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Svobodová G, Horní M, Velecká E, Boušová I. Metabolic dysfunction-associated steatotic liver disease-induced changes in the antioxidant system: a review. Arch Toxicol 2025; 99:1-22. [PMID: 39443317 PMCID: PMC11748479 DOI: 10.1007/s00204-024-03889-x] [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: 07/11/2024] [Accepted: 10/09/2024] [Indexed: 10/25/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition characterized by liver steatosis, inflammation, consequent fibrosis, and cirrhosis. Chronic impairment of lipid metabolism is closely related to oxidative stress, leading to cellular lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress. The detrimental effect of oxidative stress is usually accompanied by changes in antioxidant defense mechanisms, with the alterations in antioxidant enzymes expression/activities during MASLD development and progression reported in many clinical and experimental studies. This review will provide a comprehensive overview of the present research on MASLD-induced changes in the catalytic activity and expression of the main antioxidant enzymes (superoxide dismutases, catalase, glutathione peroxidases, glutathione S-transferases, glutathione reductase, NAD(P)H:quinone oxidoreductase) and in the level of non-enzymatic antioxidant glutathione. Furthermore, an overview of the therapeutic effects of vitamin E on antioxidant enzymes during the progression of MASLD will be presented. Generally, at the beginning of MASLD development, the expression/activity of antioxidant enzymes usually increases to protect organisms against the increased production of reactive oxygen species. However, in advanced stage of MASLD, the expression/activity of several antioxidants generally decreases due to damage to hepatic and extrahepatic cells, which further exacerbates the damage. Although the results obtained in patients, in various experimental animal or cell models have been inconsistent, taken together the importance of antioxidant enzymes in MASLD development and progression has been clearly shown.
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Affiliation(s)
- Gabriela Svobodová
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05, Hradec Králové, Czech Republic
| | - Martin Horní
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05, Hradec Králové, Czech Republic
| | - Eva Velecká
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05, Hradec Králové, Czech Republic
| | - Iva Boušová
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05, Hradec Králové, Czech Republic.
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Sabatini S, Sen P, Carli F, Pezzica S, Rosso C, Lembo E, Verrastro O, Daly A, Govaere O, Cockell S, Hyötyläinen T, Mingrone G, Bugianesi E, Anstee QM, Orešič M, Gastaldelli A. Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis. Cell Rep Med 2024; 5:101820. [PMID: 39566466 PMCID: PMC11604487 DOI: 10.1016/j.xcrm.2024.101820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 07/25/2024] [Accepted: 10/16/2024] [Indexed: 11/22/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6-2H2-glucose, U-2H5-glycerol) and liver-specific genome-scale metabolic models (GEMs). Tracer-measured HGP is increased with liver fibrosis and inflammation, but not steatosis, and is associated with lipolysis and IR. The GEM-derived gluconeogenesis is elevated due to high glucogenic/energy metabolite uptakes (lactate, glycerol, and free fatty acid [FFA]), and the expression of insulin action genes (IRS1, IRS2, and AKT2) is reduced in MASH with fibrosis F2-F4, with/without T2D, suggesting these as putative mechanisms for increased fasting HGP and hyperglycemia. In conclusion, elevated HGP, lipolysis, and IR help to explain the mechanisms for the increased risk of hyperglycemia and T2D in MASH.
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Affiliation(s)
- Silvia Sabatini
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy
| | - Partho Sen
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland
| | - Fabrizia Carli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy
| | - Samantha Pezzica
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy
| | - Chiara Rosso
- Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, 10124 Turin, Italy
| | - Erminia Lembo
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Ornella Verrastro
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Ann Daly
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Olivier Govaere
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Simon Cockell
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Tuulia Hyötyläinen
- School of Science and Technology, Örebro University, 70281 Örebro, Sweden
| | - Geltrude Mingrone
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Division of Diabetes & Nutritional Sciences, School of Cardiovascular and Metabolic Medicine & Sciences, King's College Hospital, London, UK
| | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, 10124 Turin, Italy
| | - Quentin M Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne NE7 7DN, UK
| | - Matej Orešič
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; School of Medical Sciences, Örebro University, 70281 Örebro, Sweden.
| | - Amalia Gastaldelli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy; Diabetes Division, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
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Personnaz J, Guillou H, Kautz L. Fibrinogen-like 1: A hepatokine linking liver physiology to hematology. Hemasphere 2024; 8:e115. [PMID: 38966209 PMCID: PMC11223652 DOI: 10.1002/hem3.115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/30/2024] [Accepted: 06/05/2024] [Indexed: 07/06/2024] Open
Abstract
A recent study identified the critical contribution of the hepatokine FGL1 to the regulation of iron metabolism during the recovery from anemia. FGL1 is secreted by hepatocytes in response to hypoxia to sequester BMP ligands and repress the transcription of the iron-regulatory hormone hepcidin. This process ensures the proper supply of iron to the bone marrow for new red blood cell synthesis and the restoration of physiological oxygen levels. FGL1 may therefore contribute to the recovery from common anemias and cause iron overload in chronic anemias with ineffective erythropoiesis, such as ß-thalassemia, dyserythropoietic anemia, and myelodysplastic syndromes. However, FGL1 has also been described as a regulator of hepatocyte proliferation, glucose homeostasis, and insulin signaling, as well as a mediator of liver steatosis and immune evasion. Chronic exposure to elevated levels of FGL1 during anemia may therefore have systemic metabolic effects besides iron regulation and erythropoiesis. Here, we are providing an overview of the proposed functions of FGL1 in physiology and pathophysiology.
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Affiliation(s)
- Jean Personnaz
- IRSD, Université de ToulouseINSERM, INRAE, ENVT, Univ Toulouse III‐Paul Sabatier (UPS)ToulouseFrance
| | - Hervé Guillou
- Toxalim (Research Center in Food Toxicology)INRAE, ENVT, INP‐PURPAN, UMR 1331, UPS, Université de ToulouseToulouseFrance
| | - Léon Kautz
- IRSD, Université de ToulouseINSERM, INRAE, ENVT, Univ Toulouse III‐Paul Sabatier (UPS)ToulouseFrance
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Nguyen VD, Hughes TR, Zhou Y. From complement to complosome in non-alcoholic fatty liver disease: When location matters. Liver Int 2024; 44:316-329. [PMID: 38010880 DOI: 10.1111/liv.15796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/21/2023] [Accepted: 11/09/2023] [Indexed: 11/29/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a growing public health threat and becoming the leading cause of liver transplantation. Nevertheless, no approved specific treatment is currently available for NAFLD. The pathogenesis of NAFLD is multifaceted and not yet fully understood. Accumulating evidence suggests a significant role of the complement system in the development and progression of NAFLD. Here, we provide an overview of the complement system, incorporating the novel concept of complosome, and summarise the up-to-date evidence elucidating the association between complement dysregulation and the pathogenesis of NAFLD. In this process, the extracellular complement system is activated through various pathways, thereby directly contributing to, or working together with other immune cells in the disease development and progression. We also introduce the complosome and assess the evidence that implicates its potential influence in NAFLD through its direct impact on hepatocytes or non-parenchymal liver cells. Additionally, we expound upon how complement system and the complosome may exert their effects in relation with hepatic zonation in NAFLD. Furthermore, we discuss the potential therapeutic implications of targeting the complement system, extracellularly and intracellularly, for NAFLD treatment. Finally, we present future perspectives towards a better understanding of the complement system's contribution to NAFLD.
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Affiliation(s)
- Van-Dien Nguyen
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK
| | - Timothy R Hughes
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK
| | - You Zhou
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK
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Gîlcă-Blanariu GE, Budur DS, Mitrică DE, Gologan E, Timofte O, Bălan GG, Olteanu VA, Ștefănescu G. Advances in Noninvasive Biomarkers for Nonalcoholic Fatty Liver Disease. Metabolites 2023; 13:1115. [PMID: 37999211 PMCID: PMC10672868 DOI: 10.3390/metabo13111115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/15/2023] [Accepted: 10/24/2023] [Indexed: 11/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) currently represents one of the most common liver diseases worldwide. Early diagnosis and disease staging is crucial, since it is mainly asymptomatic, but can progress to nonalcoholic steatohepatitis (NASH) or cirrhosis or even lead to the development of hepatocellular carcinoma. Over time, efforts have been put into developing noninvasive diagnostic and staging methods in order to replace the use of a liver biopsy. The noninvasive methods used include imaging techniques that measure liver stiffness and biological markers, with a focus on serum biomarkers. Due to the impressive complexity of the NAFLD's pathophysiology, biomarkers are able to assay different processes involved, such as apoptosis, fibrogenesis, and inflammation, or even address the genetic background and "omics" technologies. This article reviews not only the currently validated noninvasive methods to investigate NAFLD but also the promising results regarding recently discovered biomarkers, including biomarker panels and the combination of the currently validated evaluation methods and serum markers.
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Affiliation(s)
- Georgiana-Emmanuela Gîlcă-Blanariu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Daniela Simona Budur
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Dana Elena Mitrică
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Elena Gologan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Oana Timofte
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gheorghe Gh Bălan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Vasile Andrei Olteanu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gabriela Ștefănescu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
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Metro D, Buda M, Manasseri L, Corallo F, Cardile D, Lo Buono V, Quartarone A, Bonanno L. Role of Nutrition in the Etiopathogenesis and Prevention of Nonalcoholic Fatty Liver Disease (NAFLD) in a Group of Obese Adults. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59030638. [PMID: 36984639 PMCID: PMC10055888 DOI: 10.3390/medicina59030638] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/15/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is liver damage characterized by an accumulation of triglycerides in hepatocytes of >5% (due to an alteration of the balance of the lipid metabolism in favour of lipogenesis compared to lipolysis) that is not induced by the consumption of alcohol. The pathology includes simple steatosis and nonalcoholic steatohepatitis, or NASH (steatosis associated with microinflammatory activities), which can evolve in 15% of subjects with hepatic fibrosis to cirrhosis and the development of hepatocellular carcinoma. The aim of this study is to report the role of macro- and micronutrients in the pathogenesis and prevention of NAFLD in obese subjects. A total of 22 obese or overweight patients with hepatic steatosis were monitored periodically, evaluating their eating habits, fasting glycaemia, lipid picture, liver enzymes, anthropometric parameters, nutrition status, liver ultrasound, oxidative stress, and adherence to the Mediterranean diet. A statistical analysis shows a significant positive relationship between total cholesterol and the Mediterranean adequacy index (MAI) (r = -0.57; p = 0.005) and a significant negative relationship between ALT transaminases and the MAI (r = -0.56; p = 0.007). Nutrition and diet are important factors in the pathogenesis and prevention of NAFLD. The dietary model, based on the canons of the Mediterranean diet, prevents and reduces the accumulation of fat in hepatocytes. Therefore, in agreement with other studies in the literature, we can state that a dietary model characterized by foods rich in fibre, carotenoids, polyphenols, ω3 fatty acids, folic acid, and numerous other molecules is inversely correlated with the serum levels of ALT transaminases, an enzyme whose level increases when the liver is damaged and before the most obvious symptoms of organ damage appear.
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Affiliation(s)
- Daniela Metro
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98122 Messina, Italy
| | - Martina Buda
- Department Oncological D.A.I., UOC of General Surgery-Oncology, 98125 Messina, Italy
| | - Luigi Manasseri
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98122 Messina, Italy
| | - Francesco Corallo
- IRCCS Centro Neurolesi Bonino-Pulejo, S.S. 113 Via Palermo, C. da Casazza, 98124 Messina, Italy
| | - Davide Cardile
- IRCCS Centro Neurolesi Bonino-Pulejo, S.S. 113 Via Palermo, C. da Casazza, 98124 Messina, Italy
| | - Viviana Lo Buono
- IRCCS Centro Neurolesi Bonino-Pulejo, S.S. 113 Via Palermo, C. da Casazza, 98124 Messina, Italy
| | - Angelo Quartarone
- IRCCS Centro Neurolesi Bonino-Pulejo, S.S. 113 Via Palermo, C. da Casazza, 98124 Messina, Italy
| | - Lilla Bonanno
- IRCCS Centro Neurolesi Bonino-Pulejo, S.S. 113 Via Palermo, C. da Casazza, 98124 Messina, Italy
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Luo Y, Woodie LN, Graff EC, Zhang J, Fowler S, Wang X, Wang X, O'Neill AM, Greene MW. Role of liquid fructose/sucrose in regulating the hepatic transcriptome in a high-fat Western diet model of NAFLD. J Nutr Biochem 2023; 112:109174. [PMID: 36280127 DOI: 10.1016/j.jnutbio.2022.109174] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 08/08/2022] [Accepted: 08/19/2022] [Indexed: 11/07/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD), which ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), is the most common chronic liver disease. Yet, the molecular mechanisms for the progression of steatosis to NASH remain largely undiscovered. Thus, there is a need for identifying specific gene and pathway changes that drive the progression of NAFLD. This study uses high-fat Western diet (HFWD) together with liquid sugar [fructose and sucrose (F/S)] feeding for 12 weeks in mice to induce obesity and examine hepatic transcriptomic changes that occur in NAFLD progression. The combination of a HFWD+F/S in the drinking water exacerbated HFWD-induced obesity, hyperinsulinemia, hyperglycemia, hepatic steatosis, inflammation, and human and murine fibrosis gene set enrichment that is consistent with progression to NASH. RNAseq analysis revealed differentially expressed genes (DEGs) associated with HFWD and HFWD+F/S dietary treatments compared to Chow-fed mice. However, liquid sugar consumption resulted in a unique set of hepatic DEGs in HFWD+F/S-fed mice, which were enriched in the complement and coagulation cascades using network and biological analysis. Cluster analysis identified Orosomucoid (ORM) as a HFWD+F/S upregulated complement and coagulation cascades gene that was also upregulated in hepatocytes treated with TNFα or free fatty acids in combination with hypoxia. ORM expression was found to correlate with NAFLD parameters in obese mice. Taken together, this study examined key genes, biological processes, and pathway changes in the liver of HFWD+F/S mice in an effort to provide insight into the molecular basis for which the addition of liquid sugar promotes the progression of NAFLD.
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Affiliation(s)
| | | | - Emily C Graff
- Department of Pathobiology; Boshell Metabolic Diseases and Diabetes Program, Auburn University, Auburn, Alabama, USA
| | | | | | | | - Xu Wang
- Department of Pathobiology; HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA
| | | | - Michael W Greene
- Department of Nutritional Sciences; Boshell Metabolic Diseases and Diabetes Program, Auburn University, Auburn, Alabama, USA.
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Fatty Liver Disease-Alcoholic and Non-Alcoholic: Similar but Different. Int J Mol Sci 2022; 23:ijms232416226. [PMID: 36555867 PMCID: PMC9783455 DOI: 10.3390/ijms232416226] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
In alcohol-induced liver disease (ALD) and in non-alcoholic fatty liver disease (NAFLD), there are abnormal accumulations of fat in the liver. This phenomenon may be related to excessive alcohol consumption, as well as the combination of alcohol consumption and medications. There is an evolution from simple steatosis to steatohepatitis, fibrosis and cirrhosis leading to hepatocellular carcinoma (HCC). Hepatic pathology is very similar regarding non-alcoholic fatty liver disease (NAFLD) and ALD. Initially, there is lipid accumulation in parenchyma and progression to lobular inflammation. The morphological changes in the liver mitochondria, perivenular and perisinusoidal fibrosis, and hepatocellular ballooning, apoptosis and necrosis and accumulation of fibrosis may lead to the development of cirrhosis and HCC. Medical history of ethanol consumption, laboratory markers of chronic ethanol intake, AST/ALT ratio on the one hand and features of the metabolic syndrome on the other hand, may help in estimating the contribution of alcohol intake and the metabolic syndrome, respectively, to liver steatosis.
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Zhao J, Wu Y, Lu P, Wu X, Han J, Shi Y, Liu Y, Cheng Y, Gao L, Zhao J, Wang Z, Fan X. Association of complement components with the risk and severity of NAFLD: A systematic review and meta-analysis. Front Immunol 2022; 13:1054159. [PMID: 36569882 PMCID: PMC9782972 DOI: 10.3389/fimmu.2022.1054159] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 11/18/2022] [Indexed: 12/14/2022] Open
Abstract
Background It is generally believed that complement system is strongly associated with the risk of nonalcoholic fatty liver disease (NAFLD). However, complement system contains a variety of complement components, and the relationship between complement components and the risk and severity of NAFLD is inconsistent. The aim of this meta-analysis was to evaluate the association of complement components with the risk and severity of NAFLD. Methods We searched PubMed, Embase, Cochrane Library, Google Scholar, Scopus, and ZhiWang Chinese databases from inception to May 2022 for observational studies reporting the risk of NAFLD with complement components. Random-effects meta-analysis was used to obtain pooled estimates of the effect due to heterogeneity. Results We identified 18 studies with a total of 18560 included subjects. According to recent studies, levels of complement component 3 (C3) (mean difference (MD): 0.43, 95% confidence interval (CI) 0.26-0.60), complement component 4 (C4) (MD: 0.04, 95% CI 0.02-0.07), complement component 5(C5) (MD: 34.03, 95% CI 30.80-37.27), complement factor B (CFB) (MD: 0.22, 95% CI 0.13-0.31) and acylation stimulating protein (ASP) (standard mean difference (SMD): 5.17, 95% CI 2.57-7.77) in patients with NAFLD were significantly higher than those in the control group. However, no statistical significance was obtained in complement factor D (CFD) levels between NAFLD and non-NAFLD (MD=156.51, 95% CI -59.38-372.40). Moreover, the levels of C3, C5, CFB, and ASP in patients with moderate and severe NAFLD were significantly higher than those in patients with mild NAFLD. Except for C4 and CFD, the included studies did not explore the changes in the severity of NAFLD according to the concentration of C4 and CFD. Conclusions This meta-analysis demonstrates that an increase in complement components including C3, C5, CFB, and ASP is associated with an increased risk and severity of NAFLD, indicating that they may be good biomarkers and targets for the diagnosis and treatment of NAFLD. Systematic review registration PROSPERO [https://www.crd.york.ac.uk/PROSPERO/], identifier CRD42022348650.
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Affiliation(s)
- Jianbo Zhao
- Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Yafei Wu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Peng Lu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Xiaoqin Wu
- Department of Inflammation and Immunity, Cleveland Clinic, OH, Cleveland, United States
| | - Junming Han
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Yingzhou Shi
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Yue Liu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Yiping Cheng
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Ling Gao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Jiajun Zhao
- Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Zhen Wang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Xiude Fan
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
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10
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Bathish B, Robertson H, Dillon JF, Dinkova-Kostova AT, Hayes JD. Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2. Free Radic Biol Med 2022; 188:221-261. [PMID: 35728768 DOI: 10.1016/j.freeradbiomed.2022.06.226] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 06/13/2022] [Indexed: 12/11/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) represents a global health concern. It is characterised by fatty liver, hepatocyte cell death and inflammation, which are associated with lipotoxicity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, iron overload and oxidative stress. NF-E2 p45-related factor 2 (Nrf2) is a transcription factor that combats oxidative stress. Remarkably, Nrf2 is downregulated during the development of NASH, which probably accelerates disease, whereas in pre-clinical studies the upregulation of Nrf2 inhibits NASH. We now review the scientific literature that proposes Nrf2 downregulation during NASH involves its increased ubiquitylation and proteasomal degradation, mediated by Kelch-like ECH-associated protein 1 (Keap1) and/or β-transducin repeat-containing protein (β-TrCP) and/or HMG-CoA reductase degradation protein 1 (Hrd1, also called synoviolin (SYVN1)). Additionally, downregulation of Nrf2-mediated transcription during NASH may involve diminished recruitment of coactivators by Nrf2, due to increased levels of activating transcription factor 3 (ATF3) and nuclear factor-kappaB (NF-κB) p65, or competition for promoter binding due to upregulation of BTB and CNC homology 1 (Bach1). Many processes that downregulate Nrf2 are triggered by transforming growth factor-beta (TGF-β), with oxidative stress amplifying its signalling. Oxidative stress may also increase suppression of Nrf2 by β-TrCP through facilitating formation of the DSGIS-containing phosphodegron in Nrf2 by glycogen synthase kinase-3. In animal models, knockout of Nrf2 increases susceptibility to NASH, while pharmacological activation of Nrf2 by inducing agents that target Keap1 inhibits development of NASH. These inducing agents probably counter Nrf2 downregulation affected by β-TrCP, Hrd1/SYVN1, ATF3, NF-κB p65 and Bach1, by suppressing oxidative stress. Activation of Nrf2 is also likely to inhibit NASH by ameliorating lipotoxicity, inflammation, ER stress and iron overload. Crucially, pharmacological activation of Nrf2 in mice in which NASH has already been established supresses liver steatosis and inflammation. There is therefore compelling evidence that pharmacological activation of Nrf2 provides a comprehensive multipronged strategy to treat NASH.
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Affiliation(s)
- Boushra Bathish
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK
| | - Holly Robertson
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SA, UK
| | - John F Dillon
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
| | - Albena T Dinkova-Kostova
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK
| | - John D Hayes
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK.
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11
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Vachher M, Bansal S, Kumar B, Yadav S, Arora T, Wali NM, Burman A. Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma. J Cell Biochem 2022; 123:1553-1584. [PMID: 35818831 DOI: 10.1002/jcb.30252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/17/2022] [Accepted: 03/29/2022] [Indexed: 12/16/2022]
Abstract
Globally the incidence of hepatocellular carcinoma (HCC) is on an upsurge. Evidence is accumulating that liver disorders like nonalcoholic fatty liver disease (NAFLD) and its more progressive form nonalcoholic steatohepatitis (NASH) are associated with increased risk of developing HCC. NAFLD has a prevalence of about 25% and 50%-90% in obese population. With the growing burden of obesity epidemic worldwide, HCC presents a major healthcare burden. While cirrhosis is one of the major risk factors of HCC, available literature suggests that NAFLD/NASH associated HCC also develops in minimum or noncirrhotic livers. Therefore, there is an urgent need to understand the pathogenesis and risk factors associated with NAFLD and NASH related HCC that would help in early diagnosis and favorable prognosis of HCC secondary to NAFLD. Adipokines, hepatokines and myokines are factors secreted by adipocytes, hepatocytes and myocytes, respectively, playing essential roles in cellular homeostasis, energy balance and metabolism with autocrine, paracrine and endocrine effects. In this review, we endeavor to focus on the role of these organokines in the pathogenesis of NAFLD/NASH and its progression to HCC to augment the understanding of the factors stimulating hepatocytes to acquire a malignant phenotype. This shall aid in the development of novel therapeutic strategies and tools for early diagnosis of NAFLD/NASH and HCC.
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Affiliation(s)
- Meenakshi Vachher
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Savita Bansal
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Bhupender Kumar
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Sandeep Yadav
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Taruna Arora
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Nalini Moza Wali
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
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12
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Protective Effects of Sesamol against Liver Oxidative Stress and Inflammation in High-Fat Diet-Induced Hepatic Steatosis. Nutrients 2021; 13:nu13124484. [PMID: 34960036 PMCID: PMC8704932 DOI: 10.3390/nu13124484] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/12/2021] [Accepted: 12/14/2021] [Indexed: 12/30/2022] Open
Abstract
Chronic high-fat diet (HFD) is associated with the onset and progression of hepatic steatosis, and oxidative stress is highly involved in this process. The potential role of sesamol (SEM) against oxidative stress and inflammation at the transcriptional level in a mice model of hepatic steatosis is not known. In this study, we aimed to investigate the scavenging effects of SEM towards reactive oxygen generated by lipid accumulation in the liver of obese mice and to explore the mechanisms of protection. Markers of oxidative stress, vital enzymes involved in stimulating oxidative stress or inflammation, and nuclear transcription of Nrf2 were examined. Our results showed that SEM significantly inhibited the activity of the HFD-induced hepatic enzymes CYP2E1 and NOX2, associated with oxidative stress generation. Additionally, SEM reversed HFD-induced activation of NF-κB, a redox-sensitive transcription factor, and attenuated the expression of hepatic TNF-α, a proinflammatory molecule. Moreover, SEM enhanced HFD-induced hepatic Nrf2 nuclear transcription and increased the levels of its downstream target genes Ho1 and Nqo1, which indicated antiinflammation and antioxidant properties. Our study suggests that chronic HFD led to hepatic steatosis, while SEM exhibited protective effects on the liver by counteracting the oxidative stress and inflammation induced by HFD. The underlying mechanism might involve multiple pathways at the transcriptional level; the antioxidant defense mechanism was in partly mediated by the upregulation of Nrf2.
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13
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Subudhi S, Drescher HK, Dichtel LE, Bartsch LM, Chung RT, Hutter MM, Gee DW, Meireles OR, Witkowski ER, Gelrud L, Masia R, Osganian SA, Gustafson JL, Rwema S, Bredella MA, Bhatia SN, Warren A, Miller KK, Lauer GM, Corey KE. Distinct Hepatic Gene-Expression Patterns of NAFLD in Patients With Obesity. Hepatol Commun 2021; 6:77-89. [PMID: 34558849 PMCID: PMC8710788 DOI: 10.1002/hep4.1789] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 06/13/2021] [Indexed: 02/06/2023] Open
Abstract
Approaches to manage nonalcoholic fatty liver disease (NAFLD) are limited by an incomplete understanding of disease pathogenesis. The aim of this study was to identify hepatic gene‐expression patterns associated with different patterns of liver injury in a high‐risk cohort of adults with obesity. Using the NanoString Technologies (Seattle, WA) nCounter assay, we quantified expression of 795 genes, hypothesized to be involved in hepatic fibrosis, inflammation, and steatosis, in liver tissue from 318 adults with obesity. Liver specimens were categorized into four distinct NAFLD phenotypes: normal liver histology (NLH), steatosis only (steatosis), nonalcoholic steatohepatitis without fibrosis (NASH F0), and NASH with fibrosis stage 1‐4 (NASH F1‐F4). One hundred twenty‐five genes were significantly increasing or decreasing as NAFLD pathology progressed. Compared with NLH, NASH F0 was characterized by increased inflammatory gene expression, such as gamma‐interferon‐inducible lysosomal thiol reductase (IFI30) and chemokine (C‐X‐C motif) ligand 9 (CXCL9), while complement and coagulation related genes, such as C9 and complement component 4 binding protein beta (C4BPB), were reduced. In the presence of NASH F1‐F4, extracellular matrix degrading proteinases and profibrotic/scar deposition genes, such as collagens and transforming growth factor beta 1 (TGFB1), were simultaneously increased, suggesting a dynamic state of tissue remodeling. Conclusion: In adults with obesity, distinct states of NAFLD are associated with intrahepatic perturbations in genes related to inflammation, complement and coagulation pathways, and tissue remodeling. These data provide insights into the dynamic pathogenesis of NAFLD in high‐risk individuals.
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Affiliation(s)
- Sonu Subudhi
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Hannah K Drescher
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Laura E Dichtel
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lea M Bartsch
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Raymond T Chung
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Matthew M Hutter
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Denise W Gee
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ozanan R Meireles
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Elan R Witkowski
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Louis Gelrud
- Department of Medicine, St. Mary's Hospital Bon Secours, Richmond, VA, USA
| | - Ricard Masia
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Stephanie A Osganian
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jenna L Gustafson
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Steve Rwema
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Miriam A Bredella
- Division of Musculoskeletal Radiology and Interventions, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Sangeeta N Bhatia
- Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Andrew Warren
- Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Karen K Miller
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Georg M Lauer
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Kathleen E Corey
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Wernberg CW, Ravnskjaer K, Lauridsen MM, Thiele M. The Role of Diagnostic Biomarkers, Omics Strategies, and Single-Cell Sequencing for Nonalcoholic Fatty Liver Disease in Severely Obese Patients. J Clin Med 2021; 10:930. [PMID: 33804302 PMCID: PMC7957539 DOI: 10.3390/jcm10050930] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/23/2021] [Accepted: 02/24/2021] [Indexed: 12/29/2022] Open
Abstract
Liver disease due to metabolic dysfunction constitute a worldwide growing health issue. Severe obesity is a particularly strong risk factor for non-alcoholic fatty liver disease, which affects up to 93% of these patients. Current diagnostic markers focus on the detection of advanced fibrosis as the major predictor of liver-related morbidity and mortality. The most accurate diagnostic tools use elastography to measure liver stiffness, with diagnostic accuracies similar in normal-weight and severely obese patients. The effectiveness of elastography tools are however hampered by limitations to equipment and measurement quality in patients with very large abdominal circumference and subcutaneous fat. Blood-based biomarkers are therefore attractive, but those available to date have only moderate diagnostic accuracy. Ongoing technological advances in omics technologies such as genomics, transcriptomics, and proteomics hold great promise for discovery of biomarkers and increased pathophysiological understanding of non-alcoholic liver disease and steatohepatitis. Very recent developments have allowed for single-cell sequencing and cell-type resolution of gene expression and function. In the near future, we will therefore likely see a multitude of breakthrough biomarkers, developed from a deepened understanding of the biological function of individual cell types in the healthy and injured liver.
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Affiliation(s)
- Charlotte W. Wernberg
- Department of Gastroenterology and Hepatology, Hospital Southwest of Jutland, 6700 Esbjerg, Denmark; (C.W.W.); (M.M.L.)
- Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense, Denmark;
| | - Kim Ravnskjaer
- Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense, Denmark;
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark
| | - Mette M. Lauridsen
- Department of Gastroenterology and Hepatology, Hospital Southwest of Jutland, 6700 Esbjerg, Denmark; (C.W.W.); (M.M.L.)
- Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense, Denmark;
| | - Maja Thiele
- Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense, Denmark;
- Center for Liver Research, Department of Hepatology and Gastroenterology, Odense University Hospital, 5000 Odense, Denmark
- Institute for Clinical Research, University of Southern Denmark, 5230 Odense, Denmark
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15
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New insight and potential therapy for NAFLD: CYP2E1 and flavonoids. Biomed Pharmacother 2021; 137:111326. [PMID: 33556870 DOI: 10.1016/j.biopha.2021.111326] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 01/21/2021] [Accepted: 01/25/2021] [Indexed: 12/13/2022] Open
Abstract
Over the years, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased year by year; however, due to its complicated pathogenesis, there is no effective treatment so far. It is reported that Cytochrome P450 2E1 (CYP2E1) plays an indispensable role in the development of NAFLD, and numerous studies have shown that flavonoids have a hepatoprotective effect and can exert a beneficial effect on NAFLD by regulating the activity of CYP2E1. Therefore, flavonoids may become effective drugs for the treatment of NAFLD in the future. This prompted us to review the research progress of the pathological mechanism of NAFLD and the impact of CYP2E1 activity changes during the pathological process, and to summarize the protective effect of flavonoids against CYP2E1 activity.
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16
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Nunes VS, Andrade AR, Guedes ALV, Diniz MA, Oliveira CP, CanÇado ELR. DISTINCT PHENOTYPE OF NON-ALCOHOLIC FATTY LIVER DISEASE IN PATIENTS WITH LOW LEVELS OF FREE COPPER AND OF CERULOPLASMIN. ARQUIVOS DE GASTROENTEROLOGIA 2021; 57:249-253. [PMID: 32935743 DOI: 10.1590/s0004-2803.202000000-47] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 06/05/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Copper deficiency has been linked to alterations in lipid metabolism and hepatic steatosis. Oxidative stress plays a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). One of the enzymes that neutralize oxidative stress is Cu/Zn superoxide dismutase, which depends on the availability of adequate amounts of copper. OBJECTIVE Correlate the levels of ceruloplasmin and of non-ceruloplasmin-bound copper (NCBC) with clinical, biochemical and histological parameters of non-alcoholic fatty liver disease (NAFLD) patients. METHODS Data from 95 consecutively admitted NAFLD patients who underwent liver biopsy composed the groups based on ceruloplasmin levels lower than 25 mg/dL and on negative NCBC. The risk factors for NAFLD in each group were compared. RESULTS Body mass index was lower in patients with ceruloplasmin <25 mg/dL (29.1±3.47 vs 32.8±6.24 kg/m2; P=0.005) as were the levels of LDL, HDL and total cholesterol, when compared with their counterparts with ceruloplasmin >25 mg/dL (101±38 vs 116±35 mg/dL, P=0.05; 43±9 vs 51±16 mg/dL, P=0.01; 174±43 vs 197±39 mg/dL, P=0.01, respectively). Mean serum ferritin levels were higher in the ceruloplasmin <25 mg/dL group (343±327 vs 197±190 ng/mL; P=0.02). Otherwise, patients with negative NCBC had higher HOMA-IR (8.2±14.7 vs 4.6±3.7; P=0.03). Age, gender, hypertension and diabetes showed no statistical difference. CONCLUSION Patients with NAFLD had different clinical and biochemical markers according to the levels of NCBC and ceruloplasmin.
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Affiliation(s)
- Vinicius S Nunes
- Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Departamento de Gastroenterologia, São Paulo, SP, Brasil
| | - Adriana R Andrade
- Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Departamento de Gastroenterologia, São Paulo, SP, Brasil
| | - Ana L V Guedes
- Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Departamento de Gastroenterologia, São Paulo, SP, Brasil
| | - Marcio A Diniz
- Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Departamento de Gastroenterologia, São Paulo, SP, Brasil
| | - Claudia P Oliveira
- Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Departamento de Gastroenterologia, São Paulo, SP, Brasil
| | - Eduardo L R CanÇado
- Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Departamento de Gastroenterologia, São Paulo, SP, Brasil
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17
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Luo Y, Lin H. Inflammation initiates a vicious cycle between obesity and nonalcoholic fatty liver disease. IMMUNITY INFLAMMATION AND DISEASE 2020; 9:59-73. [PMID: 33332766 PMCID: PMC7860600 DOI: 10.1002/iid3.391] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/23/2020] [Accepted: 11/26/2020] [Indexed: 12/14/2022]
Abstract
Low‐level of chronic inflammation activation is characteristic of obesity. Nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity and is an emerging health problem, it originates from abnormal accumulation of triglycerides in the liver, and sometimes causes inflammatory reactions that could contribute to cirrhosis and liver cancer, thus its pathogenesis needs to be clarified for more treatment options. Once NAFLD is established, it contributes to systemic inflammation, the low‐grade inflammation is continuously maintained during NAFLD causing impaired resolution of inflammation in obesity, which subsequently exacerbates its severity. This study focuses on the effects of obesity‐induced inflammations, which are the underlying causes of the disease progression and development of more severe inflammatory and fibrotic stages. Understanding the relationship between obesity and NAFLD could help in establishing attractive therapeutic targets or diagnostic markers in obesity‐induced inflammation response and provides new approaches for the prevention and treatment of NAFLD in obesity.
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Affiliation(s)
- Yunfei Luo
- Department of Pathophysiology, Schools of Basic Sciences, Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University, Nanchang, China
| | - Hui Lin
- Department of Pathophysiology, Schools of Basic Sciences, Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University, Nanchang, China
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18
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Perakakis N, Stefanakis K, Mantzoros CS. The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease. Metabolism 2020; 111S:154320. [PMID: 32712221 PMCID: PMC7377759 DOI: 10.1016/j.metabol.2020.154320] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/15/2020] [Accepted: 07/18/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose spectrum covers clinical, histological and pathophysiological developments ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and liver fibrosis, potentially evolving into cirrhosis, hepatocellular carcinoma and liver failure. Liver biopsy remains the gold standard for diagnosing NAFLD, while there are no specific treatments. An ever-increasing number of high-throughput Omics investigations on the molecular pathobiology of NAFLD at the cellular, tissue and system levels produce comprehensive biochemical patient snapshots. In the clinical setting, these applications are considerably enhancing our efforts towards obtaining a holistic insight on NAFLD pathophysiology. Omics are also generating non-invasive diagnostic modalities for the distinct stages of NAFLD, that remain though to be validated in multiple, large, heterogenous and independent cohorts, both cross-sectionally as well as prospectively. Finally, they aid in developing novel therapies. By tracing the flow of information from genomics to epigenomics, transcriptomics, proteomics, metabolomics, lipidomics and glycomics, the chief contributions of these techniques in understanding, diagnosing and treating NAFLD are summarized herein.
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Affiliation(s)
- Nikolaos Perakakis
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA..
| | - Konstantinos Stefanakis
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Christos S Mantzoros
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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19
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Watt MJ, Miotto PM, De Nardo W, Montgomery MK. The Liver as an Endocrine Organ-Linking NAFLD and Insulin Resistance. Endocr Rev 2019; 40:1367-1393. [PMID: 31098621 DOI: 10.1210/er.2019-00034] [Citation(s) in RCA: 380] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/04/2019] [Indexed: 02/06/2023]
Abstract
The liver is a dynamic organ that plays critical roles in many physiological processes, including the regulation of systemic glucose and lipid metabolism. Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. Through the use of advanced mass spectrometry "omics" approaches and detailed experimentation in cells, mice, and humans, we now understand that the liver secretes a wide array of proteins, metabolites, and noncoding RNAs (miRNAs) and that many of these secreted factors exert powerful effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the rapidly evolving field of "hepatokine" biology with a particular focus on delineating previously unappreciated communication between the liver and other tissues in the body. We describe the NAFLD-induced changes in secretion of liver proteins, lipids, other metabolites, and miRNAs, and how these molecules alter metabolism in liver, muscle, adipose tissue, and pancreas to induce insulin resistance. We also synthesize the limited information that indicates that extracellular vesicles, and in particular exosomes, may be an important mechanism for intertissue communication in normal physiology and in promoting metabolic dysregulation in NAFLD.
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Affiliation(s)
- Matthew J Watt
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
| | - Paula M Miotto
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
| | - William De Nardo
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
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Bessone F, Razori MV, Roma MG. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci 2019; 76:99-128. [PMID: 30343320 PMCID: PMC11105781 DOI: 10.1007/s00018-018-2947-0] [Citation(s) in RCA: 373] [Impact Index Per Article: 62.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/10/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a main hepatic manifestation of metabolic syndrome. It represents a wide spectrum of histopathological abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis and, eventually, cirrhosis and hepatocellular carcinoma. While hepatic simple steatosis seems to be a rather benign manifestation of hepatic triglyceride accumulation, the buildup of highly toxic free fatty acids associated with insulin resistance-induced massive free fatty acid mobilization from adipose tissue and the increased de novo hepatic fatty acid synthesis from glucose acts as the "first hit" for NAFLD development. NAFLD progression seems to involve the occurrence of "parallel, multiple-hit" injuries, such as oxidative stress-induced mitochondrial dysfunction, endoplasmic reticulum stress, endotoxin-induced, TLR4-dependent release of inflammatory cytokines, and iron overload, among many others. These deleterious factors are responsible for the triggering of a number of signaling cascades leading to inflammation, cell death, and fibrosis, the hallmarks of NASH. This review is aimed at integrating the overwhelming progress made in the characterization of the physiopathological mechanisms of NAFLD at a molecular level, to better understand the factor influencing the initiation and progression of the disease.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - María Valeria Razori
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina.
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Bessone F, Dirchwolf M, Rodil MA, Razori MV, Roma MG. Review article: drug-induced liver injury in the context of nonalcoholic fatty liver disease - a physiopathological and clinical integrated view. Aliment Pharmacol Ther 2018; 48:892-913. [PMID: 30194708 DOI: 10.1111/apt.14952] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 03/25/2018] [Accepted: 07/30/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Nonalcoholic fatty disease (NAFLD) is the most common liver disease, since it is strongly associated with obesity and metabolic syndrome pandemics. NAFLD may affect drug disposal and has common pathophysiological mechanisms with drug-induced liver injury (DILI); this may predispose to hepatoxicity induced by certain drugs that share these pathophysiological mechanisms. In addition, drugs may trigger fatty liver and inflammation per se by mimicking NAFLD pathophysiological mechanisms. AIMS To provide a comprehensive update on (a) potential mechanisms whereby certain drugs can be more hepatotoxic in NAFLD patients, (b) the steatogenic effects of drugs, and (c) the mechanism involved in drug-induced steatohepatitis (DISH). METHODS A language- and date-unrestricted Medline literature search was conducted to identify pertinent basic and clinical studies on the topic. RESULTS Drugs can induce macrovesicular steatosis by mimicking NAFLD pathogenic factors, including insulin resistance and imbalance between fat gain and loss. Other forms of hepatic fat accumulation exist, such as microvesicular steatosis and phospholipidosis, and are mostly associated with acute mitochondrial dysfunction and defective lipophagy, respectively. Drug-induced mitochondrial dysfunction is also commonly involved in DISH. Patients with pre-existing NAFLD may be at higher risk of DILI induced by certain drugs, and polypharmacy in obese individuals to treat their comorbidities may be a contributing factor. CONCLUSIONS The relationship between DILI and NAFLD may be reciprocal: drugs can cause NAFLD by acting as steatogenic factors, and pre-existing NAFLD could be a predisposing condition for certain drugs to cause DILI. Polypharmacy associated with obesity might potentiate the association between this condition and DILI.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - Melisa Dirchwolf
- Unidad de Transplante Hepático, Servicio de Hepatología, Hospital Privado de Rosario, Rosario, Argentina
| | - María Agustina Rodil
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - María Valeria Razori
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
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Catalase and nonalcoholic fatty liver disease. Pflugers Arch 2018; 470:1721-1737. [PMID: 30120555 DOI: 10.1007/s00424-018-2195-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/01/2018] [Accepted: 08/06/2018] [Indexed: 02/06/2023]
Abstract
Obesity and insulin resistance are considered the main causes of nonalcoholic fatty liver disease (NAFLD), and oxidative stress accelerates the progression of NAFLD. Free fatty acids, which are elevated in the liver by obesity or insulin resistance, lead to incomplete oxidation in the mitochondria, peroxisomes, and microsomes, leading to the production of reactive oxygen species (ROS). Among the ROS generated, H2O2 is mainly produced in peroxisomes and decomposed by catalase. However, when the H2O2 concentration increases because of decreased expression or activity of catalase, it migrates to cytosol and other organelles, causing cell injury and participating in the Fenton reaction, resulting in serious oxidative stress. To date, numerous studies have been shown to inhibit the pathogenesis of NAFLD, but treatment for this disease mainly depends on weight loss and exercise. Various molecules such as vitamin E, metformin, liraglutide, and resveratrol have been proposed as therapeutic agents, but further verification of the dose setting, clinical application, and side effects is needed. Reducing oxidative stress may be a fundamental method for improving not only the progression of NAFLD but also obesity and insulin resistance. However, the relationship between NAFLD progression and antioxidants, particularly catalase, which is most commonly expressed in the liver, remains unclear. Therefore, this review summarizes the role of catalase, focusing on its potential therapeutic effects in NAFLD progression.
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Takahashi H, Kotani K, Tanaka K, Egucih Y, Anzai K. Therapeutic Approaches to Nonalcoholic Fatty Liver Disease: Exercise Intervention and Related Mechanisms. Front Endocrinol (Lausanne) 2018; 9:588. [PMID: 30374329 PMCID: PMC6196235 DOI: 10.3389/fendo.2018.00588] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 09/17/2018] [Indexed: 12/16/2022] Open
Abstract
Exercise training ameliorates nonalcoholic fatty liver disease (NAFLD) as well as obesity and metabolic syndrome. Although it is difficult to eliminate the effects of body weight reduction and increased energy expenditure-some pleiotropic effects of exercise training-a number of studies involving either aerobic exercise training or resistance training programs showed ameliorations in NAFLD that are independent of the improvements in obesity and insulin resistance. In vivo studies have identified effects of exercise training on the liver, which may help to explain the "direct" or "independent" effect of exercise training on NAFLD. Exercise training increases peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression, improves mitochondrial function and leads to reduced hepatic steatosis, inflammation, fibrosis, and tumor genesis. Crosstalk between the liver and adipose tissue, skeletal muscle and the microbiome is also a possible mechanism for the effect of exercise training on NAFLD. Although numerous studies have reported benefits of exercise training on NAFLD, the optimal duration and intensity of exercise for the prevention or treatment of NAFLD have not been established. Maintaining adherence of patients with NAFLD to exercise training regimes is another issue to be resolved. The use of comprehensive analytical approaches to identify biomarkers such as hepatokines that specifically reflect the effect of exercise training on liver functions might help to monitor the effect of exercise on NAFLD, and thereby improve adherence of these patients to exercise training. Exercise training is a robust approach for alleviating the pathogenesis of NAFLD, although further clinical and experimental studies are required.
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Affiliation(s)
- Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
- Liver Center, Saga University Hospital, Saga University, Saga, Japan
| | - Kazuhiko Kotani
- Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Kenichi Tanaka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Yuichiro Egucih
- Liver Center, Saga University Hospital, Saga University, Saga, Japan
| | - Keizo Anzai
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
- *Correspondence: Keizo Anzai
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Machado MV, Diehl AM. Pathogenesis of Nonalcoholic Fatty Liver Disease. ZAKIM AND BOYER'S HEPATOLOGY 2018:369-390.e14. [DOI: 10.1016/b978-0-323-37591-7.00025-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Mendes IKS, Matsuura C, Aguila MB, Daleprane JB, Martins MA, Mury WV, Brunini TMC. Weight loss enhances hepatic antioxidant status in a NAFLD model induced by high-fat diet. Appl Physiol Nutr Metab 2018; 43:23-29. [PMID: 28834687 DOI: 10.1139/apnm-2017-0317] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a benign condition that can progress to more severe liver damage in a process mediated, in part, by disturbances in redox balance. Additionally, some argue that it is set to become the main cause of end-stage liver disease in the near future. Here, we investigated whether diet-induced weight loss is able to reverse hepatic lipid accumulation and reduce oxidative stress in liver from C57BL/6 mice fed a high-fat (HF) diet. Male C57BL/6 mice were divided into 4 groups: standard chow (SC; 10% energy from fat, 16 weeks); HF (50% energy from fat, 16 weeks); SC-HF (SC for 8 weeks followed by HF for 8 weeks); and HF-SC (HF for 8 weeks followed by SC for 8 weeks). The HF diet during 8 (SC-HF) and 16 weeks (HF) downregulated messenger RNA levels and protein expression of Nrf2 and endogenous antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase) in the liver; caused liver steatosis; affected liver function markers; increased intra-abdominal and subcutaneous adipose tissue; and induced glucose intolerance and hypercholesterolemia compared with controls (SC). Diet-induced weight loss significantly reduced the intrahepatic lipid accumulation, improved glucose tolerance, and restored both gene and protein expression of the antioxidant enzymes. Our findings suggest that a dietary intervention aimed to induce weight loss may exert protective effects in NAFLD as it can reduce hepatic oxidative stress and intrahepatic lipid accumulation, which can hinder the progression of this condition to more severe states.
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Affiliation(s)
- Iara Karise Santos Mendes
- a Department of Pharmacology and Psychobiology, University of the State of Rio de Janeiro, Rio de Janeiro 20551-030, Brazil
| | - Cristiane Matsuura
- a Department of Pharmacology and Psychobiology, University of the State of Rio de Janeiro, Rio de Janeiro 20551-030, Brazil
| | - Marcia Barbosa Aguila
- b Laboratory of Morphometry and Cardiovascular Morphology, University of the State of Rio de Janeiro, Rio de Janeiro 20551-030, Brazil
| | - Julio Beltrame Daleprane
- c Laboratory for Studies on Interactions between Nutrition and Genetics, Department of Basic and Experimental Nutrition, University of the State of Rio de Janeiro, Rio de Janeiro 20550-900, Brazil
| | - Marcela Anjos Martins
- a Department of Pharmacology and Psychobiology, University of the State of Rio de Janeiro, Rio de Janeiro 20551-030, Brazil
| | - Wanda Vianna Mury
- a Department of Pharmacology and Psychobiology, University of the State of Rio de Janeiro, Rio de Janeiro 20551-030, Brazil
| | - Tatiana Marlowe Cunha Brunini
- a Department of Pharmacology and Psychobiology, University of the State of Rio de Janeiro, Rio de Janeiro 20551-030, Brazil
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Shearn CT, Saba LM, Roede JR, Orlicky DJ, Shearn AH, Petersen DR. Differential carbonylation of proteins in end-stage human fatty and nonfatty NASH. Free Radic Biol Med 2017; 113:280-290. [PMID: 28988798 PMCID: PMC5704928 DOI: 10.1016/j.freeradbiomed.2017.10.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 10/02/2017] [Accepted: 10/04/2017] [Indexed: 02/06/2023]
Abstract
OBJECTIVE In the liver, a contributing factor in the pathogenesis of non-alcoholic fatty liver disease is oxidative stress leading to the accumulation of highly reactive electrophilic α/β unsaturated aldehydes. The objective of this study was to determine if significant differences were evident when evaluating carbonylation in human end-stage fatty nonalcoholic steatohepatitis (fNASH) compared to end-stage nonfatty NASH (nfNASH). METHODS Using hepatic tissue obtained from healthy humans and patients diagnosed with end stage nfNASH or fNASH, overall carbonylation was assessed by immunohistochemistry (IHC) and LC-MS/MS followed by bioinformatics. RESULTS Picrosirius red staining revealed extensive fibrosis in both fNASH and nfNASH which corresponded with increased reactive aldehyde staining. Although significantly elevated when compared to normal hepatic tissue, no significant differences in overall carbonylation and fibrosis were evident when comparing fNASH with nfNASH. Examining proteins that are critical for anti-oxidant defense revealed elevated expression of thioredoxin, thioredoxin interacting protein, glutathione S-transferase p1 and mitochondrial superoxide dismutase in human NASH. As important, using immunohistochemistry, significant colocalization of the aforementioned proteins occurred in cytokeratin 7 positive cells indicating that they are part of the ductular reaction. Expression of catalase and Hsp70 decreased in both groups when compared to normal human liver. Mass spectrometric analysis revealed a total of 778 carbonylated proteins. Of these, 194 were common to all groups, 124 unique to tissue prepared from healthy individuals, 357 proteins exclusive to NASH, 124 proteins distinct to samples from patients with fNASH and 178 unique to nfNASH. Using functional enrichment analysis of hepatic carbonylated proteins revealed a propensity for increased carbonylation of proteins regulating cholesterol and Huntington's disease related pathways occurred in nfNASH. Examining fNASH, increased carbonylation was evident in proteins regulating Rho cytoskeletal pathways, nicotinic acetylcholine receptor signaling and chemokine/cytokine inflammatory pathways. Using LC-MS/MS analysis and trypsin digests, sites of carbonylation were identified on peptides isolated from vimentin, endoplasmin and serum albumin in nfNASH and fNASH respectively. CONCLUSIONS These results indicate that cellular factors regulating mechanisms of protein carbonylation may be different depending on pathological diagnosis of NASH. Furthermore these studies are the first to use LC-MS/MS analysis of carbonylated proteins in human NAFLD and explore possible mechanistic links with end stage cirrhosis due to fatty liver disease and the generation of reactive aldehydes.
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Affiliation(s)
- Colin T Shearn
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States.
| | - Laura M Saba
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - James R Roede
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - David J Orlicky
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Alisabeth H Shearn
- Alpine Achievement Systems, Inc., 9635 Maroon Circle, Suite 120, Englewood, CO 80112, United States
| | - Dennis R Petersen
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
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Atanasovska B, Rensen SS, van der Sijde MR, Marsman G, Kumar V, Jonkers I, Withoff S, Shiri-Sverdlov R, Greve JWM, Faber KN, Moshage H, Wijmenga C, van de Sluis B, Hofker MH, Fu J. A liver-specific long noncoding RNA with a role in cell viability is elevated in human nonalcoholic steatohepatitis. Hepatology 2017; 66:794-808. [PMID: 28073183 DOI: 10.1002/hep.29034] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 12/12/2016] [Accepted: 01/06/2017] [Indexed: 12/28/2022]
Abstract
UNLABELLED Hepatocyte apoptosis in nonalcoholic steatohepatitis (NASH) can lead to fibrosis and cirrhosis, which permanently damage the liver. Understanding the regulation of hepatocyte apoptosis is therefore important to identify therapeutic targets that may prevent the progression of NASH to fibrosis. Recently, increasing evidence has shown that long noncoding (lnc) RNAs are involved in various biological processes and that their dysregulation underlies a number of complex human diseases. By performing gene expression profiling of 4,383 lncRNAs in 82 liver samples from individuals with NASH (n = 48), simple steatosis but no NASH (n = 11), and healthy controls (n = 23), we discovered a liver-specific lncRNA (RP11-484N16.1) on chromosome 18 that showed significantly elevated expression in the liver tissue of NASH patients. This lncRNA, which we named lnc18q22.2 based on its chromosomal location, correlated with NASH grade (r = 0.51, P = 8.11 × 10-7 ), lobular inflammation (r = 0.49, P = 2.35 × 10-6 ), and nonalcoholic fatty liver disease activity score (r = 0.48, P = 4.69 × 10-6 ). The association of lnc18q22.2 to liver steatosis and steatohepatitis was replicated in 44 independent liver biopsies (r = 0.47, P = 0.0013). We provided a genetic structure of lnc18q22.2 showing an extended exon 2 in liver. Knockdown of lnc18q22.2 in four different hepatocyte cell lines resulted in severe phenotypes ranging from reduced cell growth to lethality. This observation was consistent with pathway analyses of genes coexpressed with lnc18q22.2 in human liver or affected by lnc18q22.2 knockdown. CONCLUSION We identified an lncRNA that can play an important regulatory role in liver function and provide new insights into the regulation of hepatocyte viability in NASH. (Hepatology 2017;66:794-808).
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Affiliation(s)
- Biljana Atanasovska
- Department of Pediatrics, Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Sander S Rensen
- Department of Surgery, University Hospital Maastricht, and Nutrition and Toxicology Research Institute, University of Maastricht, Maastricht, The Netherlands
| | - Marijke R van der Sijde
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Glenn Marsman
- Department of Pediatrics, Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Vinod Kumar
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Iris Jonkers
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Sebo Withoff
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ronit Shiri-Sverdlov
- Departments of Molecular Genetics, Molecular Cell Biology, and Population Genetics, Nutrition and Toxicology Research Institute, University of Maastricht, Maastricht, The Netherlands
| | - Jan Willem M Greve
- Department of Surgery, Zuyderland Medical Center, Heerlen, The Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University of Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University of Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Cisca Wijmenga
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bart van de Sluis
- Department of Pediatrics, Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Marten H Hofker
- Department of Pediatrics, Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Jingyuan Fu
- Department of Pediatrics, Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Abstract
Hepatic steatosis is an underlying feature of nonalcoholic fatty liver disease (NAFLD), which is the most common form of liver disease and is present in up to ∼70% of individuals who are overweight. NAFLD is also associated with hypertriglyceridaemia and low levels of HDL, glucose intolerance, insulin resistance and type 2 diabetes mellitus. Hepatic steatosis is a strong predictor of the development of insulin resistance and often precedes the onset of other known mediators of insulin resistance. This sequence of events suggests that hepatic steatosis has a causal role in the development of insulin resistance in other tissues, such as skeletal muscle. Hepatokines are proteins that are secreted by hepatocytes, and many hepatokines have been linked to the induction of metabolic dysfunction, including fetuin A, fetuin B, retinol-binding protein 4 (RBP4) and selenoprotein P. In this Review, we describe the factors that influence the development of hepatic steatosis, provide evidence of strong links between hepatic steatosis and insulin resistance in non-hepatic tissues, and discuss recent advances in our understanding of how steatosis alters hepatokine secretion to influence metabolic phenotypes through inter-organ communication.
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Affiliation(s)
- Ruth C R Meex
- Monash Biomedicine Discovery Institute, Metabolic Disease and Obesity Program and the Department of Physiology, Monash University, Wellington Road, Clayton, Victoria 3800, Australia
- Department of Human Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
| | - Matthew J Watt
- Monash Biomedicine Discovery Institute, Metabolic Disease and Obesity Program and the Department of Physiology, Monash University, Wellington Road, Clayton, Victoria 3800, Australia
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Krishnan A, Abdullah TS, Mounajjed T, Hartono S, McConico A, White T, LeBrasseur N, Lanza I, Nair S, Gores G, Charlton M. A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol 2017; 312:G666-G680. [PMID: 28232454 PMCID: PMC6146305 DOI: 10.1152/ajpgi.00213.2016] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 02/14/2017] [Accepted: 02/14/2017] [Indexed: 01/31/2023]
Abstract
The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) is incompletely understood. Hence, we investigated the chronology of whole body, tissue, and cellular events that occur during the evolution of diet-induced NASH. Male C57Bl/6 mice were assigned to a fast-food (FF; high calorie, high cholesterol, high fructose) or standard-chow (SC) diet over a period of 36 wk. Liver histology, body composition, mitochondrial respiration, metabolic rate, gene expression, and hepatic lipid content were analyzed. Insulin resistance [homeostasis model assessment-insulin resistance (HOMA-IR)] increased 10-fold after 4 wk. Fibrosing NASH was fully established by 16 wk. Total hepatic lipids increased by 4 wk and remained two- to threefold increased throughout. Hepatic triglycerides declined from sixfold increase at 8 wk to threefold increase by 36 wk. In contrast, hepatic cholesterol levels steadily increased from baseline at 8 wk to twofold by 36 wk. The hepatic immune cell population altered over time with macrophages persisting beyond 16 wk. Mitochondrial oxygen flux rates of FF mice diet were uniformly lower with all the tested substrates (13-276 pmol·s-1·ml-1 per unit citrate synthase) than SC mice (17-394 pmol·s-1·ml-1 per unit citrate synthase) and was accompanied by decreased mitochondrial:nuclear gene copy number ratios after 4 wk. Metabolic rate was lower in FF mice. Mitochondrial glutathione was significantly decreased at 24 wk in FF mice. Expression of dismutases and catalase was also decreased in FF mice. The evolution of NASH in the FF diet-induced model is multiphasic, particularly in terms of hepatic lipid composition. Insulin resistance precedes hepatic inflammation and fibrosis. Mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Collectively, these observations provide a unique overview of the sequence of changes that coevolve with the histological evolution of NASH.NEW & NOTEWORTHY This study demonstrates in a first of kind longitudinal analysis, the evolution of nonalcoholic steatohepatitis (NASH) on a fast-food diet-induced model. Key findings include 1) hepatic lipid composition changes in a multiphasic fashion as NASH evolves; 2) insulin resistance precedes hepatic inflammation and fibrosis, answering a longstanding chicken-and-egg question regarding the relationship of insulin resistance to liver histology in NASH; and 3) mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent.
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Affiliation(s)
| | - Tasduq Sheikh Abdullah
- 2Indian Institute of Integrative Medicine, Council of Scientific and Industrial Research, Jammu and Kashmir, India;
| | - Taofic Mounajjed
- 3Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota;
| | - Stella Hartono
- 4Division of Immunology, Mayo Clinic, Rochester, Minnesota;
| | - Andrea McConico
- 5Division of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota;
| | - Thomas White
- 6Robert and Arlene Kogod Centre for Aging, Mayo Clinic, Rochester, Minnesota;
| | - Nathan LeBrasseur
- 6Robert and Arlene Kogod Centre for Aging, Mayo Clinic, Rochester, Minnesota;
| | - Ian Lanza
- 7Division of Endocrinology, Mayo Clinic, Rochester, Minnesota; and
| | - Sreekumaran Nair
- 7Division of Endocrinology, Mayo Clinic, Rochester, Minnesota; and
| | - Gregory Gores
- 1Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota;
| | - Michael Charlton
- Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota; .,Division of Hepatology, Intermountain Healthcare, Salt Lake City, Utah
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Nishimura T, Itoh Y, Yamashita S, Koide K, Harada N, Yano Y, Ikeda N, Azuma K, Atsumi Y. Clinical significance of serum complement factor 3 in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2017; 127:132-139. [PMID: 28365560 DOI: 10.1016/j.diabres.2017.03.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Accepted: 03/16/2017] [Indexed: 02/07/2023]
Abstract
AIMS Although serum complement factor 3 (C3) is an acute phase reactant mainly synthesized in the liver, several recent studies have shown high C3 gene expression in adipose tissue (AT). However, the relationship between C3 and AT levels has not been fully clarified in type 2 diabetes mellitus (T2DM) patients. METHODS A total of 164 T2DM patients (109men and 55 women) participated in this cross-sectional study. A computed tomography scan was performed to measure visceral, subcutaneous, and total AT. The correlation between these factors and C3 levels was examined using Pearson's correlation analysis. A multivariate regression model was used to assess an independent determinant associated with C3 levels after adjusting the explanatory variables (i.e., all ATs [visceral, subcutaneous, and total], and clinical features [sex, age, body mass index, waist circumference, glycated hemoglobin, duration of diabetes, systolic blood pressure, diastolic blood pressure, aspartate aminotransferase levels, alanine aminotransferase levels, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, log(triglyceride levels), estimated glomerular filtration rate, and log(high-sensitivity C-reactive protein levels)]). RESULTS Serum C3 levels were correlated with visceral, subcutaneous, and total AT among both men (r=0.505, p<0.001; r=0.545, p<0.001; r=0.617, p<0.001, respectively) and women (r=0.396, p=0.003; r=0.517, p<0.001; r=0.548, p<0.001, respectively). In the multivariate regression model, the association between total AT and C3 levels remained significantly positive (β=0.490, p<0.001). CONCLUSIONS Serum C3 levels are associated with visceral, subcutaneous, and total AT in T2DM patients. Furthermore, C3 levels seem to be a marker for overall adiposity rather than regional adiposity.
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Affiliation(s)
- Takeshi Nishimura
- Department of Diabetes and Endocrinology, Eiju General Hospital, Life Extension Research Institute, Japan.
| | - Yoshihisa Itoh
- Medical Laboratory, Eiju General Hospital, Life Extension Research Institute, Japan
| | - Shigeo Yamashita
- Department of Diabetes and Endocrinology, Eiju General Hospital, Life Extension Research Institute, Japan
| | - Keiko Koide
- Diabetes Research Center, Eiju General Hospital, Life Extension Research Institute, Japan
| | - Noriaki Harada
- Medical Laboratory, Eiju General Hospital, Life Extension Research Institute, Japan
| | - Yasuo Yano
- Medical Laboratory, Eiju General Hospital, Life Extension Research Institute, Japan
| | - Nobuko Ikeda
- Medical Laboratory, Eiju General Hospital, Life Extension Research Institute, Japan
| | - Koichiro Azuma
- Institute for Integrated Sports Medicine, Keio University School of Medicine, Japan
| | - Yoshihito Atsumi
- Diabetes Research Center, Eiju General Hospital, Life Extension Research Institute, Japan
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In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis. PLoS One 2017; 12:e0173822. [PMID: 28339466 PMCID: PMC5365109 DOI: 10.1371/journal.pone.0173822] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 02/27/2017] [Indexed: 12/15/2022] Open
Abstract
Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.
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Massart J, Begriche K, Moreau C, Fromenty B. Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity. J Clin Transl Res 2017; 3:212-232. [PMID: 28691103 PMCID: PMC5500243 DOI: 10.18053/jctres.03.2017s1.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. AIM The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. RELEVANCE FOR PATIENTS Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening.
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Affiliation(s)
- Julie Massart
- Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | | | - Caroline Moreau
- INSERM, U991, Université de Rennes 1, Rennes, France.,Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes, France
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Liu L, Zhao X, Wang Q, Sun X, Xia L, Wang Q, Yang B, Zhang Y, Montgomery S, Meng H, Geng T, Gong D. Prosteatotic and Protective Components in a Unique Model of Fatty Liver: Gut Microbiota and Suppressed Complement System. Sci Rep 2016; 6:31763. [PMID: 27550859 PMCID: PMC4994046 DOI: 10.1038/srep31763] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 07/27/2016] [Indexed: 01/07/2023] Open
Abstract
Goose can develop severe hepatic steatosis without overt injury, thus it may serve as a unique model for uncovering how steatosis-related injury is prevented. To identify the markedly prosteatotic and protective mechanisms, we performed an integrated analysis of liver transcriptomes and gut microbial metagenomes using samples collected from overfed and normally-fed geese at different time points. The results indicated that the fatty liver transcriptome, initially featuring a ‘metabolism’ pathway, was later joined by ‘cell growth and death’ and ‘immune diseases’ pathways. Gut microbiota played a synergistic role in the liver response as microbial and hepatic genes affected by overfeeding shared multiple pathways. Remarkably, the complement system, an inflammatory component, was comprehensively suppressed in fatty liver, which was partially due to increased blood lactic acid from enriched Lactobacillus. Data from in vitro studies suggested that lactic acid suppressed TNFα via the HNF1α/C5 pathway. In conclusion, gut microbes and their hosts respond to excess energy influx as an organic whole, severe steatosis and related tolerance of goose liver may be partially attributable to gut microbiotic products and suppressed complement system, and lactic acid from gut microbiota participates in the suppression of hepatic TNFα/inflammation through the HNF1α/C5 pathway.
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Affiliation(s)
- Long Liu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Xing Zhao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Qian Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Xiaoxian Sun
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Lili Xia
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Qianqian Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Biao Yang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Yihui Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Sean Montgomery
- Department of Botany, University of British Columbia, 6270 University Boulevard, British Columbia, V6T 1Z4, Canada
| | - He Meng
- School of Agriculture and Biology, Shanghai Jiaotong University; Shanghai Key Laboratory of Veterinary Biotechnology, 800 Dongchuan Road, Shanghai 200240, China
| | - Tuoyu Geng
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Daoqing Gong
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
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Tolosa L, Gómez-Lechón MJ, Jiménez N, Hervás D, Jover R, Donato MT. Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis. Toxicol Appl Pharmacol 2016; 302:1-9. [PMID: 27089845 DOI: 10.1016/j.taap.2016.04.007] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 04/06/2016] [Accepted: 04/09/2016] [Indexed: 12/11/2022]
Abstract
Only a few in vitro assays have been proposed to evaluate the steatotic potential of new drugs. The present study examines the utility of HepaRG cells as a cell-based assay system for screening drug-induced liver steatosis. A high-content screening assay was run to evaluate multiple toxicity-related cell parameters in HepaRG cells exposed to 28 compounds, including drugs reported to cause steatosis through different mechanisms and non-steatotic compounds. Lipid content was the most sensitive parameter for all the steatotic drugs, whereas no effects on lipid levels were produced by non-steatotic compounds. Apart from fat accumulation, increased ROS production and altered mitochondrial membrane potential were also found in the cells exposed to steatotic drugs, which indicates that all these cellular events contributed to drug-induced hepatotoxicity. These findings are of clinical relevance as most effects were observed at drug concentrations under 100-fold of the therapeutic peak plasmatic concentration. HepaRG cells showed increased lipid overaccumulation vs. HepG2 cells, which suggests greater sensitivity to drug-induced steatosis. An altered expression profile of transcription factors and the genes that code key proteins in lipid metabolism was also found in the cells exposed to drugs capable of inducing liver steatosis. Our results generally indicate the value of HepaRG cells for assessing the risk of liver damage associated with steatogenic compounds and for investigating the molecular mechanisms involved in drug-induced steatosis.
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Affiliation(s)
- Laia Tolosa
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026, Spain
| | - M José Gómez-Lechón
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026, Spain; CIBERehd, FIS, Barcelona 08036, Spain
| | - Nuria Jiménez
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026, Spain
| | - David Hervás
- Biostatistics Unit, Instituto de Investigación Sanitaria La Fe, Valencia 46026, Spain
| | - Ramiro Jover
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026, Spain; CIBERehd, FIS, Barcelona 08036, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia 46010, Spain
| | - M Teresa Donato
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026, Spain; CIBERehd, FIS, Barcelona 08036, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia 46010, Spain.
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Yang ZR, Wang HF, Zuo TC, Guan LL, Dai N. Salidroside alleviates oxidative stress in the liver with non- alcoholic steatohepatitis in rats. BMC Pharmacol Toxicol 2016; 17:16. [PMID: 27075663 PMCID: PMC4831194 DOI: 10.1186/s40360-016-0059-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2015] [Accepted: 03/29/2016] [Indexed: 01/19/2023] Open
Abstract
Background Nonalcoholic steatohepatitis (NASH) is characterized by fat accumulation in the hepatocyte, inflammation, liver cell injury, and varying degrees of fibrosis, and can lead to oxidative stress in liver. Here, we investigated whether Salidroside, a natural phenolic antioxidant product, can protect rat from liver injury during NASH. Methods NASH model was established by feeding the male SD rats with high-fat and high-cholesterol diet for 14 weeks. Four groups of male SD rats including, normal diet control group, NASH model group, and Salidroside treatment group with150mg/kg and 300 mg/kg respectively, were studied. Salidroside was given by oral administration to NASH in rats from 9 weeks to 14 weeks. At the end of 14 weeks, liver and serum were harvested, and the liver injury, oxidative stress and histological features were evaluated. Results NASH rats exhibited significant increases in the following parameters as compared to normal diet control rats: fat droplets with foci of inflammatory cell infiltration in the liver. ALT, AST in serum and TG, TC in hepatocyte elevated. Oxidative responsive genes including CYP2E1 and Nox2 increased. Additionally, NASH model decreased antioxidant enzymes SOD, GSH, GPX, and CAT in the liver due to their rapid depletion after battling against oxidative stress. Compared to NASH model group, treatment rats with Salidroside effectively reduced lipid accumulation, inhibited liver injury in a does-dependent manner. Salidroside treatment restored antioxidant enzyme levels, inhibited expression of CYP2E1 and Nox2 mRNA in liver, which prevented the initial step of generating free radicals from NASH. Conclusion The data presented here show that oral administration of Salidroside prevented liver injury in the NASH model, likely through exerting antioxidant actions to suppress oxidative stress and the free radical–generating CYP2E1 enzyme, Nox2 in liver.
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Affiliation(s)
- Ze-ran Yang
- Department of Gastroenterology, the first Affiliated Hospital of Dalian Medical University, 222, Zhongshan Road, Dalian, 116011, Liaoning Province, China
| | - Hui-fang Wang
- Department of Gastroenterology, the first Affiliated Hospital of Dalian Medical University, 222, Zhongshan Road, Dalian, 116011, Liaoning Province, China
| | - Tie-cheng Zuo
- Department of Gastroenterology, the first Affiliated Hospital of Dalian Medical University, 222, Zhongshan Road, Dalian, 116011, Liaoning Province, China
| | - Li-li Guan
- Department of Digestive Physiology, Dalian Medical University, Dalian, Liaoning Province, China
| | - Ning Dai
- Department of Gastroenterology, the first Affiliated Hospital of Dalian Medical University, 222, Zhongshan Road, Dalian, 116011, Liaoning Province, China.
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Xanthakos SA, Jenkins TM, Kleiner DE, Boyce TW, Mourya R, Karns R, Brandt ML, Harmon CM, Helmrath MA, Michalsky MP, Courcoulas AP, Zeller MH, Inge TH. High Prevalence of Nonalcoholic Fatty Liver Disease in Adolescents Undergoing Bariatric Surgery. Gastroenterology 2015; 149:623-34.e8. [PMID: 26026390 PMCID: PMC4654456 DOI: 10.1053/j.gastro.2015.05.039] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 05/14/2015] [Accepted: 05/20/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Little is known about the prevalence of nonalcoholic fatty liver disease (NAFLD) among severely obese adolescents or factors that determine its development. We investigated the prevalence of NAFLD in a multicenter cohort of adolescents undergoing bariatric surgery and the factors associated with it. METHODS We enrolled 242 adolescents undergoing bariatric surgery between March 2007 and February 2012 at 5 tertiary care centers into a multicenter, prospective observational cohort study. Intraoperative core liver biopsies were collected from 165 subjects; 17 were excluded because of insufficient liver tissue or use of hepatotoxic medications, so 148 remained in the study (mean age, 16.8 ± 1.6 years; median body mass index = 52 kg/m(2)). Liver tissues were analyzed by histology using validated criteria. Hepatic gene expression was analyzed in 67 samples. RESULTS NAFLD was present in 59% of this predominantly female (72%), white (68%), non-Hispanic (91%) cohort. Of subjects with NAFLD, 24% had borderline and 10% had definite nonalcoholic steatohepatitis (NASH). Mild fibrosis (stage 2 or lower) was observed in 18% of liver biopsies and stage 3 was observed in 0.7%, but cirrhosis was not detected. Dyslipidemia was present in 78% of subjects, hypertension in 44%, and diabetes in 14%. More severe NAFLD was associated with increasing levels of alanine aminotransferase, fasting glucose level, hypertension (each P < .01), and white blood cell count (P = .04). Only diabetes was associated with detection of fibrosis (odds ratio = 3.56; 95% confidence interval: 1.93-6.56). Microarray analysis associated presence of NASH with altered expression of genes that regulate macrophage chemotaxis, cholesterol absorption, and fatty acid binding. CONCLUSIONS More than half of adolescents undergoing bariatric surgery in this cohort had NAFLD, yet the prevalence of severe or fibrotic NASH was low. Increasing severity of NAFLD was associated with level of alanine aminotransferase and cardiometabolic risk factors, but not body mass index. Based on gene expression analysis, borderline and definite NASH were associated with abnormal immune function, intestinal cholesterol absorption, and lipid metabolism.
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Affiliation(s)
- Stavra A Xanthakos
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
| | - Todd M Jenkins
- Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Tawny W Boyce
- University of New Mexico Cancer Center, Biostatistics Shared Resource, Albuquerque, New Mexico
| | - Reena Mourya
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Rebekah Karns
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Mary L Brandt
- Division of Pediatric Surgery, Texas Children's Hospital, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
| | - Carroll M Harmon
- Division of Pediatric Surgery, Women & Children's Hospital of Buffalo, University of Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York
| | - Michael A Helmrath
- Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Marc P Michalsky
- Department of Pediatric Surgery, The Ohio State University College of Medicine and Nationwide Children's Hospital, Columbus, Ohio
| | - Anita P Courcoulas
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Meg H Zeller
- Division of Behavioral Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Thomas H Inge
- Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
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Machado MV, Michelotti GA, Xie G, de Almeida TP, Boursier J, Bohnic B, Guy CD, Diehl AM. Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PLoS One 2015; 10:e0127991. [PMID: 26017539 PMCID: PMC4446215 DOI: 10.1371/journal.pone.0127991] [Citation(s) in RCA: 242] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 04/22/2015] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet. METHODS Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared. RESULTS The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation. CONCLUSION Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH.
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Affiliation(s)
- Mariana Verdelho Machado
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America
- Gastroenterology Department, Hospital de Santa Maria, CHLN, Lisbon, Portugal
| | - Gregory Alexander Michelotti
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America
| | - Guanhua Xie
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America
| | - Thiago Pereira de Almeida
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America
| | - Jerome Boursier
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America
| | - Brittany Bohnic
- Division of Endocrinology, Duke University Medical Center, Durham, NC 27710, United States of America
| | - Cynthia D. Guy
- Division of Pathology, Duke University Medical Center, Durham, NC 27710, United States of America
| | - Anna Mae Diehl
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America
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Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease. J Nutr Biochem 2015; 26:996-1006. [PMID: 26033743 DOI: 10.1016/j.jnutbio.2015.04.009] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 04/08/2015] [Accepted: 04/13/2015] [Indexed: 12/18/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes nonalcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decreases liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w) or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high-sucrose or low-Cu diet had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase and fatty acid synthase gene transcription (fold change > 2, P < 0.02). Low dietary Cu decreased hepatic and serum Cu (P ≤ 0.05), promoted lipid peroxidation and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis.
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Segers FM, Verdam FJ, de Jonge C, Boonen B, Driessen A, Shiri-Sverdlov R, Bouvy ND, Greve JWM, Buurman WA, Rensen SS. Complement alternative pathway activation in human nonalcoholic steatohepatitis. PLoS One 2014; 9:e110053. [PMID: 25299043 PMCID: PMC4192551 DOI: 10.1371/journal.pone.0110053] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 09/08/2014] [Indexed: 01/07/2023] Open
Abstract
The innate immune system plays a major role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Recently we reported complement activation in human NASH. However, it remained unclear whether the alternative pathway of complement, which amplifies C3 activation and which is frequently associated with pathological complement activation leading to disease, was involved. Here, alternative pathway components were investigated in liver biopsies of obese subjects with healthy livers (n = 10) or with NASH (n = 12) using quantitative PCR, Western blotting, and immunofluorescence staining. Properdin accumulated in areas where neutrophils surrounded steatotic hepatocytes, and colocalized with the C3 activation product C3c. C3 activation status as expressed by the C3c/native C3 ratio was 2.6-fold higher (p<0.01) in subjects with NASH despite reduced native C3 concentrations (0.94±0.12 vs. 0.57±0.09; p<0.01). Hepatic properdin levels positively correlated with levels of C3c (rs = 0.69; p<0.05) and C3c/C3 activation ratio (rs = 0.59; p<0.05). C3c, C3 activation status (C3c/C3 ratio) and properdin levels increased with higher lobular inflammation scores as determined according to the Kleiner classification (C3c: p<0.01, C3c/C3 ratio: p<0.05, properdin: p<0.05). Hepatic mRNA expression of factor B and factor D did not differ between subjects with healthy livers and subjects with NASH (factor B: 1.00±0.19 vs. 0.71±0.07, p = 0.26; factor D: 1.00±0.21 vs. 0.66±0.14, p = 0.29;). Hepatic mRNA and protein levels of Decay Accelerating Factor tended to be increased in subjects with NASH (mRNA: 1.00±0.14 vs. 2.37±0.72; p = 0.22; protein: 0.51±0.11 vs. 1.97±0.67; p = 0.28). In contrast, factor H mRNA was downregulated in patients with NASH (1.00±0.09 vs. 0.71±0.06; p<0.05) and a similar trend was observed with hepatic protein levels (1.12±0.16 vs. 0.78±0.07; p = 0.08). Collectively, these data suggest a role for alternative pathway activation in driving hepatic inflammation in NASH. Therefore, alternative pathway factors may be considered attractive targets for treating NASH by inhibiting complement activation.
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Affiliation(s)
- Filip M. Segers
- Department of General Surgery, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Froukje J. Verdam
- Department of General Surgery, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Charlotte de Jonge
- Department of General Surgery, Maastricht University Medical Centre+, Maastricht, the Netherlands
- Department of Surgery, Atrium Medical Centre Parkstad, Heerlen, the Netherlands
| | - Bas Boonen
- Department of General Surgery, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Ann Driessen
- Department of Pathology, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Ronit Shiri-Sverdlov
- Department of Genetics and Cell Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Nicole D. Bouvy
- Department of General Surgery, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Jan Willem M. Greve
- Department of Surgery, Atrium Medical Centre Parkstad, Heerlen, the Netherlands
| | - Wim A. Buurman
- Department of General Surgery, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Sander S. Rensen
- Department of General Surgery, Maastricht University Medical Centre+, Maastricht, the Netherlands
- * E-mail:
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40
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Tanaka T, Sugawara Y, Tamura S, Kaneko J, Takazawa Y, Aoki T, Hasegawa K, Sakamoto Y, Yamashiki N, Kokudo N. Living donor liver transplantation for non-alcoholic steatohepatitis: A single center experience. Hepatol Res 2014; 44:E3-E10. [PMID: 23834427 DOI: 10.1111/hepr.12200] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Revised: 06/18/2013] [Accepted: 07/03/2013] [Indexed: 12/13/2022]
Abstract
AIM The number of patients referred for liver transplantation (LT) with non-alcoholic steatohepatitis (NASH) continues to increase, but information about living donor liver transplantation (LDLT) for NASH is scarce. We conducted this study to document the details of LDLT for NASH in a Japanese LT center. METHODS Among all LDLT recipients in our institution from March 1996 to March 2013 (n = 425), we identified seven patients that underwent LDLT for NASH. RESULTS Of all the seven recipients, most of the patients (86%) were obese. The median follow-up period post-LDLT was 5.3 years. All were alive at the last follow-up. Recurrent NASH was detected in one patient (14%), and no recurrent hepatic steatosis was detected among the remaining six recipients on prospectively performed ultrasonography. No significant comorbidities were observed following donor surgery among the respective living donors during the follow-up period. We also retrospectively reviewed 22 patients with NASH-related end-stage liver disease (ESLD) who were evaluated but rejected for LDLT during the same period. The reasons for rejection for LDLT were presumably associated with the nature of NAFLD/NASH in either potential recipients or donors. CONCLUSION The post-transplant outcome of LDLT for NASH-related ESLD in our institution was feasible, although the sample size was small. Further studies in a larger patient cohort are warranted to investigate the long-term outcome of LDLT for NASH, both for recipients and living donors.
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Affiliation(s)
- Tomohiro Tanaka
- Organ Transplantation Service, The University of Tokyo Hospital, Tokyo, Japan
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41
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Fitzpatrick E, Dhawan A. Noninvasive biomarkers in non-alcoholic fatty liver disease: Current status and a glimpse of the future. World J Gastroenterol 2014; 20:10851-10863. [PMID: 25152587 PMCID: PMC4138464 DOI: 10.3748/wjg.v20.i31.10851] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
The development of non invasive biomarkers of disease has become a major focus of interest in nonalcoholic fatty liver disease (NAFLD). The large prevalence of the disease and the invasive nature of the investigation means that screening with liver biopsy is impractical. In addition to screening, the differentiation of those with simple steatosis vs steatohepatitis and fibrosis is clinically important as the prognosis of each differs. Serum biomarkers may be a combination of simple markers derived from large data sets or direct markers of disease activity. Serum markers of inflammation, apoptosis and oxidative stress in addition to fibrosis have been extensively studied in patients with NAFLD. Other techniques such as transient elastography, magnetic resonance elastography and acoustic radiation force imaging are becoming more established as noninvasive methods of detecting fibrosis in a variety of chronic liver conditions in addition to NAFLD. Newer high throughput methods such as proteomics and glycomics allow the nonhypothesis-driven identification of novel markers and may also potentially contribute to our understanding of the pathogenesis of the condition. This review addresses some of the methodological issues which need to be considered in the search for the ideal biomarker. It is likely that a combination of serum biomarkers and techniques such as transient elastography may provide the optimal diagnostic discrimination however this remains to be proven in large studies.
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Ackerman Z, Skarzinski G, Grozovski M, Oron-Herman M, Sela BA. Effects of Antihypertensive and Triglyceride-lowering Agents on Hepatic Copper Concentrations in Rats with Fatty Liver Disease. Basic Clin Pharmacol Toxicol 2014; 115:545-51. [DOI: 10.1111/bcpt.12283] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 06/03/2014] [Indexed: 12/11/2022]
Affiliation(s)
- Zvi Ackerman
- Departments of Medicine; Hadassah-Hebrew University Medical Center; Jerusalem Israel
| | - Galina Skarzinski
- Departments of Medicine; Hadassah-Hebrew University Medical Center; Jerusalem Israel
| | | | - Mor Oron-Herman
- Institute of Chemical Pathology; Sheba Medical Center; Tel Hashomer Israel
| | - Ben-Ami Sela
- Institute of Chemical Pathology; Sheba Medical Center; Tel Hashomer Israel
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43
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Gori M, Barbaro B, Arciello M, Maggio R, Viscomi C, Longo A, Balsano C. Protective effect of the Y220C mutant p53 against steatosis: good news? J Cell Physiol 2014; 229:1182-92. [PMID: 24395441 DOI: 10.1002/jcp.24550] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 12/04/2013] [Accepted: 01/03/2014] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to steatohepatitis, which may progress to fibrosis, and cirrhosis, leading eventually to hepatocarcinoma development. Recently, cases of hepatocarcinoma have been diagnosed in steatotic patients without nonalcoholic steatohepatitis (NASH) and cirrhosis. The p53 protein, besides its function as tumor suppressor, is emerging as an important regulator of cellular metabolism, but its role in steatosis remains unclear. We induced steatosis in HepG2 (wt-p53) and Huh7.5.1 (Y220C-mutant p53) cells using free fatty acids. We observed a different modulation of p53, different intracellular lipid content, and similar down-regulation of the de novo lipid synthesis genes but opposite modulation of the fatty acid β-oxidation pathway between HepG2 and Huh7.5.1. Accordingly, we found a diverse amount of apoptosis and reactive oxygen species between the two cell lines. Transfection of the wt-p53 in Huh7.5.1 cells reverted the different lipid metabolism behavior observed in these cells. In conclusion, unlike the wt-p53, the Y220C mutant provides a specific protection against steatosis and potentially against its progression. Our findings highlight for the first time an unknown role of a p53 mutant in the setting of steatosis. Being this mutation very frequent in human cancers, this study could be a breakthrough in explaining the occurrence of hepatocarcinoma in steatotic patients without NASH and cirrhosis.
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Affiliation(s)
- Manuele Gori
- Laboratory of Molecular Virology and Oncology, Francesco Balsano Foundation, Rome, Italy
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44
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The complement system in human cardiometabolic disease. Mol Immunol 2014; 61:135-48. [PMID: 25017306 DOI: 10.1016/j.molimm.2014.06.031] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Revised: 06/18/2014] [Accepted: 06/23/2014] [Indexed: 02/07/2023]
Abstract
The complement system has been implicated in obesity, fatty liver, diabetes and cardiovascular disease (CVD). Complement factors are produced in adipose tissue and appear to be involved in adipose tissue metabolism and local inflammation. Thereby complement links adipose tissue inflammation to systemic metabolic derangements, such as low-grade inflammation, insulin resistance and dyslipidaemia. Furthermore, complement has been implicated in pathophysiological mechanisms of diet- and alcohol induced liver damage, hyperglycaemia, endothelial dysfunction, atherosclerosis and fibrinolysis. In this review, we summarize current evidence on the role of the complement system in several processes of human cardiometabolic disease. C3 is the central component in complement activation, and has most widely been studied in humans. C3 concentrations are associated with insulin resistance, liver dysfunction, risk of the metabolic syndrome, type 2 diabetes and CVD. C3 can be activated by the classical, the lectin and the alternative pathway of complement activation; and downstream activation of C3 activates the terminal pathway. Complement may also be activated via extrinsic proteases of the coagulation, fibrinolysis and the kinin systems. Studies on the different complement activation pathways in human cardiometabolic disease are limited, but available evidence suggests that they may have distinct roles in processes underlying cardiometabolic disease. The lectin pathway appeared beneficial in some studies on type 2 diabetes and CVD, while factors of the classical and the alternative pathway were related to unfavourable cardiometabolic traits. The terminal complement pathway was also implicated in insulin resistance and liver disease, and appears to have a prominent role in acute and advanced CVD. The available human data suggest a complex and potentially causal role for the complement system in human cardiometabolic disease. Further, preferably longitudinal studies are needed to disentangle which aspects of the complement system and complement activation affect the different processes in human cardiometabolic disease.
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Hennig EE, Mikula M, Goryca K, Paziewska A, Ledwon J, Nesteruk M, Woszczynski M, Walewska-Zielecka B, Pysniak K, Ostrowski J. Extracellular matrix and cytochrome P450 gene expression can distinguish steatohepatitis from steatosis in mice. J Cell Mol Med 2014; 18:1762-72. [PMID: 24913135 PMCID: PMC4196652 DOI: 10.1111/jcmm.12328] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 04/15/2014] [Indexed: 12/22/2022] Open
Abstract
One of the main questions regarding nonalcoholic fatty liver disease is the molecular background of the transition from simple steatosis (SS) to the inflammatory and fibrogenic condition of steatohepatitis (NASH). We examined the gene expression changes during progression from histologically normal liver to SS and NASH in models of obesity caused by hyperphagia or a high-fat diet. Microarray-based analysis revealed that the expression of 1445 and 264 probe sets was changed exclusively in SS and NASH samples, respectively, and 1577 probe sets were commonly altered in SS and NASH samples. Functional annotations indicated that transcriptome alterations that were common for NASH and SS, as well as exclusive for NASH, involved extracellular matrix (ECM)-related processes, although they differed in the type of matrix structure change. The expression of 80 genes was significantly changed in all three comparisons: SS versus control, NASH versus control and NASH versus SS. Of these genes, epithelial membrane protein 1, IKBKB interacting protein and decorin were progressively up-regulated in both SS and NASH compared to normal tissue. The molecular context of interactions of encoded 80 proteins revealed that they are highly interconnected and significantly enriched for processes involving metabolism by cytochrome P450. Validation of 10 selected mRNAs encoding genes related to ECM and cytochrome P450 with quantitative RT-PCR analysis showed consistent changes in their expression during NASH development. The expression profile of these genes has the potential to distinguish NASH from SS and normal tissue and may possibly be beneficial in the clinical diagnosis of NASH.
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Affiliation(s)
- Ewa E Hennig
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland; Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
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Abstract
Liver fibrosis is the final common pathway for almost all causes of chronic liver injury. Liver fibrosis is now known to be a dynamic process having significant potential for resolution. Therefore, fibrosis prediction is an essential part of the assessment and management of patients with chronic liver disease. As such, there is strong demand for reliable liver biomarkers that provide insight into disease etiology, diagnosis, therapy, and prognosis in lieu of more invasive approaches such as liver biopsy. Current diagnostic strategies range from use of serum biomarkers to more advanced imaging techniques including transient elastography and magnetic resonance imaging. In addition to these modalities, there are other approaches including the use of novel, but yet to be validated, biomarkers. In this chapter, we discuss the biomarkers of liver fibrosis including the use of invasive and noninvasive biomarkers and disease-specific biomarkers in various chronic liver diseases.
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An Intimate Relationship between ROS and Insulin Signalling: Implications for Antioxidant Treatment of Fatty Liver Disease. Int J Cell Biol 2014; 2014:519153. [PMID: 24672550 PMCID: PMC3944655 DOI: 10.1155/2014/519153] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 12/20/2013] [Indexed: 01/22/2023] Open
Abstract
Oxidative stress damages multiple cellular components including DNA, lipids, and proteins and has been linked to pathological alterations in nonalcoholic fatty liver disease (NAFLD). Reactive oxygen species (ROS) emission, resulting from nutrient overload and mitochondrial dysfunction, is thought to be a principal mediator in NAFLD progression, particularly toward the development of hepatic insulin resistance. In the context of insulin signalling, ROS has a dual role, as both a facilitator and inhibitor of the insulin signalling cascade. ROS mediate these effects through redox modifications of cysteine residues affecting phosphatase enzyme activity, stress-sensitive kinases, and metabolic sensors. This review highlights the intricate relationship between redox-sensitive proteins and insulin signalling in the context of fatty liver disease, and to a larger extent, the importance of reactive oxygen species as primary signalling molecules in metabolically active cells.
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Nutrigenomics of high fat diet induced obesity in mice suggests relationships between susceptibility to fatty liver disease and the proteasome. PLoS One 2013; 8:e82825. [PMID: 24324835 PMCID: PMC3855786 DOI: 10.1371/journal.pone.0082825] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 10/28/2013] [Indexed: 01/22/2023] Open
Abstract
Nutritional factors play important roles in the etiology of obesity, type 2 diabetes mellitus and their complications through genotype x environment interactions. We have characterised molecular adaptation to high fat diet (HFD) feeding in inbred mouse strains widely used in genetic and physiological studies. We carried out physiological tests, plasma lipid assays, obesity measures, liver histology, hepatic lipid measurements and liver genome-wide gene transcription profiling in C57BL/6J and BALB/c mice fed either a control or a high fat diet. The two strains showed marked susceptibility (C57BL/6J) and relative resistance (BALB/c) to HFD-induced insulin resistance and non alcoholic fatty liver disease (NAFLD). Global gene set enrichment analysis (GSEA) of transcriptome data identified consistent patterns of expression of key genes (Srebf1, Stard4, Pnpla2, Ccnd1) and molecular pathways in the two strains, which may underlie homeostatic adaptations to dietary fat. Differential regulation of pathways, including the proteasome, the ubiquitin mediated proteolysis and PPAR signalling in fat fed C57BL/6J and BALB/c suggests that altered expression of underlying diet-responsive genes may be involved in contrasting nutrigenomic predisposition and resistance to insulin resistance and NAFLD in these models. Collectively, these data, which further demonstrate the impact of gene x environment interactions on gene expression regulations, contribute to improved knowledge of natural and pathogenic adaptive genomic regulations and molecular mechanisms associated with genetically determined susceptibility and resistance to metabolic diseases.
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Shimozono R, Asaoka Y, Yoshizawa Y, Aoki T, Noda H, Yamada M, Kaino M, Mochizuki H. Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat model. Mol Pharmacol 2013; 84:62-70. [PMID: 23592516 DOI: 10.1124/mol.112.084269] [Citation(s) in RCA: 102] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Oxidative stress is considered to be a key mechanism of hepatocellular injury and disease progression in patients with nonalcoholic steatohepatitis (NASH). The transcription factor Nrf2 (nuclear factor-erythroid-2-related factor 2) plays a central role in stimulating expression of various antioxidant-associated genes in the cellular defense against oxidative stress. As the cytosolic repressor kelch-like ECH-associated protein 1 (Keap1) negatively regulates Nrf2, activation of Nrf2 facilitated by its release from Keap1 may represent a promising strategy in the treatment of NASH. To test this hypothesis, we used two chemically distinct types of Nrf2 activator. One is the thiol-reactive agent oltipraz (OPZ), a typical Nrf2 activator, and the other is a novel biaryl urea compound, termed NK-252 (1-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-ylmethyl)urea). NK-252 exhibits a greater Nrf2-activating potential than OPZ. Furthermore, in vitro binding studies revealed that NK-252 interacts with the domain containing the Nrf2-binding site of Keap1, whereas OPZ does not. This finding indicates that NK-252 is more potent than OPZ due to its unique mechanism of action. For in vivo animal model studies, we used rats on a choline-deficient L-amino acid-defined (CDAA) diet, which demonstrate pathologic findings similar to those seen in human NASH. The administration of OPZ or NK-252 significantly attenuated the progression of histologic abnormalities in rats on a CDAA diet, especially hepatic fibrosis. In conclusion, by using Nrf2 activators with independent mechanisms of action, we show that, in a rat model of NASH, the activation of Nrf2 is responsible for the antifibrotic effects of these drugs. This strategy of Nrf2 activation presents new opportunities for treatment of NASH patients with hepatic fibrosis.
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Affiliation(s)
- Rieko Shimozono
- Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
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50
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The role of the complement system in metabolic organs and metabolic diseases. Semin Immunol 2013; 25:47-53. [PMID: 23684628 DOI: 10.1016/j.smim.2013.04.003] [Citation(s) in RCA: 101] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Accepted: 04/13/2013] [Indexed: 12/20/2022]
Abstract
Emerging evidence points to a close crosstalk between metabolic organs and innate immunity in the course of metabolic disorders. In particular, cellular and humoral factors of innate immunity are thought to contribute to metabolic dysregulation of the adipose tissue or the liver, as well as to dysfunction of the pancreas; all these conditions are linked to the development of insulin resistance and diabetes mellitus. A central component of innate immunity is the complement system. Interestingly, the classical view of complement as a major system of host defense that copes with infections is changing to that of a multi-functional player in tissue homeostasis, degeneration, and regeneration. In the present review, we will discuss the link between complement and metabolic organs, focusing on the pancreas, adipose tissue, and liver and the diverse effects of complement system on metabolic disorders.
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