Thus, the present study elucidated that dietary Fx not only inhibited hepatic oxidative stress and inflammation but also prevented early phase of fibrosis in the diet-induced NASH model mice.
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Affiliation(s)
- Naoki Takatani
- Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minato, Hakodate, Hokkaido, 041-8611, Japan
| | - Yuka Kono
- Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minato, Hakodate, Hokkaido, 041-8611, Japan
| | - Fumiaki Beppu
- Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minato, Hakodate, Hokkaido, 041-8611, Japan
| | - Yuko Okamatsu-Ogura
- Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
| | - Yumiko Yamano
- Laboratory of Organic Chemistry for Life Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan
| | - Kazuo Miyashita
- Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minato, Hakodate, Hokkaido, 041-8611, Japan
| | - Masashi Hosokawa
- Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minato, Hakodate, Hokkaido, 041-8611, Japan.
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17
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Tanwar S, Rhodes F, Srivastava A, Trembling PM, Rosenberg WM. Inflammation and fibrosis in chronic liver diseases including non-alcoholic fatty liver disease and hepatitis C. World J Gastroenterol 2020; 26:109-133. [PMID: 31969775 PMCID: PMC6962431 DOI: 10.3748/wjg.v26.i2.109] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 12/18/2019] [Accepted: 01/01/2020] [Indexed: 02/06/2023] Open
Abstract
At present chronic liver disease (CLD), the third commonest cause of premature death in the United Kingdom is detected late, when interventions are ineffective, resulting in considerable morbidity and mortality. Injury to the liver, the largest solid organ in the body, leads to a cascade of inflammatory events. Chronic inflammation leads to the activation of hepatic stellate cells that undergo trans-differentiation to become myofibroblasts, the main extra-cellular matrix producing cells in the liver; over time increased extra-cellular matrix production results in the formation of liver fibrosis. Although fibrogenesis may be viewed as having evolved as a “wound healing” process that preserves tissue integrity, sustained chronic fibrosis can become pathogenic culminating in CLD, cirrhosis and its associated complications. As the reference standard for detecting liver fibrosis, liver biopsy, is invasive and has an associated morbidity, the diagnostic assessment of CLD by non-invasive testing is attractive. Accordingly, in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice. Due to differing disease prevalence and treatment efficacy, disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection. To facilitate this, a review of the pathogenesis of both conditions is also conducted. Finally, the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed, including the current use of antifibrotic therapy.
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Affiliation(s)
- Sudeep Tanwar
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, Royal Free Campus, Hampstead, London NW3 2PF United Kingdom
- Department of Gastroenterology, Whipps Cross University Hospital, Barts Health NHS Trust, Leytonstone, London E11 1NR, United Kingdom
| | - Freya Rhodes
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, Royal Free Campus, Hampstead, London NW3 2PF United Kingdom
| | - Ankur Srivastava
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, Royal Free Campus, Hampstead, London NW3 2PF United Kingdom
| | - Paul M Trembling
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, Royal Free Campus, Hampstead, London NW3 2PF United Kingdom
| | - William M Rosenberg
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, Royal Free Campus, Hampstead, London NW3 2PF United Kingdom
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18
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Sihali-Beloui O, Aroune D, Benazouz F, Hadji A, El-Aoufi S, Marco S. A hypercaloric diet induces hepatic oxidative stress, infiltration of lymphocytes, and mitochondrial reshuffle in Psammomys obesus, a murine model of insulin resistance. C R Biol 2019; 342:209-219. [PMID: 31151779 DOI: 10.1016/j.crvi.2019.04.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 04/04/2019] [Accepted: 04/21/2019] [Indexed: 02/07/2023]
Abstract
The aim of this study was to show, for the first time, the effect of a hypercaloric diet on the mitochondrial reshuffle of hepatocytes during the progression from steatosis to steatohepatitis to cirrhosis in Psammomys obesus, a typical animal model of the metabolic syndrome. Metabolic and oxidative stresses were induced by feeding the animal through a standard laboratory diet (SD) for nine months. Metabolic parameters, liver malondialdehyde (MDA) and glutathione (GSH), were evaluated. The pathological evolution was examined by histopathology and immunohistochemistry, using CD3 and CD20 antibodies. The dynamics of the mitochondrial structure was followed by transmission electron microscopy. SD induced a steatosis in this animal that evolved under the effect of oxidative and metabolic stress by the appearance of adaptive inflammation and fibrosis leading the animal to the cirrhosis stage with serious hepatocyte damage by the triggering, at first the mitochondrial fusion-fission cycles, which attempted to maintain the mitochondria intact and functional, but the hepatocellular oxidative damage was increased inducing a vicious circle of mitochondrial alteration and dysfunction and their elimination by mitophagy. P. obesus is an excellent animal model of therapeutic research that targets mitochondrial dysfunction in the progression of steatosis.
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Affiliation(s)
- Ouahiba Sihali-Beloui
- Laboratory of Biology and Physiology of Organisms/Molecular Modelling Endothlial Dysfunction and Diabetes, Faculty of Biological Sciences, University of Science and Technology Houari Boumediene (USTHB), P.O. Box 32, El Alia, Dar El Beida, 16111 Alger, Algeria.
| | - Djamila Aroune
- Laboratory of Biology and Physiology of Organisms/Molecular Modelling Endothlial Dysfunction and Diabetes, Faculty of Biological Sciences, University of Science and Technology Houari Boumediene (USTHB), P.O. Box 32, El Alia, Dar El Beida, 16111 Alger, Algeria
| | - Fella Benazouz
- Laboratory of Biology and Physiology of Organisms/Molecular Modelling Endothlial Dysfunction and Diabetes, Faculty of Biological Sciences, University of Science and Technology Houari Boumediene (USTHB), P.O. Box 32, El Alia, Dar El Beida, 16111 Alger, Algeria
| | - Adile Hadji
- Pathological Anatomy and Cytology Service, Djillali Bounaama Hospital, Douera-Alger, Algeria
| | - Salima El-Aoufi
- Laboratory of Biology and Physiology of Organisms/Molecular Modelling Endothlial Dysfunction and Diabetes, Faculty of Biological Sciences, University of Science and Technology Houari Boumediene (USTHB), P.O. Box 32, El Alia, Dar El Beida, 16111 Alger, Algeria
| | - Sergio Marco
- Institut Curie, Centre de recherche, 91405 Orsay, France; INSERM, U1196, 91405 Orsay, France; CNRS, UMR9187, 91405 Orsay, France; Université Paris-Sud, Université Paris-Saclay, 91190 Saint-Auban, France
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19
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Jiang J, Yan L, Shi Z, Wang L, Shan L, Efferth T. Hepatoprotective and anti-inflammatory effects of total flavonoids of Qu Zhi Ke (peel of Citrus changshan-huyou) on non-alcoholic fatty liver disease in rats via modulation of NF-κB and MAPKs. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 64:153082. [PMID: 31541796 DOI: 10.1016/j.phymed.2019.153082] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 08/30/2019] [Accepted: 09/03/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Citrus flavonoids, consisting of naringin, narirutin, neohesperidine, etc., have therapeutic activities for the treatment of lipometabolic disorders. The peel of Citrus changshan-huyou (Qu Zhi Ke, QZK) is a new source of flavonoids, but attracted little attention so far. HYPOTHESIS QZK should possess therapeutic effects against lipometabolic disorders due to the flavonoids it contains. STUDY DESIGN In this study, we extracted and purified the flavonoids of QZK (TFCH) and established an obesity-induced non-alcoholic fatty liver disease (NAFLD) model of rats. TFCH was given orally for 8 weeks, and its anti-NAFLD effects and potential mechanism were evaluated. METHODS The flavonoid chemoprofile of TFCH was determined by using HPLC. High-fat diet was employed to induce NAFLD model in rats, and six groups were set up: negative control group, reference treatment group, model group, low-dose TFCH (25 mg/kg), intermediate-dose TFCH (50 mg/kg), and high-dose TFCH (100 mg/kg). Serum and liver levels of inflammatory cytokines and NAFLD markers were measured biochemically. The relative mRNA expressions of liver T-bet, GATA3, and TNF-α were tested by real time PCR (qPCR) analysis. The protein expression of p38 and the phosphorylation of NF-κB, ERK1/2, and p38 in liver were tested by Western blot analysis. RESULTS The histopathological observation showed that TFCH attenuated hepatic lesions with significantly decreased NAFLD activity scores. The biochemical data showed that TFCH significantly suppressed both systemic and intrahepatic inflammation by inhibiting IL-1β, IL-6, IL-12, TNF-α, and IFN-γ, and the qPCR analysis revealed a Th1/Th2 related anti-inflammatory mechanism of TFCH. Western blot results clarified that TFCH exerted hepatoprotective and anti-inflammatory effects by suppression of phosphorylated NF-κB and MAPKs, indicating a mechanism associated with NF-κB and MAPK signaling pathways. CONCLUSION QZK is a new source of Citrus flavonoids for therapeutic use, and TFCH is a promising representative of Citrus flavonoids for anti-NAFLD therapy.
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Affiliation(s)
- Jianping Jiang
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China; Key Laboratory of Integrative Chinese and Western Medicine for the Diagnosis and Treatment of Circulatory Diseases of Zhejiang Province, Hangzhou, China; Zhejiang You-du Biotech Limited Company, Quzhou, China
| | - Li Yan
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zheng Shi
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Lixia Wang
- Citrus changshan-huyou Research Institute of Changshan City, Quzhou, China
| | - Letian Shan
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany
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20
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Schwenger KJ, Clermont-Dejean N, Allard JP. The role of the gut microbiome in chronic liver disease: the clinical evidence revised. JHEP Rep 2019; 1:214-226. [PMID: 32039372 PMCID: PMC7001555 DOI: 10.1016/j.jhepr.2019.04.004] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 04/08/2019] [Accepted: 04/27/2019] [Indexed: 02/07/2023] Open
Abstract
Recent research has suggested a role for the intestinal microbiota in the pathogenesis and potential treatment of a wide range of liver diseases. The intestinal microbiota and bacterial products may contribute to the development of liver diseases through multiple mechanisms including increased intestinal permeability, chronic systemic inflammation, production of short-chain fatty acids and changes in metabolism. This suggests a potential role for pre-, pro- and synbiotic products in the prevention or treatment of some liver diseases. In addition, there is emerging evidence on the effects of faecal microbial transplant. Herein, we discuss the relationship between the intestinal microbiota and liver diseases, as well as reviewing intestinal microbiota-based treatment options that are currently being investigated.
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Affiliation(s)
- Katherine Jp Schwenger
- Toronto General Hospital, University Health Network, Toronto, Canada.,Department of Medicine, University of Toronto, Toronto, Canada
| | | | - Johane P Allard
- Toronto General Hospital, University Health Network, Toronto, Canada.,Department of Medicine, University of Toronto, Toronto, Canada.,Department of Nutritional Sciences, University of Toronto, Toronto, Canada
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21
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Lee Y, Hu S, Park YK, Lee JY. Health Benefits of Carotenoids: A Role of Carotenoids in the Prevention of Non-Alcoholic Fatty Liver Disease. Prev Nutr Food Sci 2019; 24:103-113. [PMID: 31328113 PMCID: PMC6615349 DOI: 10.3746/pnf.2019.24.2.103] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 04/02/2019] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases with a prevalence of ~25% worldwide. NAFLD includes simple hepatic steatosis, non-alcoholic steatohepatitis, fibrosis, and cirrhosis, which can further progress to hepatocellular carcinoma. Therefore, effective strategies for the prevention of NAFLD are needed. The pathogenesis of NAFLD is complicated due to diverse injury insults, such as fat accumulation, oxidative stress, inflammation, lipotoxicity, and apoptosis, which may act synergistically. Studies have shown that carotenoids, a natural group of isoprenoid pigments, prevent the development of NAFLD by exerting antioxidant, lipid-lowering, anti-inflammatory, anti-fibrotic, and insulin-sensitizing properties. This review summarizes the protective action of carotenoids, with primary focuses on astaxanthin, lycopene, β-carotene, β-cryptoxanthin, lutein, fucoxanthin, and crocetin, against the development and progression of NAFLD.
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Affiliation(s)
- Yoojin Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Siqi Hu
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.,Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Korea
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22
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Haas JT, Vonghia L, Mogilenko DA, Verrijken A, Molendi-Coste O, Fleury S, Deprince A, Nikitin A, Woitrain E, Ducrocq-Geoffroy L, Pic S, Derudas B, Dehondt H, Gheeraert C, Van Gaal L, Driessen A, Lefebvre P, Staels B, Francque S, Dombrowicz D. Transcriptional Network Analysis Implicates Altered Hepatic Immune Function in NASH development and resolution. Nat Metab 2019; 1:604-614. [PMID: 31701087 PMCID: PMC6837876 DOI: 10.1038/s42255-019-0076-1] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Progression of fatty liver to non-alcoholic steatohepatitis (NASH) is a rapidly growing health problem. Presence of inflammatory infiltrates in the liver and hepatocyte damage distinguish NASH from simple steatosis. However, the underlying molecular mechanisms involved in the development of NASH remain to be fully understood. Here we perform transcriptional and immune profiling of NASH patients before and after lifestyle intervention (LSI). Analysis of liver microarray data from a cohort of patients with histologically assessed NAFLD reveals a hepatic gene signature, which is associated with NASH and is sensitive to regression of NASH activity upon LSI independently of body weight loss. Enrichment analysis reveals the presence of immune-associated genes linked to inflammatory responses, antigen presentation and cytotoxic cells in the NASH-linked gene signature. In an independent cohort, NASH is also associated with alterations in blood immune cell populations, including conventional dendritic cells (cDC) type 1 and 2, and cytotoxic CD8 T cells. Lobular inflammation and ballooning are associated with the accumulation of CD8 T cells in the liver. Progression from simple steatosis to NASH in a mouse model of diet-driven NASH results in a comparable immune-related hepatic expression signature and the accumulation of intra-hepatic cDC and CD8 T cells. These results show that NASH, compared to normal liver or simple steatosis, is associated with a distinct hepatic immune-related gene signature, elevated hepatic CD8 T cells, and altered antigen-presenting and cytotoxic cells in blood. These findings expand our understanding of NASH and may identify potential targets for NASH therapy.
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Affiliation(s)
- Joel T. Haas
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Luisa Vonghia
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Address for correspondence: David Dombrowicz. Inserm U1011. Institut Pasteur de Lille. 1, r. Prof. Calmette BP245. 59019 Lille Cedex. France. . Luisa Vonghia. Universitair Ziekenhuis Antwerp. Gastro-enterologie en Hepatologie. Wilrijkstraat 10. 2650 Edegem. Belgium.
| | - Denis A. Mogilenko
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - An Verrijken
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Olivier Molendi-Coste
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Sébastien Fleury
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Audrey Deprince
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Artemii Nikitin
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Eloïse Woitrain
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Lucie Ducrocq-Geoffroy
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Samuel Pic
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Bruno Derudas
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Hélène Dehondt
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Céline Gheeraert
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Luc Van Gaal
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Ann Driessen
- Department of Pathology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Philippe Lefebvre
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Bart Staels
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - David Dombrowicz
- University of Lille, EGID, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, Lille, France
- Address for correspondence: David Dombrowicz. Inserm U1011. Institut Pasteur de Lille. 1, r. Prof. Calmette BP245. 59019 Lille Cedex. France. . Luisa Vonghia. Universitair Ziekenhuis Antwerp. Gastro-enterologie en Hepatologie. Wilrijkstraat 10. 2650 Edegem. Belgium.
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Vonghia L, Van Herck MA, Weyler J, Francque S. Targeting Myeloid-Derived Cells: New Frontiers in the Treatment of Non-alcoholic and Alcoholic Liver Disease. Front Immunol 2019; 10:563. [PMID: 30972062 PMCID: PMC6446913 DOI: 10.3389/fimmu.2019.00563] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 03/04/2019] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and Alcoholic Liver Disease (ALD) are major causes of liver-related morbidity and mortality and constitute important causes of liver transplantation. The spectrum of the liver disease is wide and includes isolated steatosis, steatohepatitis, and cirrhosis. The treatment of NAFLD and ALD remains, however, an unmet need, and therefore it is a public health priority to develop effective treatments for these diseases. Alcoholic and non-alcoholic liver disease share common complex pathogenetic pathways that involve different organs and systems beyond the liver, including the gut, the adipose tissue, and the immune system, which cross-talk to generate damage. Myeloid-derived cells have been widely studied in the setting of NAFLD and ALD and are implicated at different levels in the onset and progression of this disease. Among these cells, monocytes and macrophages have been found to be involved in the induction of inflammation and in the progression to fibrosis, both in animal models and clinical studies and they have become interesting potential targets for the treatment of both NAFLD and ALD. The different mechanisms by which these cells can be targeted include modulation of Kupffer cell activation, monocyte recruitment in the liver and macrophage polarization and differentiation. Evidence from preclinical studies and clinical trials (some of them already in phase II and III) have shown encouraging results in ameliorating steatohepatitis, fibrosis, and the metabolic profile, individuating promising candidates for the pharmacological treatment of these diseases. The currently available results of myeloid-derived cells targeted treatments in NAFLD and ALD are covered in this review.
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Affiliation(s)
- Luisa Vonghia
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.,Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium
| | - Mikhaïl A Van Herck
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.,Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium
| | - Jonas Weyler
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.,Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.,Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium
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24
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Van Herck MA, Weyler J, Kwanten WJ, Dirinck EL, De Winter BY, Francque SM, Vonghia L. The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity. Front Immunol 2019; 10:82. [PMID: 30787925 PMCID: PMC6372559 DOI: 10.3389/fimmu.2019.00082] [Citation(s) in RCA: 175] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 01/11/2019] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) constitutes a spectrum of disease states characterized by hepatic steatosis and is closely associated to obesity and the metabolic syndrome. In non-alcoholic steatohepatitis (NASH), additionally, inflammatory changes and hepatocellular damage are present, representing a more severe condition, for which the treatment is an unmet medical need. Pathophysiologically, the immune system is one of the main drivers of NAFLD progression and other obesity-related comorbidities, and both the innate and adaptive immune system are involved. T cells form the cellular component of the adaptive immune system and consist of multiple differentially active subsets, i.e., T helper (Th) cells, regulatory T (Treg) cells, and cytotoxic T (Tc) cells, as well as several innate T-cell subsets. This review focuses on the role of these T-cell subsets in the pathogenesis of NAFLD, as well as the association with obesity and type 2 diabetes mellitus, reviewing the available evidence from both animal and human studies. Briefly, Th1, Th2, Th17, and Th22 cells seem to have an attenuating effect on adiposity. Th2, Th22, and Treg cells seem to decrease insulin resistance, whereas Th1, Th17, and Tc cells have an aggravating effect. Concerning NAFLD, both Th22 and Treg cells appear to have an overall tempering effect, whereas Th17 and Tc cells seem to induce more liver damage and fibrosis progression. The evidence regarding the role of the innate T-cell subsets is more controversial and warrants further exploration.
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Affiliation(s)
- Mikhaïl A Van Herck
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Jonas Weyler
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Wilhelmus J Kwanten
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Eveline L Dirinck
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Antwerp, Belgium
| | - Benedicte Y De Winter
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium
| | - Sven M Francque
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Luisa Vonghia
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.,Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
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25
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Lee Y, Lee JY. Protective Actions of Polyphenols in the Development of Nonalcoholic Fatty Liver Disease. DIETARY INTERVENTIONS IN LIVER DISEASE 2019:91-99. [DOI: 10.1016/b978-0-12-814466-4.00008-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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26
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Malandrino N, Capristo E, Taveira TH, Mingrone G, Wu WC. Cognitive Function in Individuals with Normal Weight Obesity: Results from the Third National Health and Nutrition Examination Survey (NHANES III). J Alzheimers Dis 2018; 65:125-135. [DOI: 10.3233/jad-180264] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Noemi Malandrino
- Department of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Esmeralda Capristo
- Department of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Tracey H. Taveira
- Veterans Affairs Medical Center, Center of Innovation for Long Term Services and Support, Providence, RI, USA
- Department of Medicine, Brown University Warren Alpert Medical School, Providence, RI, USA
- University of Rhode Island, College of Pharmacy, Kingston, RI, USA
| | - Geltrude Mingrone
- Department of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Wen-Chih Wu
- Department of Medicine, Section of Cardiology, Veterans Affairs Medical Center, Providence, RI, USA
- Center for Cardiac Fitness, The Miriam Hospital, Providence, RI, USA
- Department of Medicine, Division of Cardiology, Brown University Warren Alpert Medical School, Providence, RI, USA
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27
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Animal Models of Nonalcoholic Fatty Liver Disease-A Starter's Guide. Nutrients 2017; 9:nu9101072. [PMID: 28953222 PMCID: PMC5691689 DOI: 10.3390/nu9101072] [Citation(s) in RCA: 254] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 09/13/2017] [Accepted: 09/25/2017] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) constitutes a major health concern with the increasing incidence of obesity and diabetes in many Western countries, reaching a prevalence of up to 30% in the general population. Animal models have played a vital role in elucidating the pathophysiological mechanisms of NAFLD and continue to do so. A myriad of different models exists, each with its advantages and disadvantages. This review presents a brief overview of these models with a particular focus on the basic mechanisms and physical, biochemical and histological phenotype. Both nutritional and chemically induced, as well as genetic models are examined, including models combining different approaches.
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Świderska M, Jaroszewicz J, Stawicka A, Parfieniuk-Kowerda A, Chabowski A, Flisiak R. The interplay between Th17 and T-regulatory responses as well as adipokines in the progression of non-alcoholic fatty liver disease. Clin Exp Hepatol 2017; 3:127-134. [PMID: 29062902 PMCID: PMC5649483 DOI: 10.5114/ceh.2017.68466] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/07/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic progressive liver disease, coupled with metabolic syndrome, which may progress to non-alcoholic steatohepatitis (NASH). Diabetes, obesity, hypertension, hypercholesterolemia, and hypertriglyceridemia are considered to be the most common causes leading to the incidence of NAFLD. It is assumed that the accumulation of lipid deposits in hepatocytes leads to production of proinflammatory cytokines that triggers the development of liver inflammation. Regulatory T cells (Tregs) play a critical role in regulating inflammatory processes in NASH, while T helper type 17 (Th17) might functionally oppose Treg-mediated responses. In addition, important mediators of hepatic steatosis are fatty hormones known as adipokines. We aimed to describe the significance and interaction between Treg and Th17-related cytokines as well as adipokines in pathogenesis and its potential use as biomarkers of NAFLD, especially with respect to progression to NASH.
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Affiliation(s)
- Magdalena Świderska
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, Bytom, Poland
| | - Agnieszka Stawicka
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
| | - Anna Parfieniuk-Kowerda
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
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29
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New insight into inter-organ crosstalk contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Protein Cell 2017. [PMID: 28643267 PMCID: PMC5818366 DOI: 10.1007/s13238-017-0436-0] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver dysfunction and a significant global health problem with substantial rise in prevalence over the last decades. It is becoming increasingly clear that NALFD is not only predominantly a hepatic manifestation of metabolic syndrome, but also involves extra-hepatic organs and regulatory pathways. Therapeutic options are limited for the treatment of NAFLD. Accordingly, a better understanding of the pathogenesis of NAFLD is critical for gaining new insight into the regulatory network of NAFLD and for identifying new targets for the prevention and treatment of NAFLD. In this review, we emphasize on the current understanding of the inter-organ crosstalk between the liver and peripheral organs that contributing to the pathogenesis of NAFLD.
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Mulligan C, Kondakala S, Yang EJ, Stokes JV, Stewart JA, Kaplan BLF, Howell GE. Exposure to an environmentally relevant mixture of organochlorine compounds and polychlorinated biphenyls Promotes hepatic steatosis in male Ob/Ob mice. ENVIRONMENTAL TOXICOLOGY 2017; 32:1399-1411. [PMID: 27533883 DOI: 10.1002/tox.22334] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 07/25/2016] [Accepted: 07/30/2016] [Indexed: 05/19/2023]
Abstract
Hepatic steatosis is recognized as an independent risk factor for the development of cardiovascular disease. While obesity and type 2 diabetes are well-established risk factors in the development of hepatic steatosis, recent studies have revealed exposure to mixtures of persistent organic pollutants (POPs), which are environmental contaminants in various fatty foods, can promote steatosis. Thus, the present study was designed to determine if exposure to a defined mixture of prevalent polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides or their metabolites promote hepatic steatosis in a genetically induced model of type 2 diabetes, the leptin-deficient ob/ob mouse. Male C57BL/6J wild type (WT) or ob/ob mice were administered an environmentally relevant mixture of PCBs and OCs for 7 weeks via oral gavage. Exposure to POPs did not significantly alter fasting serum glucose or insulin levels. However, POPs exposure significantly increased hepatic triglyceride content in ob/ob animals, while decreasing serum triglyceride levels. This POPs-mediated increase in hepatic triglyceride content did not appear to be associated with significantly increased inflammation in either the liver or adipose. Exposure to POPs significantly induced the expression of cytochrome P450 3a11 in WT animals, yet the expression of this cytochrome was significantly downregulated in ob/ob animals regardless of POPs exposure. Taken together, the present data indicate exposure to an environmentally relevant mixture of both PCBs and OC pesticides in ob/ob mice promotes hepatic steatosis while decreasing hypertriglyceridemia, which demonstrates exposure to a defined mixture of POPs alters systemic lipid metabolism in a genetically induced model of obesity and type 2 diabetes. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1399-1411, 2017.
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Affiliation(s)
- Charlee Mulligan
- Department of Basic Sciences, Mississippi State University, College of Veterinary Medicine, Mississippi State, Mississippi, 39762
| | - Sandeep Kondakala
- Department of Basic Sciences, Mississippi State University, College of Veterinary Medicine, Mississippi State, Mississippi, 39762
| | - Eun-Ju Yang
- Department of Basic Sciences, Mississippi State University, College of Veterinary Medicine, Mississippi State, Mississippi, 39762
| | - John V Stokes
- Department of Basic Sciences, Mississippi State University, College of Veterinary Medicine, Mississippi State, Mississippi, 39762
| | - James A Stewart
- Department of Basic Sciences, Mississippi State University, College of Veterinary Medicine, Mississippi State, Mississippi, 39762
| | - Barbara L F Kaplan
- Department of Basic Sciences, Mississippi State University, College of Veterinary Medicine, Mississippi State, Mississippi, 39762
| | - George E Howell
- Department of Basic Sciences, Mississippi State University, College of Veterinary Medicine, Mississippi State, Mississippi, 39762
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31
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Watanabe S, Takahashi T, Ogawa H, Uehara H, Tsunematsu T, Baba H, Morimoto Y, Tsuneyama K. Daily Coffee Intake Inhibits Pancreatic Beta Cell Damage and Nonalcoholic Steatohepatitis in a Mouse Model of Spontaneous Metabolic Syndrome, Tsumura-Suzuki Obese Diabetic Mice. Metab Syndr Relat Disord 2017; 15:170-177. [PMID: 28358620 DOI: 10.1089/met.2016.0114] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Metabolic syndrome is one of the most important health issues worldwide. Obesity causes insulin resistance, hyperlipidemia, diabetes, and various diseases throughout the body. The liver phenotype, which is called nonalcoholic steatohepatitis (NASH), frequently progresses to hepatocellular carcinoma. We recently established a new animal model, Tsumura-Suzuki obese diabetic (TSOD) mice, which spontaneously exhibit obesity, diabetes, hyperlipidemia, and NASH with liver nodules. METHODS We examined the effects of coffee intake on various conditions of the metabolic syndrome using TSOD mice. The daily volume of coffee administered was limited so that it reflected the appropriate quantities consumed in humans. To clarify the effects of the specific components, animals were divided into two coffee-intake groups that included with and without caffeine. RESULTS Coffee intake did not significantly affect obesity and hyperlipidemia in TSOD mice. In contrast, coffee intake caused various degrees of improvement in the pancreatic beta cell damage and steatohepatitis with liver carcinogenesis. Most of the effects were believed to be caused by a synergistic effect of caffeine with other components such as polyphenols. However, the antifibrotic effects of coffee appeared to be due to the polyphenols rather than the caffeine. CONCLUSIONS A daily habit of drinking coffee could possibly play a role in the prevention of metabolic syndrome.
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Affiliation(s)
- Syunsuke Watanabe
- 1 Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima, Japan
| | - Tetsuyuki Takahashi
- 2 Department of Anatomy and Cell Biology, Faculty of Pharmacy, Research Institute of Pharmaceutical Science, Musashino University , Nishitokyo, Japan
| | - Hirohisa Ogawa
- 1 Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima, Japan
| | - Hisanori Uehara
- 1 Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima, Japan
| | - Takaaki Tsunematsu
- 1 Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima, Japan
| | - Hayato Baba
- 1 Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima, Japan
| | - Yuki Morimoto
- 1 Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima, Japan
| | - Koichi Tsuneyama
- 1 Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima, Japan
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Inzaugarat ME, De Matteo E, Baz P, Lucero D, García CC, Gonzalez Ballerga E, Daruich J, Sorda JA, Wald MR, Cherñavsky AC. New evidence for the therapeutic potential of curcumin to treat nonalcoholic fatty liver disease in humans. PLoS One 2017; 12:e0172900. [PMID: 28257515 PMCID: PMC5336246 DOI: 10.1371/journal.pone.0172900] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 02/10/2017] [Indexed: 02/06/2023] Open
Abstract
Introduction The immune system acts on different metabolic tissues that are implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Leptin and linoleic acid have the ability to potentially affect immune cells, whereas curcumin is a known natural polyphenol with antioxidant and anti-inflammatory properties. Aims This study was designed to evaluate the pro-inflammatory and pro-oxidant effects of leptin and linoleic acid on immune cells from patients with NAFLD and to corroborate the modulatory effects of curcumin and its preventive properties against the progression of NAFLD using a high-fat diet (HFD)-induced NAFLD/nonalcoholic steatohepatitis mouse model. Results The ex vivo experiments showed that linoleic acid increased the production of reactive oxygen species in monocytes and liver macrophages, whereas leptin enhanced tumor necrosis factor-α (TNF-α) production in monocytes and interferon-γ production in circulating CD4+ cells. Conversely, oral administration of curcumin prevented HFD-induced liver injury, metabolic alterations, intrahepatic CD4+ cell accumulation and the linoleic acid- and leptin- induced pro-inflammatory and pro-oxidant effects on mouse liver macrophages. Conclusion Our findings provide new evidence for the therapeutic potential of curcumin to treat human NAFLD. However, the development of a preventive treatment targeting human circulating monocytes and liver macrophages as well as peripheral and hepatic CD4+ cells requires additional research.
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Affiliation(s)
- María Eugenia Inzaugarat
- Instituto de Inmunología, Genética y Metabolismo-CONICET- Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Elena De Matteo
- Hospital de Niños “Dr. R. Gutiérrez”, Servicio de Patología, Buenos Aires, Argentina
| | - Placida Baz
- Instituto de Inmunología, Genética y Metabolismo-CONICET- Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Diego Lucero
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica - Departamento de Bioquímica Clínica, Laboratorio de Lípidos y Arterioesclerosis, Buenos Aires, Argentina
| | - Cecilia Claudia García
- Instituto de Inmunología, Genética y Metabolismo-CONICET- Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Esteban Gonzalez Ballerga
- Universidad de Buenos Aires, Hospital de Clínicas "José de San Martin"- División de Gastroenterología, Buenos Aires, Argentina
| | - Jorge Daruich
- Universidad de Buenos Aires, Hospital de Clínicas "José de San Martin"- División de Gastroenterología, Buenos Aires, Argentina
| | - Juan Antonio Sorda
- Universidad de Buenos Aires, Hospital de Clínicas "José de San Martin"- División de Gastroenterología, Buenos Aires, Argentina
| | - Miriam Ruth Wald
- Instituto de Investigaciones Biomédicas (BIOMED)- Universidad católica Argentina-Consejo Nacional de Investigaciones Científicas y Tecnológicas, Buenos Aires, Argentina
| | - Alejandra Claudia Cherñavsky
- Instituto de Inmunología, Genética y Metabolismo-CONICET- Universidad de Buenos Aires, Buenos Aires, Argentina
- * E-mail:
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Magee N, Zou A, Zhang Y. Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells. BIOMED RESEARCH INTERNATIONAL 2016; 2016:5170402. [PMID: 27822476 PMCID: PMC5086374 DOI: 10.1155/2016/5170402] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 09/22/2016] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in the Western countries, affecting up to 25% of the general population and becoming a major health concern in both adults and children. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is a manifestation of the metabolic syndrome and hepatic disorders with the presence of steatosis, hepatocyte injury (ballooning), inflammation, and, in some patients, progressive fibrosis leading to cirrhosis. The pathogenesis of NASH is a complex process and implicates cell interactions between liver parenchymal and nonparenchymal cells as well as crosstalk between various immune cell populations in liver. Lipotoxicity appears to be the central driver of hepatic cellular injury via oxidative stress and endoplasmic reticulum (ER) stress. This review focuses on the contributions of hepatocytes and nonparenchymal cells to NASH, assessing their potential applications to the development of novel therapeutic agents. Currently, there are limited pharmacological treatments for NASH; therefore, an increased understanding of NASH pathogenesis is pertinent to improve disease interventions in the future.
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Affiliation(s)
- Nancy Magee
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - An Zou
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Qu BG. Inflammatory and immune changes and treatment in patients with fatty liver disease. Shijie Huaren Xiaohua Zazhi 2016; 24:2931-2942. [DOI: 10.11569/wcjd.v24.i19.2931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Fatty liver disease (FLD) is a common chronic inflammatory and immune disease. Current research suggests that it is associated with a variety of clinical metabolic diseases, however, its etiology is very complex, and its exact mechanism is not fully clear. Enormous studies have found that inflammation and immunity play roles in the pathogenesis of FLD, via mechanisms involving inflammatory mediators or inflammatory factors, neutrophil infiltration, inflammasomes, peroxisome proliferator-activated receptors (PPARs), gut microbes-related inflammation, immune cells, Toll-like receptors (TLRs) and its downstream signal transduction pathways, gut microbe-related immune response, immunocytes, oxidative stress, other new markers of immune response and so on. In order to provide a reliable basis for accurate diagnosis and treatment of FLD, studies on the prevention, early diagnosis and prospective intervention of FLD should be strengthened. In addition, according to different pathogenesis, corresponding measures should be taken to reduce the risk of FLD and its related diseases.
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Bozzetto L, Annuzzi G, Ragucci M, Di Donato O, Della Pepa G, Della Corte G, Griffo E, Anniballi G, Giacco A, Mancini M, Rivellese AA. Insulin resistance, postprandial GLP-1 and adaptive immunity are the main predictors of NAFLD in a homogeneous population at high cardiovascular risk. Nutr Metab Cardiovasc Dis 2016; 26:623-629. [PMID: 27134062 DOI: 10.1016/j.numecd.2016.01.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 11/06/2015] [Accepted: 01/25/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS The role of the different factors associated with fatty liver is still poorly defined. We evaluated the relationships between liver fat content (LF) and metabolic, inflammatory and nutritional factors in a homogeneous cohort of individuals at high cardio-metabolic risk. METHODS AND RESULTS In 70 individuals with high waist circumference and at least one more criterion for metabolic syndrome enrolled in a nutritional intervention study, LF was evaluated at baseline by hepatic/renal echo intensity ratio (H/R), together with dietary habits (7-day dietary record), insulin sensitivity and β-cell function (fasting and OGTT-derived indices), fasting and postprandial plasma GLP-1 and lipoproteins, and plasma inflammatory markers. H/R correlated positively with fasting and OGTT plasma glucose and insulin concentrations, HOMA-IR and β-cell function, and IL-4, IL-17, IFN-γ, TNF-α, FGF and GCSF plasma concentrations (p < 0.05 for all), and negatively with insulin sensitivity (OGIS), dietary, polyphenols and fiber (p < 0.05 for all). By multiple stepwise regression analysis, the best predictors of H/R were OGIS (β = -0.352 p = 0.001), postprandial GLP-1 (β = -0.344; p = 0.001), HDL-cholesterol (β = -0.323; p = 0.002) and IFN-γ (β = 0.205; p = 0.036). CONCLUSION A comprehensive evaluation of factors associated with liver fat, in a homogeneous population at high cardio-metabolic risk, indicated a pathogenic combination of the same pathways underlying the atherosclerotic process, namely whole body insulin sensitivity and inflammation. The higher predictive value of postprandial variables suggests that liver fat is essentially a postprandial phenomenon, with a relevant role possibly played by GLP-1. REGISTRATION NUMBER FOR CLINICAL TRIALS NCT01154478.
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Affiliation(s)
- L Bozzetto
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - G Annuzzi
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - M Ragucci
- Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy
| | - O Di Donato
- Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy
| | - G Della Pepa
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - G Della Corte
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - E Griffo
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - G Anniballi
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - A Giacco
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - M Mancini
- Institute of Biostructures and Bioimaging, National Research Council, Naples, Italy
| | - A A Rivellese
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
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Novel Action of Carotenoids on Non-Alcoholic Fatty Liver Disease: Macrophage Polarization and Liver Homeostasis. Nutrients 2016; 8:nu8070391. [PMID: 27347998 PMCID: PMC4963867 DOI: 10.3390/nu8070391] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 06/15/2016] [Accepted: 06/22/2016] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is considered a hepatic manifestation of metabolic syndrome; however, mechanisms underlying the onset and progression of NAFLD are still unclear. Resident and recruited macrophages are key players in the homeostatic function of the liver and in the progression of NAFLD to NASH. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of macrophages. New NAFLD therapies will likely involve modification of macrophage polarization by restraining M1 activation or driving M2 activation. Carotenoids are potent antioxidants and anti-inflammatory micronutrients that have been used to prevent and treat NAFLD. In addition to their antioxidative action, carotenoids can regulate macrophage polarization and thereby halt the progression of NASH. In this review, we summarize the molecular mechanisms of macrophage polarization and the function of liver macrophages/Kupffer cells in NAFLD. From our review, we propose that dietary carotenoids, such as β-cryptoxanthin and astaxanthin, be used to prevent or treat NAFLD through the regulation of macrophage polarization and liver homeostasis.
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Uhanova J, Minuk G, Lopez Ficher F, Chandok N. Nonalcoholic Fatty Liver Disease in Canadian First Nations and Non-First Nations Patients. Can J Gastroenterol Hepatol 2016; 2016:6420408. [PMID: 27446857 PMCID: PMC4904639 DOI: 10.1155/2016/6420408] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 02/25/2016] [Indexed: 02/06/2023] Open
Abstract
Background. Features of nonalcoholic fatty liver disease (NAFLD) have yet to be described in the Canadian First Nations (FN) population. The aim of this study was to compare the prevalence, severity, and outcome of NAFLD in FN versus non-FN patients at an urban, tertiary care centre. Methods. Adults with NAFLD and no additional liver disease were identified in a prospectively derived database at the University of Manitoba. Demographic, clinical, laboratory, imaging, and histologic data were analyzed. Results. 482 subjects fulfilled diagnostic criteria for NAFLD, including 33 (7%) FN. Aside from rural residence, diabetes and cholestasis being more common in FN patients, the ages, gender distributions, clinical and radiologic features, and liver enzyme/function test results were similar in the two cohorts. Noninvasive tests of fibrosis (APRI and NAFLD fibrosis scores) were also similar in the two cohorts. There were no significant differences in liver enzyme or function tests in either cohort after approximately three years of follow-up. Conclusion. Compared to the prevalence of FN persons in the general population of this study site (10-15%), FN patients were underrepresented in this NAFLD population. The severity and progression of liver disease in FN patients appear to be similar to those in non-FN patients.
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Affiliation(s)
- Julia Uhanova
- Section of Hepatology, Department of Internal Medicine, University of Manitoba, 804D-715 McDermot Avenue, Winnipeg, MB, Canada R3E 3P4
| | - Gerald Minuk
- Section of Hepatology, Department of Internal Medicine, University of Manitoba, 804D-715 McDermot Avenue, Winnipeg, MB, Canada R3E 3P4
| | - Federico Lopez Ficher
- Section of Hepatology, Department of Internal Medicine, University of Manitoba, 804D-715 McDermot Avenue, Winnipeg, MB, Canada R3E 3P4
| | - Natasha Chandok
- Section of Hepatology, Department of Internal Medicine, University of Manitoba, 804D-715 McDermot Avenue, Winnipeg, MB, Canada R3E 3P4
- Division of Gastroenterology, University of Western Ontario, Room ALL-107, 339 Windermere Road, London, ON, Canada N6A 5A5
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Li J, Cordero P, Nguyen V, Oben JA. The Role of Vitamins in the Pathogenesis of Non-alcoholic Fatty Liver Disease. INTEGRATIVE MEDICINE INSIGHTS 2016; 11:19-25. [PMID: 27147819 PMCID: PMC4849418 DOI: 10.4137/imi.s31451] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 11/19/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023]
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) is rising rapidly in parallel with obesity rates. The underlying pathogenesis of NAFLD remains an enigma but is largely influenced by individual lifestyle choices involving diet and exercise. Therefore, studies have highlighted the importance of calorie reduction and macronutrient composition (eg, carbohydrate and fat) in modifying disease outcomes. Micronutrients are also believed to play a role in disease progression. There are now an increasing number of studies linking vitamins with NAFLD, particularly vitamin E, and the supplementation of several different vitamins has been demonstrated as a promising therapeutic option in the treatment of NAFLD. This review provides a broad overview of the potential role of vitamins in NAFLD development and disease management.
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Affiliation(s)
- Jiawei Li
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Paul Cordero
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Vi Nguyen
- Institute for Liver and Digestive Health, University College London, London, UK.; Department of Gastroenterology and Hepatology, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK
| | - Jude A Oben
- Institute for Liver and Digestive Health, University College London, London, UK.; Department of Gastroenterology and Hepatology, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK
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Oxidative Stress and Inflammation in Hepatic Diseases: Therapeutic Possibilities of N-Acetylcysteine. Int J Mol Sci 2015; 16:30269-308. [PMID: 26694382 PMCID: PMC4691167 DOI: 10.3390/ijms161226225] [Citation(s) in RCA: 171] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Revised: 12/02/2015] [Accepted: 12/04/2015] [Indexed: 12/12/2022] Open
Abstract
Liver disease is highly prevalent in the world. Oxidative stress (OS) and inflammation are the most important pathogenetic events in liver diseases, regardless the different etiology and natural course. N-acetyl-l-cysteine (the active form) (NAC) is being studied in diseases characterized by increased OS or decreased glutathione (GSH) level. NAC acts mainly on the supply of cysteine for GSH synthesis. The objective of this review is to examine experimental and clinical studies that evaluate the antioxidant and anti-inflammatory roles of NAC in attenuating markers of inflammation and OS in hepatic damage. The results related to the supplementation of NAC in any form of administration and type of study are satisfactory in 85.5% (n = 59) of the cases evaluated (n = 69, 100%). Within this percentage, the dosage of NAC utilized in studies in vivo varied from 0.204 up to 2 g/kg/day. A standard experimental design of protection and treatment as well as the choice of the route of administration, with a broader evaluation of OS and inflammation markers in the serum or other biological matrixes, in animal models, are necessary. Clinical studies are urgently required, to have a clear view, so that, the professionals can be sure about the effectiveness and safety of NAC prescription.
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Haas JT, Francque S, Staels B. Pathophysiology and Mechanisms of Nonalcoholic Fatty Liver Disease. Annu Rev Physiol 2015; 78:181-205. [PMID: 26667070 DOI: 10.1146/annurev-physiol-021115-105331] [Citation(s) in RCA: 299] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders characterized by abnormal hepatic fat accumulation, inflammation, and hepatocyte dysfunction. Importantly, it is also closely linked to obesity and the metabolic syndrome. NAFLD predisposes susceptible individuals to cirrhosis, hepatocellular carcinoma, and cardiovascular disease. Although the precise signals remain poorly understood, NAFLD pathogenesis likely involves actions of the different hepatic cell types and multiple extrahepatic signals. The complexity of this disease has been a major impediment to the development of appropriate metrics of its progression and effective therapies. Recent clinical data place increasing importance on identifying fibrosis, as it is a strong indicator of hepatic disease-related mortality. Preclinical modeling of the fibrotic process remains challenging, particularly in the contexts of obesity and the metabolic syndrome. Future studies are needed to define the molecular pathways determining the natural progression of NAFLD, including key determinants of fibrosis and disease-related outcomes. This review covers the evolving concepts of NAFLD from both human and animal studies. We discuss recent clinical and diagnostic methods assessing NAFLD diagnosis, progression, and outcomes; compare the features of genetic and dietary animal models of NAFLD; and highlight pharmacological approaches for disease treatment.
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Affiliation(s)
- Joel T Haas
- European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France; , .,Université de Lille, F-59000 Lille, France.,INSERM UMR 1011, F-59000 Lille, France.,Institut Pasteur de Lille, F-59000 Lille, France
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2650 Antwerp, Belgium; .,Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Antwerp, Belgium
| | - Bart Staels
- European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France; , .,Université de Lille, F-59000 Lille, France.,INSERM UMR 1011, F-59000 Lille, France.,Institut Pasteur de Lille, F-59000 Lille, France
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Rau M, Schilling AK, Meertens J, Hering I, Weiss J, Jurowich C, Kudlich T, Hermanns HM, Bantel H, Beyersdorf N, Geier A. Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher Frequency of Th17 Cells in the Liver and an Increased Th17/Resting Regulatory T Cell Ratio in Peripheral Blood and in the Liver. THE JOURNAL OF IMMUNOLOGY 2015; 196:97-105. [PMID: 26621860 DOI: 10.4049/jimmunol.1501175] [Citation(s) in RCA: 217] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 10/30/2015] [Indexed: 12/16/2022]
Abstract
Nonalcoholic fatty liver disease is increasing in prevalence. It can be subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Five to twenty percent of cases progress from NAFL to NASH. Increased hepatic Th17 cells and IL-17 expression were observed in NASH mice and patients, respectively. We analyzed CD4(+) effector T cells and regulatory T cells (Tregs) from peripheral blood and livers of NAFL and NASH patients. A total of 51 NAFL patients, 30 NASH patients, 31 nonalcoholic fatty liver disease patients (without histology), and 43 healthy controls were included. FACS analysis was performed on PBMCs and intrahepatic lymphocytes. Compared with healthy controls, a lower frequency of resting Tregs (rTregs; CD4(+)CD45RA(+)CD25(++)) and higher frequencies of IFN-γ(+) and/or IL-4(+) cells were detected among CD4(+) T cells of peripheral blood in NASH, and to a lesser degree in NAFL. In hepatic tissue, NAFL to NASH progression was marked by an increase in IL-17(+) cells among intrahepatic CD4(+) T cells. To define immunological parameters in peripheral blood to distinguish NAFL from NASH, we calculated different ratios. Th17/rTreg and Th2/rTreg ratios were significantly increased in NASH versus NAFL. The relevance of our findings for NASH pathogenesis was highlighted by the normalization of all of the changes 1 y after bariatric surgery. In conclusion, our data indicate that NAFL patients show changes in their immune cell profile compared with healthy controls. NAFL to NASH progression is marked by an increased frequency of IL-17(+) cells among intrahepatic CD4(+) T cells and higher Th17/rTreg and Th2/rTreg ratios in peripheral blood.
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Affiliation(s)
- Monika Rau
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Anne-Kristin Schilling
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Jan Meertens
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Ilona Hering
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Johannes Weiss
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Christian Jurowich
- Department of General and Visceral Surgery, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Theodor Kudlich
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Heike M Hermanns
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Heike Bantel
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; and
| | - Niklas Beyersdorf
- Institute for Virology and Immunobiology, University of Würzburg, 97080 Würzburg, Germany
| | - Andreas Geier
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany;
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Vonghia L, Magrone T, Verrijken A, Michielsen P, Van Gaal L, Jirillo E, Francque S. Peripheral and Hepatic Vein Cytokine Levels in Correlation with Non-Alcoholic Fatty Liver Disease (NAFLD)-Related Metabolic, Histological, and Haemodynamic Features. PLoS One 2015; 10:e0143380. [PMID: 26599575 PMCID: PMC4658042 DOI: 10.1371/journal.pone.0143380] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 11/04/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Haemodynamic impairment, inflammatory mediators and glucose metabolism disturbances have been implicated in the pathogenesis of Non-Alcoholic Fatty Liver Disease (NAFLD). AIM To investigate the cytokine profile in NAFLD patients in peripheral (P) and hepatic venous (HV) blood and to compare with histology, haemodynamic and metabolic parameters. METHODS 40 obese patients with an indication for a transjugular liver biopsy were enrolled. Besides an extended liver and metabolic work-up, interleukin (IL) 1B, IL4, IL6, IL10, IL23, tumour necrosis factor (TNF) α and interferon (INF) γ were measured in plasma obtained from P and HV blood by means of multiplex immunoassay. The T helper (Th)1/Th2, the macrophage M1/M2 and the IL10/IL17a ratios were calculated. RESULTS A decrease of the P-IL10/IL17-ratio and an increase of the P-M1/M2-ratio (p<0.05) were observed in NASH versus no-NASH patients. A P-M1/M2-ratio increase was detected also in patients with portal hypertension in comparison with patients without it (p<0.05). Moreover diabetic patients showed an increase of the P-Th1/Th2-ratio in comparison with non-diabetic ones (p<0.05). The P-M1/M2 ratio positively correlated with steatosis grade (r = 0.39, p = 0.02) and insulin (r = 0.47, p = 0.003). The HV-M1/M2 ratio positively correlated with fasting insulin and Hepatic Venous Pressure Gradient (r = 0.47, p = 0.003). IL6 correlated with the visceral fat amount (r = 0.36, p = 0.02). The P- and HV-IL10/IL17 ratios negatively correlated with fasting insulin (respectively r = -0.4, p = 0.005 and r = 0.4, p = 0.01). CONCLUSIONS A proinflammatory cytokine state is associated with more disturbed metabolic, histological, and haemodynamic features in NAFLD obese patients. An increase of the M1/M2 ratio and a decrease of the IL10/IL17 ratio play a key role in this process.
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Affiliation(s)
- Luisa Vonghia
- Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, Bari, Italy.,Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium
| | - Thea Magrone
- Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, Bari, Italy
| | - An Verrijken
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital Antwerp, Antwerp, Belgium.,Laboratory of Experimental Medicine and Paediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Peter Michielsen
- Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, Bari, Italy.,Laboratory of Experimental Medicine and Paediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Luc Van Gaal
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital Antwerp, Antwerp, Belgium.,Laboratory of Experimental Medicine and Paediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Emilio Jirillo
- Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, Bari, Italy
| | - Sven Francque
- Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, Bari, Italy.,Laboratory of Experimental Medicine and Paediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
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Christ B, Brückner S, Winkler S. The Therapeutic Promise of Mesenchymal Stem Cells for Liver Restoration. Trends Mol Med 2015; 21:673-686. [PMID: 26476857 DOI: 10.1016/j.molmed.2015.09.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 09/04/2015] [Accepted: 09/11/2015] [Indexed: 12/17/2022]
Abstract
Hepatocyte transplantation aims to provide a functional substitution of liver tissue lost due to trauma or toxins. Chronic liver diseases are associated with inflammation, deterioration of tissue homeostasis, and deprivation of metabolic capacity. Recent advances in liver biology have focused on the pro-regenerative features of mesenchymal stem cells (MSCs). We argue that MSCs represent an attractive therapeutic option to treat liver disease. Indeed, their pleiotropic actions include the modulation of immune reactions, the stimulation of cell proliferation, and the attenuation of cell death responses. These characteristics are highly warranted add-ons to their capacity for hepatocyte differentiation. Undoubtedly, the elucidation of the regenerative mechanisms of MSCs in different liver diseases will promote their versatile and disease-specific therapeutic use.
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Affiliation(s)
- Bruno Christ
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, University of Leipzig, Leipzig, Germany.
| | - Sandra Brückner
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, University of Leipzig, Leipzig, Germany
| | - Sandra Winkler
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, University of Leipzig, Leipzig, Germany
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Vonghia L, Francque S. Cross talk of the immune system in the adipose tissue and the liver in non-alcoholic steatohepatitis: Pathology and beyond. World J Hepatol 2015; 7:1905-1912. [PMID: 26244065 PMCID: PMC4517150 DOI: 10.4254/wjh.v7.i15.1905] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 04/30/2015] [Accepted: 06/16/2015] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is considered to be the hepatic manifestation of the metabolic syndrome, thus has a tight correlation with systemic metabolic impairment. The complex mechanisms underlying the pathogenesis of NASH involve different organs and systems that cross talk together contributing to the onset of NASH. A crucial role is played by inflammatory mediators, especially those deriving from the adipose tissue and the liver, which are involved in the cascade of inflammation, fibrosis and eventually tumorigenesis. In this setting cytokines and adipokines as well as immunity are emerging drivers of the key features of NASH. The immune system participates in this process with disturbances of the cells constituting both the innate and the adaptive immune systems that have been reported in different organs, such as in the liver and in the adipose tissue, in clinical and preclinical studies. The role of the immune system in NASH is increasingly studied, not only because of its contribution to the pathogenetic mechanisms of NASH but also because of the new potential therapeutic options it offers in this setting. Indeed, novel treatments acting on the immune system could offer new options in the management of NASH and the correlated clinical consequences.
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Vonghia L, Ruyssers N, Schrijvers D, Pelckmans P, Michielsen P, De Clerck L, Ramon A, Jirillo E, Ebo D, De Winter B, Bridts C, Francque S. CD4+ROR γ t++ and Tregs in a Mouse Model of Diet-Induced Nonalcoholic Steatohepatitis. Mediators Inflamm 2015; 2015:239623. [PMID: 26229237 PMCID: PMC4503578 DOI: 10.1155/2015/239623] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 06/07/2015] [Accepted: 06/14/2015] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND AND AIMS Inflammatory mediators that cross-talk in different metabolically active organs are thought to play a crucial role in the pathogenesis of Nonalcoholic Steatohepatitis (NASH). This study was aimed at investigating the CD4+RORγt+ T-helper cells and their counterpart, the CD4+CD25+FOXP3+ regulatory T cells in the liver, subcutaneous adipose tissue (SAT), and abdominal adipose tissue (AAT) in a high fat diet (HFD) mouse model. METHODS C57BL6 mice were fed a HFD or a normal diet (ND). Liver enzymes, metabolic parameters, and liver histology were assessed. The expression of CD4+RORγt+ cells and regulatory T cells in different organs (blood, liver, AAT, and SAT) were analyzed by flow cytometry. Cytokine and adipokine tissue expression were studied by RT-PCR. RESULTS Mice fed a HFD developed NASH and metabolic alterations compared to normal diet. CD4+RORγt++ cells were significantly increased in the liver and the AAT while an increase of regulatory T cells was observed in the SAT of mice fed HFD compared to ND. Inflammatory cytokines were also upregulated. CONCLUSIONS CD4+RORγt++ cells and regulatory T cells are altered in NASH with a site-specific pattern and correlate with the severity of the disease. These site-specific differences are associated with increased cytokine expression.
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Affiliation(s)
- Luisa Vonghia
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2560 Antwerp, Belgium
- Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, 70100 Bari, Italy
| | - Nathalie Ruyssers
- Laboratory of Experimental Medicine and Paediatrics, Division of Gastroenterology, University of Antwerp, 2560 Antwerp, Belgium
| | - Dorien Schrijvers
- Laboratory of Pharmacology, University of Antwerp, 2560 Antwerp, Belgium
| | - Paul Pelckmans
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2560 Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics, Division of Gastroenterology, University of Antwerp, 2560 Antwerp, Belgium
| | - Peter Michielsen
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2560 Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics, Division of Gastroenterology, University of Antwerp, 2560 Antwerp, Belgium
| | - Luc De Clerck
- Laboratory of Immunology, Allergology and Rheumatology, University of Antwerp, 2560 Antwerp, Belgium
| | - Albert Ramon
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2560 Antwerp, Belgium
- International Tissue Engineering Research Association (ITERA) Life Sciences Forum, 3620 Lanaken, Belgium
- Genetisch-Diagnostisches Labor, 50939 Köln, Germany
| | - Emilio Jirillo
- Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, 70100 Bari, Italy
| | - Didier Ebo
- Laboratory of Immunology, Allergology and Rheumatology, University of Antwerp, 2560 Antwerp, Belgium
| | - Benedicte De Winter
- Laboratory of Experimental Medicine and Paediatrics, Division of Gastroenterology, University of Antwerp, 2560 Antwerp, Belgium
| | - Chris Bridts
- Laboratory of Immunology, Allergology and Rheumatology, University of Antwerp, 2560 Antwerp, Belgium
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2560 Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics, Division of Gastroenterology, University of Antwerp, 2560 Antwerp, Belgium
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Hempel M, Schmitz A, Winkler S, Kucukoglu O, Brückner S, Niessen C, Christ B. Pathological implications of cadherin zonation in mouse liver. Cell Mol Life Sci 2015; 72:2599-612. [PMID: 25687506 PMCID: PMC11113307 DOI: 10.1007/s00018-015-1861-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 02/10/2015] [Accepted: 02/11/2015] [Indexed: 02/07/2023]
Abstract
Both acute and chronic liver diseases are associated with ample re-modeling of the liver parenchyma leading to functional impairment, which is thus obviously the cause or the consequence of the disruption of the epithelial integrity. It was, therefore, the aim of this study to investigate the distribution of the adherens junction components E- and N-cadherin, which are important determinants of tissue cohesion. E-cadherin was expressed in periportal but not in perivenous hepatocytes. In contrast, N-cadherin was more enriched towards the perivenous hepatocytes. In agreement, β-catenin, which links both cadherins via α-catenin to the actin cytoskeleton, was expressed ubiquitously. This zonal expression of cadherins was preserved in acute liver injury after treatment with acetaminophen or partial hepatectomy, but disrupted in chronic liver damage like in non-alcoholic steatohepatitis (NASH) or α1-antitrypsin deficiency. Hepatocyte proliferation during acetaminophen-induced liver damage was predominant at the boundary between the damaged perivenous and the intact periportal parenchyma indicating a minor contribution of periportal hepatocytes to liver regeneration. In NASH livers, an oval cell reaction was observed pointing to massive tissue damage coinciding with the gross impairment of hepatocyte proliferation. In the liver parenchyma, metabolic functions are distributed heterogeneously. For example, the expression of phosphoenolpyruvate carboxykinase and E-cadherin overlapped in periportal hepatocytes. Thus, during liver regeneration after acute damage, the intact periportal parenchyma might sustain essential metabolic support like glucose supply or ammonia detoxification. However, disruption of epithelial integrity during chronic challenges may increase susceptibility to metabolic liver diseases such as NASH or vice versa. This might suggest the regulatory integration of tissue cohesion and metabolic functions in the liver.
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Affiliation(s)
- Madlen Hempel
- Applied Molecular Hepatology Lab, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University of Leipzig, Liebigstraße 21, 04103 Leipzig, Germany
| | - Annika Schmitz
- Department of Dermatology, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Sandra Winkler
- Applied Molecular Hepatology Lab, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University of Leipzig, Liebigstraße 21, 04103 Leipzig, Germany
| | - Ozlem Kucukoglu
- Applied Molecular Hepatology Lab, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University of Leipzig, Liebigstraße 21, 04103 Leipzig, Germany
- Translational Centre for Regenerative Medicine (TRM), Universität Leipzig, Leipzig, Germany
| | - Sandra Brückner
- Applied Molecular Hepatology Lab, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University of Leipzig, Liebigstraße 21, 04103 Leipzig, Germany
| | - Carien Niessen
- Department of Dermatology, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Bruno Christ
- Applied Molecular Hepatology Lab, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University of Leipzig, Liebigstraße 21, 04103 Leipzig, Germany
- Translational Centre for Regenerative Medicine (TRM), Universität Leipzig, Leipzig, Germany
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Choline and Cystine Deficient Diets in Animal Models with Hepatocellular Injury: Evaluation of Oxidative Stress and Expression of RAGE, TNF-α, and IL-1β. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:121925. [PMID: 26137185 PMCID: PMC4468296 DOI: 10.1155/2015/121925] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 05/15/2015] [Accepted: 05/18/2015] [Indexed: 02/06/2023]
Abstract
This study aims to evaluate the effects of diets deficient in choline and/or cystine on hepatocellular injury in animal models (young male Wistar rats, aged 21 days), by monitoring some of the oxidative stress biomarkers and the expression of RAGE, TNF-α, and IL-1β. The animals were divided into 6 groups (n = 10) and submitted to different diets over 30 days: AIN-93 diet (standard, St), AIN-93 choline deficient (CD) diet and AIN-93 choline and cystine deficient (CCD) diet, in the pellet (pl) and powder (pw) diet forms. Independently of the diet form, AIN-93 diet already led to hepatic steatosis and CD/CCD diets provoked hepatic damage. The increase of lipid peroxidation, represented by the evaluation of thiobarbituric acid reactive species, associated with the decrease of levels of antioxidant enzymes, were the parameters with higher significance toward redox profile in this model of hepatic injury. Regarding inflammation, in relation to TNF-α, higher levels were evidenced in CD(pl), while, for IL-1β, no significant alteration was detected. RAGE expression was practically the same in all groups, with exception of CCD(pw) versus CCD(pl). These results together confirm that AIN-93 causes hepatic steatosis and choline and/or cysteine deficiencies produce important hepatic injury associated with oxidative stress and inflammatory profiles.
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Stanimirovic J, Obradovic M, Zafirovic S, Resanovic I, Bogdanovic N, Gluvic Z, Mousa SA, Isenovic ER. Effects of altered hepatic lipid metabolism on regulation of hepatic iNOS. CLINICAL LIPIDOLOGY 2015; 10:167-175. [DOI: 10.2217/clp.15.8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Julijana Stanimirovic
- Vinca Institute of Nuclear Sciences, Laboratory of Radiobiology & Molecular Genetics, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia
| | - Milan Obradovic
- Vinca Institute of Nuclear Sciences, Laboratory of Radiobiology & Molecular Genetics, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia
| | - Sonja Zafirovic
- Vinca Institute of Nuclear Sciences, Laboratory of Radiobiology & Molecular Genetics, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia
| | - Ivana Resanovic
- Vinca Institute of Nuclear Sciences, Laboratory of Radiobiology & Molecular Genetics, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia
| | - Nikola Bogdanovic
- Vinca Institute of Nuclear Sciences, Laboratory of Radiobiology & Molecular Genetics, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia
| | - Zoran Gluvic
- Department of Endocrinology & ITU, Clinical Hospital Center-Zemun, Vukova Street 9, 11080 Zemun, Serbia
| | - Shaker A Mousa
- The Pharmaceutical Research Institute, Albany College of Pharmacy & Health Sciences, 1 Discovery Drive, Rensselaer, NY 12144, USA
| | - Esma R Isenovic
- Vinca Institute of Nuclear Sciences, Laboratory of Radiobiology & Molecular Genetics, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia
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Onofrio LI, Arocena AR, Paroli AF, Cabalén ME, Andrada MC, Cano RC, Gea S. Trypanosoma cruzi infection is a potent risk factor for non-alcoholic steatohepatitis enhancing local and systemic inflammation associated with strong oxidative stress and metabolic disorders. PLoS Negl Trop Dis 2015; 9:e0003464. [PMID: 25668433 PMCID: PMC4323252 DOI: 10.1371/journal.pntd.0003464] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 12/09/2014] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The immune mechanisms underlying experimental non-alcoholic steatohepatitis (NASH), and more interestingly, the effect of T. cruzi chronic infection on the pathogenesis of this metabolic disorder are not completely understood. METHODOLOGY/PRINCIPAL FINDINGS We evaluated immunological parameters in male C57BL/6 wild type and TLR4 deficient mice fed with a standard, low fat diet, LFD (3% fat) as control group, or a medium fat diet, MFD (14% fat) in order to induce NASH, or mice infected intraperitoneally with 100 blood-derived trypomastigotes of Tulahuen strain and also fed with LFD (I+LFD) or MFD (I+MFD) for 24 weeks. We demonstrated that MFD by itself was able to induce NASH in WT mice and that parasitic infection induced marked metabolic changes with reduction of body weight and steatosis revealed by histological studies. The I+MFD group also improved insulin resistance, demonstrated by homeostasis model assessment of insulin resistance (HOMA-IR) analysis; although parasitic infection increased the triglycerides and cholesterol plasma levels. In addition, hepatic M1 inflammatory macrophages and cytotoxic T cells showed intracellular inflammatory cytokines which were associated with high levels of IL6, IFNγ and IL17 plasmatic cytokines and CCL2 chemokine. These findings correlated with an increase in hepatic parasite load in I+MFD group demonstrated by qPCR assays. The recruitment of hepatic B lymphocytes, NK and dendritic cells was enhanced by MFD, and it was intensified by parasitic infection. These results were TLR4 signaling dependent. Flow cytometry and confocal microscopy analysis demonstrated that the reactive oxygen species and peroxinitrites produced by liver inflammatory leukocytes of MFD group were also exacerbated by parasitic infection in our NASH model. CONCLUSIONS We highlight that a medium fat diet by itself is able to induce steatohepatitis. Our results also suggest a synergic effect between damage associated with molecular patterns generated during NASH and parasitic infection, revealing an intense cross-talk between metabolically active tissues, such as the liver, and the immune system. Thus, T. cruzi infection must be considered as an additional risk factor since exacerbates the inflammation and accelerates the development of hepatic injury.
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Affiliation(s)
- Luisina I. Onofrio
- Centro de Investigaciones en Bioquímica Clínica e Inmunología CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Alfredo R. Arocena
- Centro de Investigaciones en Bioquímica Clínica e Inmunología CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Augusto F. Paroli
- Centro de Investigaciones en Bioquímica Clínica e Inmunología CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - María E. Cabalén
- Facultad de Ciencias Químicas, UA Área CS.AGR.ING.BIO Y S-CONICET. Universidad Católica de Córdoba, Córdoba, Argentina
| | - Marta C. Andrada
- Facultad de Ciencias Químicas, UA Área CS.AGR.ING.BIO Y S-CONICET. Universidad Católica de Córdoba, Córdoba, Argentina
| | - Roxana C. Cano
- Centro de Investigaciones en Bioquímica Clínica e Inmunología CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Facultad de Ciencias Químicas, UA Área CS.AGR.ING.BIO Y S-CONICET. Universidad Católica de Córdoba, Córdoba, Argentina
| | - Susana Gea
- Centro de Investigaciones en Bioquímica Clínica e Inmunología CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
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Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model. Exp Cell Res 2014; 326:230-9. [DOI: 10.1016/j.yexcr.2014.04.017] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 04/17/2014] [Accepted: 04/21/2014] [Indexed: 12/20/2022]
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