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Sun J, Shi R, Zhou Z, Xu W, Huai J, Cao Y, Zhang W, Nie L, Wang G, Yan Q, Wang X, Li M, Fang Z, Zhou X. Identification of CACNB1 protein as an actionable therapeutic target for hepatocellular carcinoma via metabolic dysfunction analysis in liver diseases: An integrated bioinformatics and machine learning approach for precise therapy. Int J Biol Macromol 2025; 308:142315. [PMID: 40139615 DOI: 10.1016/j.ijbiomac.2025.142315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 03/14/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025]
Abstract
In addition to histological evaluation for nonalcoholic fatty liver disease (NAFLD), a comprehensive analysis of the metabolic landscape is urgently needed to categorize patients into distinct subgroups for precise treatment. In this study, a total of 806 NAFLD and 267 normal liver samples were comprehensively analyzed. Alterations in 114 metabolic pathways were investigated and two distinct metabolic clusters were identified. Single-cell RNA sequencing (scRNA-seq) analysis was utilized to decipher the metabolic activities within the microenvironment of NAFLD-derived liver cirrhosis. A refined fibrosis prediction model was developed using a Gaussian Mixture Model (GMM), demonstrating superior performance in fibrosis discrimination across multiple independent cohorts. Additionally, using The Cancer Genome Atlas (TCGA), CACNB1 protein was identified as a promising therapeutic target for hepatocellular carcinoma (HCC) patients with elevated metabolic dysfunction scores (MBDS). Machine learning algorithms were applied to MBDS-related genes to select an optimal prognostic model for HCC. All the models were trained in an HCC cohort obtained from the Gene Expression Omnibus (GEO), and the best model was validated in two independent HCC datasets: the TCGA-HCC cohort and LIRI-JP cohort. Overall, we provide insights of metabolic molecular subtyping and its potential clinical applicability in risk stratification for NAFLD and HCC individuals.
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Affiliation(s)
- Jing Sun
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Run Shi
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhaokai Zhou
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Weilong Xu
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiaxuan Huai
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yutian Cao
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenhui Zhang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Lijuan Nie
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Gaoxiang Wang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Qianhua Yan
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xuanbin Wang
- Laboratory of Chinese Herbal Pharmacology, Department of Pharmacology, Renmin Hospital, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei, China.
| | - Minglun Li
- Department of Radiation Oncology, Lueneburg Municipal Hospital, Lueneburg, Germany.
| | - Zhuyuan Fang
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Xiqiao Zhou
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
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ElKabbany ZA, Ismail EAR, Hamed ET, Elbarbary NS. The impact of vildagliptin as an add-on therapy on matrix metalloproteinase-14 levels, liver stiffness and subclinical atherosclerosis in adolescents with type 1 diabetes and non-alcoholic steatohepatitis: A randomized controlled trial. Diabetes Obes Metab 2024; 26:5857-5869. [PMID: 39318059 DOI: 10.1111/dom.15958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 09/26/2024]
Abstract
AIM Many patients with type 1 diabetes mellitus (T1DM) met the histological criteria for non-alcoholic steatohepatitis (NASH), which leads to cardiovascular disease morbidity and mortality. Matrix metalloproteinase-14 (MMP-14) is involved in cardiovascular disease and atherosclerosis. OBJECTIVES To assess the impact of oral dipeptidyl peptidase-4 inhibitor, vildagliptin, as adjunctive therapy on NASH in adolescents with T1DM and its effect on glycaemic control, MMP-14 levels and carotid intima media thickness (CIMT). METHODS Sixty adolescents with T1DM and NASH were randomly assigned to receive oral vildagliptin (50 mg once daily) for 6 months or not. Glycated haemoglobin, lipid profile, hepatic steatosis index, triglyceride glucose (TyG) index and MMP-14 levels were assessed. Transient elastography with controlled attenuation parameter (CAP) was performed together with measuring CIMT. RESULTS By transient elastography, 12 (20%) patients with T1DM with NASH had elevated liver stiffness ≥7 kPa (F2 stage or higher). Baseline MMP-14 was positively correlated to insulin dose (p = 0.016), triglycerides and TyG index, CIMT, liver stiffness and CAP levels among the studied patients (p < 0.001 for all). After 6 months, patients with T1DM on vildagliptin therapy had significantly lower glycated haemoglobin, lipid profile, hepatic steatosis index and TyG index, as well as MMP-14 (p < 0.001). CIMT, liver stiffness and CAP were significantly decreased post-therapy compared with baseline levels and compared with the control group (p < 0.001). Vildagliptin was safe and well-tolerated. CONCLUSIONS Administration of vildagliptin for adolescents with T1DM and NASH improved glycaemic control, dyslipidaemia and MMP-14 levels and decreased liver stiffness and CIMT; hence, reducing subclinical atherosclerosis and disease progression.
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Wang H, Cheng W, Hu P, Ling T, Hu C, Chen Y, Zheng Y, Wang J, Zhao T, You Q. Integrative analysis identifies oxidative stress biomarkers in non-alcoholic fatty liver disease via machine learning and weighted gene co-expression network analysis. Front Immunol 2024; 15:1335112. [PMID: 38476236 PMCID: PMC10927810 DOI: 10.3389/fimmu.2024.1335112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 02/08/2024] [Indexed: 03/14/2024] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, with the potential to progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma. Given the absence of effective treatments to halt its progression, novel molecular approaches to the NAFLD diagnosis and treatment are of paramount importance. Methods Firstly, we downloaded oxidative stress-related genes from the GeneCards database and retrieved NAFLD-related datasets from the GEO database. Using the Limma R package and WGCNA, we identified differentially expressed genes closely associated with NAFLD. In our study, we identified 31 intersection genes by analyzing the intersection among oxidative stress-related genes, NAFLD-related genes, and genes closely associated with NAFLD as identified through Weighted Gene Co-expression Network Analysis (WGCNA). In a study of 31 intersection genes between NAFLD and Oxidative Stress (OS), we identified three hub genes using three machine learning algorithms: Least Absolute Shrinkage and Selection Operator (LASSO) regression, Support Vector Machine - Recursive Feature Elimination (SVM-RFE), and RandomForest. Subsequently, a nomogram was utilized to predict the incidence of NAFLD. The CIBERSORT algorithm was employed for immune infiltration analysis, single sample Gene Set Enrichment Analysis (ssGSEA) for functional enrichment analysis, and Protein-Protein Interaction (PPI) networks to explore the relationships between the three hub genes and other intersecting genes of NAFLD and OS. The distribution of these three hub genes across six cell clusters was determined using single-cell RNA sequencing. Finally, utilizing relevant data from the Attie Lab Diabetes Database, and liver tissues from NASH mouse model, Western Blot (WB) and Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) assays were conducted, this further validated the significant roles of CDKN1B and TFAM in NAFLD. Results In the course of this research, we identified 31 genes with a strong association with oxidative stress in NAFLD. Subsequent machine learning analysis and external validation pinpointed two genes: CDKN1B and TFAM, as demonstrating the closest correlation to oxidative stress in NAFLD. Conclusion This investigation found two hub genes that hold potential as novel targets for the diagnosis and treatment of NAFLD, thereby offering innovative perspectives for its clinical management.
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Affiliation(s)
- Haining Wang
- Medical Center for Digestive Diseases, Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Cheng
- Medical Center for Digestive Diseases, Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ping Hu
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Tao Ling
- Medical Center for Digestive Diseases, Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chao Hu
- Medical Center for Digestive Diseases, Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yongzhen Chen
- Medical Center for Digestive Diseases, Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yanan Zheng
- Medical Center for Digestive Diseases, Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Junqi Wang
- Department of Medical Oncology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Ting Zhao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Qiang You
- Medical Center for Digestive Diseases, Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Pateras IS, Igea A, Nikas IP, Leventakou D, Koufopoulos NI, Ieronimaki AI, Bergonzini A, Ryu HS, Chatzigeorgiou A, Frisan T, Kittas C, Panayiotides IG. Diagnostic Challenges during Inflammation and Cancer: Current Biomarkers and Future Perspectives in Navigating through the Minefield of Reactive versus Dysplastic and Cancerous Lesions in the Digestive System. Int J Mol Sci 2024; 25:1251. [PMID: 38279253 PMCID: PMC10816510 DOI: 10.3390/ijms25021251] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/12/2024] [Accepted: 01/16/2024] [Indexed: 01/28/2024] Open
Abstract
In the setting of pronounced inflammation, changes in the epithelium may overlap with neoplasia, often rendering it impossible to establish a diagnosis with certainty in daily clinical practice. Here, we discuss the underlying molecular mechanisms driving tissue response during persistent inflammatory signaling along with the potential association with cancer in the gastrointestinal tract, pancreas, extrahepatic bile ducts, and liver. We highlight the histopathological challenges encountered in the diagnosis of chronic inflammation in routine practice and pinpoint tissue-based biomarkers that could complement morphology to differentiate reactive from dysplastic or cancerous lesions. We refer to the advantages and limitations of existing biomarkers employing immunohistochemistry and point to promising new markers, including the generation of novel antibodies targeting mutant proteins, miRNAs, and array assays. Advancements in experimental models, including mouse and 3D models, have improved our understanding of tissue response. The integration of digital pathology along with artificial intelligence may also complement routine visual inspections. Navigating through tissue responses in various chronic inflammatory contexts will help us develop novel and reliable biomarkers that will improve diagnostic decisions and ultimately patient treatment.
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Affiliation(s)
- Ioannis S. Pateras
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Ana Igea
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
- Mobile Genomes, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela (USC), 15706 Santiago de Compostela, Spain
| | - Ilias P. Nikas
- Medical School, University of Cyprus, 2029 Nicosia, Cyprus
| | - Danai Leventakou
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Nektarios I. Koufopoulos
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Argyro Ioanna Ieronimaki
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Anna Bergonzini
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Alfred Nobels Allé 8, 141 52 Stockholm, Sweden;
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden;
| | - Han Suk Ryu
- Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea;
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece;
| | - Teresa Frisan
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden;
| | - Christos Kittas
- Department of Histopathology, Biomedicine Group of Health Company, 156 26 Athens, Greece;
| | - Ioannis G. Panayiotides
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
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Navarro-Meza M, Díaz-Muñoz M, Cruz-Ramos JA, Trinidad Gallardo JR, Rodríguez Oseguera MC, Bello-Medina PC, De Los Ríos-Arellano EA. Hepatocyte ballooning and steatosis in early and late gestation without liver malfunction: Effects of low protein/high carbohydrate diet. PLoS One 2024; 19:e0294062. [PMID: 38166013 PMCID: PMC10760903 DOI: 10.1371/journal.pone.0294062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 10/24/2023] [Indexed: 01/04/2024] Open
Abstract
Pregnancy is a challenging metabolic and physiological condition. The aim of this study was to include a second demanding situation as a low protein/high carbohydrate diet (LPHCD) to characterize the histological and functional responses of the maternal liver. It is unknown how the maternal liver responds during early and late pregnancy to LPHCD intake. We explored early pregnancy (3 and 8 gestational age, G) and late pregnancy (15 and 20 G). The results indicated that pregnant rats under control diet showed an evident presence of ballooned hepatocytes, lipid vesicles and edema at late pregnancy (15G); in contrast, pregnant rats under LPHCD showed similar pattern of histological modification but at early pregnancy (3G). Unexpectedly, the serum biomarkers didn't display functional alterations in either group, despite of the evident histological changes no liver malfunction was detected. We conclude that pregnant rats fed with control diet and experimental LPHCD, are subjected to metabolic and physiological conditions that impact the histopathological condition of the maternal liver. Control diet promoted the histological modifications during late pregnancy whereas LPCHCD advanced the onset of these changes. Further experiments are needed to explore the biochemical mechanisms that underlie these histological modifications. Our results are also an example of the resilience associated with the pregnancy: since no functional hepatic alterations accompanied the histopathological changes, another conclusion is that no evident pathological condition was detected in this nutritional protocol.
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Affiliation(s)
- Mónica Navarro-Meza
- Departamento de Promoción, Preservación y Desarrollo de la Salud, División Ciencias de la Salud, Laboratorio C de Memoria y Neuronutrición. Centro Universitario del Sur, Universidad de Guadalajara, Ciudad Guzmán, Jalisco, México
| | - Mauricio Díaz-Muñoz
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
| | - José Alfonso Cruz-Ramos
- Departamento de Clínicas Médicas, Universidad de Guadalajara, Guadalajara, Jalisco, México
- Coordinación de Investigación, Subdirección de Desarrollo institucional, Instituto Jalisciense de Cancerología, Guadalajara, Jalisco, México
| | - Jonathan Rafael Trinidad Gallardo
- Departamento de Promoción, Preservación y Desarrollo de la Salud, División Ciencias de la Salud, Laboratorio C de Memoria y Neuronutrición. Centro Universitario del Sur, Universidad de Guadalajara, Ciudad Guzmán, Jalisco, México
| | - María Conchita Rodríguez Oseguera
- Departamento de Promoción, Preservación y Desarrollo de la Salud, División Ciencias de la Salud, Laboratorio C de Memoria y Neuronutrición. Centro Universitario del Sur, Universidad de Guadalajara, Ciudad Guzmán, Jalisco, México
| | - Paola C. Bello-Medina
- Facultad de Ciencias e Instituto de Educación a distancia IDEAD, Universidad del Tolima, Ibagué, Tolima, Colombia
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Robles-Matos N, Radaelli E, Simmons RA, Bartolomei MS. Preconception and developmental DEHP exposure alter liver metabolism in a sex-dependent manner in adult mouse offspring. Toxicology 2023; 499:153640. [PMID: 37806616 PMCID: PMC10842112 DOI: 10.1016/j.tox.2023.153640] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/30/2023] [Accepted: 10/04/2023] [Indexed: 10/10/2023]
Abstract
Environmental exposure to endocrine disrupting chemicals (EDCs) during critical periods of development is associated with an increased risk of metabolic diseases, including hepatic steatosis and obesity. Di-2-ethylhexyl-phthalate (DEHP) is an EDC strongly associated with these metabolic abnormalities. DEHP developmental windows of susceptibility are unknown yet have important public health implications. The purpose of this study was to identify these windows of susceptibility and determine whether developmental DEHP exposure alters hepatic metabolism later in life. Dams were exposed to control or feed containing human exposure relevant doses of DEHP (50 μg/kg BW/d) and high dose DEHP (10 mg/kg BW/d) from preconception until weaning or only exposed to DEHP during preconception. Post-weaning, all offspring were fed a control diet throughout adulthood. Using the Metabolon Untargeted Metabolomics platform, we identified 148 significant metabolites in female adult livers that were altered by preconception-gestation-lactation DEHP exposure. We found a significant increase in the levels of acylcarnitines, diacylglycerols, sphingolipids, glutathione, purines, and pyrimidines in DEHP-exposed female livers compared to controls. These changes in fatty acid oxidation and oxidative stress-related metabolites were correlated with hepatic changes including microvesicular steatosis, hepatocyte swelling, inflammation. In contrast to females, we observed fewer metabolic alterations in male offspring, which were uniquely found in preconception-only low dose DEHP exposure group. Although we found that preconception-gestational-lactation exposure causes the most liver pathology, we surprisingly found preconception exposure linked to an abnormal liver metabolome. We also found that two doses exhibited non-monotonic DEHP-induced changes in the liver. Collectively, these findings suggest that metabolic changes in the adult liver of offspring exposed periconceptionally to DHEP depends on the timing of exposure, dose, and sex.
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Affiliation(s)
- Nicole Robles-Matos
- Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Enrico Radaelli
- Comparative Pathology Core, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rebecca A Simmons
- Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - Marisa S Bartolomei
- Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Godoy G, Bernardo C, Casagrande L, Sérgio M, Zanoni J, Perles J, Curi R, Bazotte R. Linseed oil attenuates fatty liver disease in mice fed a high-carbohydrate diet. Braz J Med Biol Res 2023; 56:e12927. [PMID: 37703111 PMCID: PMC10496762 DOI: 10.1590/1414-431x2023e12927] [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: 06/07/2023] [Accepted: 07/27/2023] [Indexed: 09/15/2023] Open
Abstract
The impact of linseed oil as a lipid source on liver disease induced by a high-carbohydrate diet (HCD) was evaluated. Adult male Swiss mice received an HCD containing carbohydrates (72.1%), proteins (14.2%), and lipids (4.0%). The Control HCD group (HCD-C) received an HCD containing lard (3.6%) and soybean oil (0.4%) as lipid sources. The L10 and L100 groups received an HCD with 10 and 100% linseed oil as lipid sources, respectively. A group of mice were euthanized before receiving the diets (day 0) and the remaining groups after 56 days of receiving the diets (HCD-C, L10, and L-100 groups). Morphological and histopathological analyses, as well as collagen deposition were evaluated. Perivenous hepatocytes (PVH) of the HCD-C group were larger (P<0.05) than periportal hepatocytes (PPH) in the median lobe (ML) and left lobe (LL). There was a greater (P<0.05) deposition of type I collagen in PPH (vs PVH) and in the ML (vs LL). The ML exhibited a higher proportion of apoptotic bodies, inflammatory infiltrate, and hepatocellular ballooning. All these alterations (hepatocyte size, deposition of type I collagen, apoptotic bodies, inflammatory infiltrate, and hepatocellular ballooning) induced by HCD were prevented or attenuated in L10 and L100 groups. Another indicator of the beneficial effects of linseed oil was the lower (P<0.05) number of binucleated hepatocytes (HCD-C vs L10 or L100 group). In general, the L100 group had greater effects than the L10 group. In conclusion, linseed oil impedes or reduces the liver injury progression induced by an HCD.
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Affiliation(s)
- G. Godoy
- Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brasil
| | - C.C.O. Bernardo
- Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brasil
| | - L. Casagrande
- Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brasil
| | - M.L.M. Sérgio
- Departamento de Ciências Morfológicas, Universidade Estadual de Maringá, Maringá, PR, Brasil
| | - J.N. Zanoni
- Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brasil
- Departamento de Ciências Morfológicas, Universidade Estadual de Maringá, Maringá, PR, Brasil
| | - J.V.C.M. Perles
- Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brasil
- Departamento de Ciências Morfológicas, Universidade Estadual de Maringá, Maringá, PR, Brasil
| | - R. Curi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, SP, Brasil
- Seção de Produção de Imunobiológicos, Centro Bioindustrial, Instituto Butantan, São Paulo, SP, Brasil
| | - R.B. Bazotte
- Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brasil
- Departamento de Farmacologia e Terapêutica, Universidade Estadual de Maringá, Maringá, PR, Brasil
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Singla T, Muneshwar KN, Pathade AG, Yelne S. Hepatocytic Ballooning in Non-alcoholic Steatohepatitis: Bridging the Knowledge Gap and Charting Future Avenues. Cureus 2023; 15:e45884. [PMID: 37885505 PMCID: PMC10598508 DOI: 10.7759/cureus.45884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 09/22/2023] [Indexed: 10/28/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is emerging as a significant global health concern, characterized by hepatic lipid accumulation, inflammation, and hepatocellular injury. Hepatocytic ballooning, a histological feature of NASH, has gained prominence for its role in disease progression and potential as a therapeutic target. This review provides an overview of the current knowledge regarding hepatocytic ballooning in NASH, highlighting the key molecular and cellular mechanisms implicated in its development. We delve into the intricate interplay of metabolic dysregulation, oxidative stress, and lipid toxicity as drivers of hepatocytic ballooning, shedding light on the pathways responsible for its initiation and perpetuation. Furthermore, we explore the diagnostic challenges associated with hepatocytic ballooning and its significance as a prognostic indicator in NASH patients. While hepatocytic ballooning holds promise as a therapeutic target, this abstract discusses the various experimental and clinical approaches to ameliorate this histological hallmark. Potential interventions, including lifestyle modifications, pharmacological agents, and emerging therapies, are evaluated in terms of their efficacy and safety profiles. In conclusion, this review underscores the need to bridge the knowledge gap surrounding hepatocytic ballooning in NASH and emphasizes its importance in understanding disease pathogenesis and progression. By charting future research avenues and clinical strategies, we aspire to advance our comprehension of NASH and ultimately improve patient outcomes in this rapidly evolving field of hepatology.
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Affiliation(s)
- Tanvi Singla
- Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Komal N Muneshwar
- Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Aniket G Pathade
- Research and Development, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Seema Yelne
- Nursing, Shalinitai Meghe College of Nursing, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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Fraile-Ramos J, Garrit A, Reig-Vilallonga J, Giménez-Llort L. Hepatic Oxi-Inflammation and Neophobia as Potential Liver-Brain Axis Targets for Alzheimer's Disease and Aging, with Strong Sensitivity to Sex, Isolation, and Obesity. Cells 2023; 12:1517. [PMID: 37296638 PMCID: PMC10252497 DOI: 10.3390/cells12111517] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/06/2023] [Accepted: 05/29/2023] [Indexed: 06/12/2023] Open
Abstract
Research on Alzheimer's disease (AD) has classically focused on alterations that occur in the brain and their intra- and extracellular neuropathological hallmarks. However, the oxi-inflammation hypothesis of aging may also play a role in neuroimmunoendocrine dysregulation and the disease's pathophysiology, where the liver emerges as a target organ due to its implication in regulating metabolism and supporting the immune system. In the present work, we demonstrate organ (hepatomegaly), tissue (histopathological amyloidosis), and cellular oxidative stress (decreased glutathione peroxidase and increased glutathione reductase enzymatic activities) and inflammation (increased IL-6 and TNF𝛼) as hallmarks of hepatic dysfunction in 16-month-old male and female 3xTg-AD mice at advanced stages of the disease, and as compared to age- and sex-matched non-transgenic (NTg) counterparts. Moreover, liver-brain axis alterations were found through behavioral (increased neophobia) and HPA axis correlations that were enhanced under forced isolation. In all cases, sex (male) and isolation (naturalistic and forced) were determinants of worse hepatomegaly, oxidative stress, and inflammation progression. In addition, obesity in old male NTg mice was translated into a worse steatosis grade. Further research is underway determine whether these alterations could correlate with a worse disease prognosis and to establish potential integrative system targets for AD research.
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Affiliation(s)
- Juan Fraile-Ramos
- Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Department of Psychiatry and Forensic Medicine, School of Medicine, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Anna Garrit
- Department of Anatomy, School of Medicine, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Josep Reig-Vilallonga
- Department of Anatomy, School of Medicine, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Lydia Giménez-Llort
- Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Department of Psychiatry and Forensic Medicine, School of Medicine, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
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10
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Nash MJ, Dobrinskikh E, Janssen RC, Lovell MA, Schady DA, Levek C, Jones KL, D’Alessandro A, Kievit P, Aagaard KM, McCurdy CE, Gannon M, Friedman JE, Wesolowski SR. Maternal Western diet is associated with distinct preclinical pediatric NAFLD phenotypes in juvenile nonhuman primate offspring. Hepatol Commun 2023; 7:e0014. [PMID: 36691970 PMCID: PMC9851700 DOI: 10.1097/hc9.0000000000000014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 10/12/2022] [Indexed: 01/25/2023] Open
Abstract
Pediatric NAFLD has distinct and variable pathology, yet causation remains unclear. We have shown that maternal Western-style diet (mWSD) compared with maternal chow diet (CD) consumption in nonhuman primates produces hepatic injury and steatosis in fetal offspring. Here, we define the role of mWSD and postweaning Western-style diet (pwWSD) exposures on molecular mechanisms linked to NAFLD development in a cohort of 3-year-old juvenile nonhuman primates offspring exposed to maternal CD or mWSD followed by CD or Western-style diet after weaning. We used histologic, transcriptomic, and metabolomic analyses to identify hepatic pathways regulating NAFLD. Offspring exposed to mWSD showed increased hepatic periportal collagen deposition but unchanged hepatic triglyceride levels and body weight. mWSD was associated with a downregulation of gene expression pathways underlying HNF4α activity and protein, and downregulation of antioxidant signaling, mitochondrial biogenesis, and PPAR signaling pathways. In offspring exposed to both mWSD and pwWSD, liver RNA profiles showed upregulation of pathways promoting fibrosis and endoplasmic reticulum stress and increased BiP protein expression with pwWSD. pwWSD increased acylcarnitines and decreased anti-inflammatory fatty acids, which was more pronounced when coupled with mWSD exposure. Further, mWSD shifted liver metabolites towards decreased purine catabolism in favor of synthesis, suggesting a mitochondrial DNA repair response. Our findings demonstrate that 3-year-old offspring exposed to mWSD but weaned to a CD have periportal collagen deposition, with transcriptional and metabolic pathways underlying hepatic oxidative stress, compromised mitochondrial lipid sensing, and decreased antioxidant response. Exposure to pwWSD worsens these phenotypes, triggers endoplasmic reticulum stress, and increases fibrosis. Overall, mWSD exposure is associated with altered expression of candidate genes and metabolites related to NAFLD that persist in juvenile offspring preceding clinical presentation of NAFLD.
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Affiliation(s)
- Michael J. Nash
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Evgenia Dobrinskikh
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Rachel C. Janssen
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Mark A. Lovell
- Department of Pathology & Laboratory Medicine, Children’s Hospital Colorado, Aurora, Colorado, USA
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Deborah A. Schady
- Department of Pathology & Immunology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, USA
| | - Claire Levek
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Kenneth L. Jones
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Paul Kievit
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Kjersti M. Aagaard
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, USA
- Department of Molecular and Cell Biology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, USA
| | - Carrie E. McCurdy
- Department of Human Physiology, University of Oregon, Eugene, Oregon, USA
| | - Maureen Gannon
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jacob E. Friedman
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Stephanie R. Wesolowski
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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11
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Gill RM, Allende D, Belt PH, Behling CA, Cummings OW, Guy CD, Carpenter D, Neuschwander-Tetri BA, Sanyal AJ, Tonascia J, Van Natta ML, Wilson LA, Yamada G, Yeh M, Kleiner DE. The nonalcoholic steatohepatitis extended hepatocyte ballooning score: histologic classification and clinical significance. Hepatol Commun 2023; 7:e0033. [PMID: 36724127 PMCID: PMC9894357 DOI: 10.1097/hc9.0000000000000033] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 10/21/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND AND AIMS The NAFLD activity score was developed to measure histologic changes in NAFLD during therapeutic trials. Hepatocyte ballooning (HB) is the most specific feature in steatohepatitis diagnosis, yet the impact of variations in HB has not been incorporated. APPROACH AND RESULTS Liver biopsies from patients enrolled in the NASH Clinical Research Network with an initial diagnosis of NASH or NAFL (n=1688) were evaluated to distinguish classic hepatocyte ballooning (cHB) from smaller, nonclassic hepatocyte ballooning (nHB), and also to designate severe ballooning and assign an extended hepatocyte ballooning (eB) score [0 points, no ballooning (NB); 1 point, few or many nHB; 2 points, few cHB; 3 points, many cHB; 4 points, severe cHB] to the biopsy assessment. The eB score was reproducible among NASH CRN liver pathologists (weighted kappa 0.76) and was significantly associated with older age (mean 52.1 y, cHB; 48.5 y, nHB, p<0.001), gender (72.3% female, cHB; 54.5% female, nHB, p<0.001), diabetes (49.8% diabetes, cHB; 28.2% diabetes, nHB, p<0.001), metabolic syndrome (68.5% metabolic syndrome, nHB; 50.2% metabolic syndrome, NB, p<0.001), and body mass index [33.2, 34.2, 35 mean body mass index (kg/m2); NB, nHB, and cHB, respectively, p<0.05]. Finally, fibrosis stage, as a marker of disease severity, was significantly correlated with the eB score (p<0.001). CONCLUSIONS The eB score allows for a reproducible and more precise delineation of the range of ballooned hepatocyte morphology and corresponds with both clinical features of NASH and fibrosis stage.
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Affiliation(s)
- Ryan M. Gill
- Department of Pathology, University of California, San Francisco, San Francisco, California, USA
| | - Daniela Allende
- Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Patricia H. Belt
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | | | - Oscar W. Cummings
- Department of Pathology, Indiana University, Indianapolis, Indiana, USA
| | - Cynthia D. Guy
- Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA
| | - Daniela Carpenter
- Department of Pathology, Saint Louis University, St. Louis, Missouri, USA
| | | | - Arun J. Sanyal
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - James Tonascia
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Mark L. Van Natta
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Laura A. Wilson
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Goro Yamada
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Matthew Yeh
- Department of Pathology, University of Washington, Seattle, Washington, USA
| | - David E. Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA
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12
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Barboza T, Beaufrère H, Reavill D, Susta L. Morphological features of hepatic lipid changes in bearded dragons ( Pogona vitticeps), and a proposed grading system. Vet Pathol 2023; 60:123-132. [PMID: 36250570 DOI: 10.1177/03009858221128921] [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] [Indexed: 01/31/2023]
Abstract
Hepatic lipidosis is commonly diagnosed in pet bearded dragons (Pogona vitticeps). However, there are no studies detailing the histological features of hepatic lipid changes in this species. This study describes the microscopic features of lipid change and details an associated scoring system. Histologic hepatic sections were retrospectively evaluated from 252 bearded dragons submitted for necropsy. Pathologic assessment was used to develop a grading scheme with 2 qualitative, 1 quantitative, and 6 semi-quantitative microscopic parameters, which were refined based on variability. The final grading system developed for diffuse and panlobular lipid accumulation included 2 semi-quantitative and 1 quantitative categories: percentage of hepatocellular vacuolation, fibrosis, and hepatocellular swelling, respectively. Hepatocellular swelling was indirectly quantified by counting the number of nuclei per unit area. There was a strong positive correlation (P < .001) between the percentage of hepatocellular vacuolation and lipid content, a strong negative correlation (P < .001) between nuclear count and lipid content, and a moderate correlation (P < .001) between fibrosis and lipid content. Each category was given a numerical value ranging from 0 to 4, with the sum of each representing the final grade. Cutoff values stratified microscopic changes into mild (final grade 1-4), moderate (5-7), and severe (≥8). There was strong interrater agreement for assessment of vacuolization, fibrosis, and severity classification and moderate for hepatocellular swelling. This study documents the features of hepatic lipid changes in bearded dragons. Although a cutoff to differentiate pathologic from nonpathologic lipid accumulation could not be estimated, the proposed grading scheme can be used to inform future studies.
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Affiliation(s)
- Trinita Barboza
- Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
- Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA
| | | | | | - Leonardo Susta
- Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
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13
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Karl M, Hasselwander S, Zhou Y, Reifenberg G, Kim YO, Park KS, Ridder DA, Wang X, Seidel E, Hövelmeyer N, Straub BK, Li H, Schuppan D, Xia N. Dual roles of B lymphocytes in mouse models of diet-induced nonalcoholic fatty liver disease. Hepatology 2022; 76:1135-1149. [PMID: 35218234 DOI: 10.1002/hep.32428] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 02/08/2022] [Accepted: 02/19/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS Growing evidence suggests an important role of B cells in the development of NAFLD. However, a detailed functional analysis of B cell subsets in NAFLD pathogenesis is lacking. APPROACH AND RESULTS In wild-type mice, 21 weeks of high fat diet (HFD) feeding resulted in NAFLD with massive macrovesicular steatosis, modest hepatic and adipose tissue inflammation, insulin resistance, and incipient fibrosis. Remarkably, Bnull (JHT) mice were partially protected whereas B cell harboring but antibody-deficient IgMi mice were completely protected from the development of hepatic steatosis, inflammation, and fibrosis. The common feature of JHT and IgMi mice is that they do not secrete antibodies, whereas HFD feeding in wild-type mice led to increased levels of serum IgG2c. Whereas JHT mice have no B cells at all, regulatory B cells were found in the liver of both wild-type and IgMi mice. HFD reduced the number of regulatory B cells and IL-10 production in the liver of wild-type mice, whereas these increased in IgMi mice. Livers of patients with advanced liver fibrosis showed abundant deposition of IgG and stromal B cells and low numbers of IL-10 expressing cells, compatible with our experimental data. CONCLUSIONS B lymphocytes have both detrimental and protective effects in HFD-induced NAFLD. The lack of secreted pathogenic antibodies protects partially from NAFLD, whereas the presence of certain B cell subsets provides additional protection. IL-10-producing regulatory B cells may represent such a protective B cell subset.
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Affiliation(s)
- Martin Karl
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Solveig Hasselwander
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Yawen Zhou
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Gisela Reifenberg
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Yong Ook Kim
- Institute of Translational Immunology and Research Center for ImmunotherapyJohannes Gutenberg University Medical CenterMainzGermany
| | - Kyoung-Sook Park
- Institute of Translational Immunology and Research Center for ImmunotherapyJohannes Gutenberg University Medical CenterMainzGermany
| | - Dirk A Ridder
- Institute of PathologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Xiaoyu Wang
- Institute of Translational Immunology and Research Center for ImmunotherapyJohannes Gutenberg University Medical CenterMainzGermany
- Department of Basic MedicineShenyang Medical CollegeShenyangChina
| | - Eric Seidel
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Nadine Hövelmeyer
- Institute for Molecular Medicine and Research Center for ImmunotherapyJohannes Gutenberg University Medical CenterMainzGermany
| | - Beate K Straub
- Institute of PathologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Huige Li
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for ImmunotherapyJohannes Gutenberg University Medical CenterMainzGermany
- Division of GastroenterologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMassachusettsUSA
| | - Ning Xia
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
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14
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Roeb E, Canbay A, Bantel H, Bojunga J, de Laffolie J, Demir M, Denzer UW, Geier A, Hofmann WP, Hudert C, Karlas T, Krawczyk M, Longerich T, Luedde T, Roden M, Schattenberg J, Sterneck M, Tannapfel A, Lorenz P, Tacke F. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:1346-1421. [PMID: 36100202 DOI: 10.1055/a-1880-2283] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- E Roeb
- Gastroenterologie, Medizinische Klinik II, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - A Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - H Bantel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - J Bojunga
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin., Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - J de Laffolie
- Allgemeinpädiatrie und Neonatologie, Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - M Demir
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte, Berlin, Deutschland
| | - U W Denzer
- Klinik für Gastroenterologie und Endokrinologie, Universitätsklinikum Gießen und Marburg, Marburg, Deutschland
| | - A Geier
- Medizinische Klinik und Poliklinik II, Schwerpunkt Hepatologie, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - W P Hofmann
- Gastroenterologie am Bayerischen Platz - Medizinisches Versorgungszentrum, Berlin, Deutschland
| | - C Hudert
- Klinik für Pädiatrie m. S. Gastroenterologie, Nephrologie und Stoffwechselmedizin, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - T Karlas
- Klinik und Poliklinik für Onkologie, Gastroenterologie, Hepatologie, Pneumologie und Infektiologie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - M Krawczyk
- Klinik für Innere Medizin II, Gastroent., Hepat., Endokrin., Diabet., Ern.med., Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - T Longerich
- Pathologisches Institut, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - T Luedde
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
| | - M Roden
- Klinik für Endokrinologie und Diabetologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
| | - J Schattenberg
- I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland
| | - M Sterneck
- Klinik für Hepatobiliäre Chirurgie und Transplantationschirurgie, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - A Tannapfel
- Institut für Pathologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - P Lorenz
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin, Deutschland
| | - F Tacke
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte, Berlin, Deutschland
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15
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Updated S2k Clinical Practice Guideline on Non-alcoholic Fatty Liver Disease (NAFLD) issued by the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) - April 2022 - AWMF Registration No.: 021-025. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:e733-e801. [PMID: 36100201 DOI: 10.1055/a-1880-2388] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
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16
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Green CD, Weigel C, Brown RDR, Bedossa P, Dozmorov M, Sanyal AJ, Spiegel S. A new preclinical model of western diet-induced progression of non-alcoholic steatohepatitis to hepatocellular carcinoma. FASEB J 2022; 36:e22372. [PMID: 35639028 DOI: 10.1096/fj.202200346r] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/29/2022] [Accepted: 05/11/2022] [Indexed: 12/24/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) results from the accumulation of excessive liver lipids leading to hepatocellular injury, inflammation, and fibrosis that greatly increase the risk for hepatocellular carcinoma (HCC). Despite the well-characterized clinical and histological pathology for NASH-driven HCC in humans, its etiology remains unclear and there is a deficiency in pre-clinical models that recapitulate the progression of the human disease. Therefore, we developed a new mouse model amenable to genetic manipulations and gene targeting that mimics the gradual NASH to HCC progression observed in humans. C57BL/6NJ mice were fed a Western high-fat diet and sugar water (HFD/SW) and monitored for effects on metabolism, liver histology, tumor development, and liver transcriptome for up to 54 weeks. Chronic HFD/SW feeding led to significantly increased weight gain, serum and liver lipid levels, liver injury, and glucose intolerance. Hepatic pathology progressed and mice developed hepatocellular ballooning, inflammation, and worse fibrosis was apparent at 16 weeks, greatly increased through 32 weeks, and remained elevated at 54 weeks. Importantly, hepatocellular cancer spontaneously developed in 75% of mice on HFD/SW, half of which were HCC, whereas none of the mice on the chow diet developed HCC. Chronic HFD/SW induced molecular markers of de novo lipogenesis, endoplasmic reticulum stress, inflammation, and accumulation of p62, all of which also participate in the human pathology. Moreover, transcriptome analysis revealed activation of HCC-related genes and signatures associated with poor prognosis of human HCC. Overall, we have identified a new preclinical model that recapitulates known hallmarks of NASH-driven HCC that can be utilized for future molecular mechanistic studies of this disease.
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Affiliation(s)
- Christopher D Green
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Cynthia Weigel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Ryan D R Brown
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Pierre Bedossa
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Liverpat, Paris, France
| | - Mikhail Dozmorov
- Departments of Biostatistics and Pathology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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17
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Susilowati R, Setiawan AM, Zahroh AF, Ashari ZN, Iffiyana A, Hertanto R, Basyarudin M, Hartiningsih I, Ismail M. Hepatoprotection of Cinnamomum burmannii ethanolic extract against high-fat and cholesterol diet in Sprague–Dawley rats (Rattus norvegicus). Vet World 2022; 15:930-936. [PMID: 35698494 PMCID: PMC9178583 DOI: 10.14202/vetworld.2022.930-936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 02/16/2022] [Indexed: 11/16/2022] Open
Abstract
Background and Aim: The pathogenesis of non-alcoholic steatohepatitis involves non-alcoholic fatty liver, oxidative stress, inflammation, and fibrosis. Although the long-term use of cinnamon bark in larger doses can negatively affect good health, proper use of its extracts effectively and efficiently improves health. Therefore, this study aimed to determine the minimal dose of Cinnamomum Burmannii extract through its activity in inhibiting oxidative stress in rats’ livers treated with a high-fat and cholesterol diet (HFCD). Materials and Methods: Forty-two Sprague–Dawley rats (Rattus norvegicus), weighing 200-250 g body weight (BW), were divided into seven treatment groups with six replications: Normal, HFCD, atorvastatin, quercetin, and C. burmannii ethanol extract group, after which they were administered different dosages (i.e., 100, 200, and 300 mg/kg BW). Except for the normal group, rats were concomitantly administered HFCD with each treatment for 21 days. Then, their malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were assessed using colorimetry. However, their steatosis levels were determined based on histological preparations with hematoxylin-eosin staining. Results: Duncan’s multiple range test (DMRT) results indicated that all treatments had a significantly lower MDA than HFCD and normal rats (a=0.01). DMRT results also showed that treating with the C. burmannii ethanol extract at all dosages resulted in a significantly higher SOD activity level in HFCD rats than those treated with quercetin and atorvastatin (a=0.01). Furthermore, results showed that treatment with C. burmannii extracts at a dosage of 300 mg/kg BW incredibly maintained SOD activity as effective as quercetin, atorvastatin, and normal rats. Besides, while steatohepatitis levels of C. burmannii ethanol extract at dosages of 200 and 300 mg/kg BW commensurated with normal rats, steatohepatitis levels were significantly lower than those administered other concentrations or treatments (a=0.05). Conclusion: Ethanolic C. burmannii extracts protected the liver by regulating oxidative stress. Therefore, a 200 mg/kg BW dose is proposed as the minimal hepatoprotection dose to prevent fatty liver formation.
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Affiliation(s)
- Retno Susilowati
- Department of Biology, Faculty of Science and Technology, State Islamic University of Maulana Malik Ibrahim Malang, Malang 65144, East Java, Indonesia
| | - Abdul Malik Setiawan
- Department of Microbiology, Faculty of Medicine and Health Sciences, State Islamic University of Maulana Malik Ibrahim Malang, Malang 65144, East Java, Indonesia
| | - Afida Fatimatuz Zahroh
- Department of Biology, Faculty of Science and Technology, State Islamic University of Maulana Malik Ibrahim Malang, Malang 65144, East Java, Indonesia
| | - Zadani Nabila Ashari
- Department of Biology, Faculty of Science and Technology, State Islamic University of Maulana Malik Ibrahim Malang, Malang 65144, East Java, Indonesia
| | - Alifatul Iffiyana
- Department of Biology, Faculty of Science and Technology, State Islamic University of Maulana Malik Ibrahim Malang, Malang 65144, East Java, Indonesia
| | - Ricky Hertanto
- Department of Biology, Faculty of Science and Technology, State Islamic University of Maulana Malik Ibrahim Malang, Malang 65144, East Java, Indonesia
| | - Muhammad Basyarudin
- Department of Biology, Faculty of Science and Technology, State Islamic University of Maulana Malik Ibrahim Malang, Malang 65144, East Java, Indonesia
| | - Isnaeni Hartiningsih
- Department of Chemistry, Faculty of Science and Technology, State Islamic University of Maulana Malik Ibrahim Malang, Malang 65144, East Java, Indonesia
| | - Mahrus Ismail
- Department of Biology, Faculty of Science and Technology, State Islamic University of Maulana Malik Ibrahim Malang, Malang 65144, East Java, Indonesia
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18
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Gindlhuber J, Schinagl M, Liesinger L, Darnhofer B, Tomin T, Schittmayer M, Birner-Gruenberger R. Hepatocyte Proteome Alterations Induced by Individual and Combinations of Common Free Fatty Acids. Int J Mol Sci 2022; 23:3356. [PMID: 35328776 PMCID: PMC8951603 DOI: 10.3390/ijms23063356] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/11/2022] [Accepted: 03/18/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease is a pathology with a hard-to-detect onset and is estimated to be present in a quarter of the adult human population. To improve our understanding of the development of non-alcoholic fatty liver disease, we treated a human hepatoma cell line model, HepG2, with increasing concentrations of common fatty acids, namely myristic, palmitic and oleic acid. To reproduce more physiologically representative conditions, we also included combinations of these fatty acids and monitored the cellular response with an in-depth proteomics approach and imaging techniques. The two saturated fatty acids initially presented a similar phenotype of a dose-dependent decrease in growth rates and impaired lipid droplet formation. Detailed analysis revealed that the drop in the growth rates was due to delayed cell-cycle progression following myristic acid treatment, whereas palmitic acid led to cellular apoptosis. In contrast, oleic acid, as well as saturated fatty acid mixtures with oleic acid, led to a dose-dependent increase in lipid droplet volume without adverse impacts on cell growth. Comparing the effects of harmful single-fatty-acid treatments and the well-tolerated fatty acid mixes on the cellular proteome, we were able to differentiate between fatty-acid-specific cellular responses and likely common lipotoxic denominators.
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Affiliation(s)
- Juergen Gindlhuber
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (M.S.); (L.L.); (B.D.)
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (T.T.); (M.S.)
| | - Maximilian Schinagl
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (M.S.); (L.L.); (B.D.)
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (T.T.); (M.S.)
| | - Laura Liesinger
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (M.S.); (L.L.); (B.D.)
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (T.T.); (M.S.)
| | - Barbara Darnhofer
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (M.S.); (L.L.); (B.D.)
| | - Tamara Tomin
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (T.T.); (M.S.)
| | - Matthias Schittmayer
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (T.T.); (M.S.)
| | - Ruth Birner-Gruenberger
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (M.S.); (L.L.); (B.D.)
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (T.T.); (M.S.)
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19
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Sharma A, Virmani T, Sharma A, Chhabra V, Kumar G, Pathak K, Alhalmi A. Potential Effect of DPP-4 Inhibitors Towards Hepatic Diseases and Associated Glucose Intolerance. Diabetes Metab Syndr Obes 2022; 15:1845-1864. [PMID: 35733643 PMCID: PMC9208633 DOI: 10.2147/dmso.s369712] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/10/2022] [Indexed: 11/23/2022] Open
Abstract
Dipeptidyl-peptidase-4 (DPP-4) is an enzyme having various properties and physiological roles in lipid accumulation, resistance to anticancer agents, and immune stimulation. DPP-4 includes membrane-bound peptidases and is a kind of enzyme that cleaves alanine or proline-containing peptides such as incretins, chemokines, and appetite-suppressing hormones (neuropeptide) at their N-terminal dipeptides. DPP-4 plays a role in the final breakdown of peptides produced by other endo and exo-peptidases from nutritious proteins and their absorption in these tissues. DPP-4 enzyme activity has different modes of action on glucose metabolism, hunger regulation, gastrointestinal motility, immune system function, inflammation, and pain regulation. According to the literature survey, as DPP-4 levels increase in individuals with liver conditions, up-regulation of hepatic DPP-4 expression is likely to be the cause of glucose intolerance or insulin resistance. This review majorly focuses on the cleavage of alanine or proline-containing peptides such as incretins by the DPP-4 and its resulting conditions like glucose intolerance and cause of DPP-4 level elevation due to some liver conditions. Thus, we have discussed the various effects of DPP-4 on the liver diseases like hepatitis C, non-alcoholic fatty liver, hepatic regeneration and stem cell, hepatocellular carcinoma, and the impact of elevated DPP-4 levels in association with liver diseases as a cause of glucose intolerance and their treatment drug of choices. In addition, the effect of DPP-4 inhibitors on obesity and their negative aspects are also discussed in brief.
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Affiliation(s)
- Ashwani Sharma
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Tarun Virmani
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Anjali Sharma
- Freelancer, Pharmacovigilance Expert, Uttar Pradesh, India
| | - Vaishnavi Chhabra
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Girish Kumar
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Kamla Pathak
- Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Uttar Pradesh, 206130, India
| | - Abdulsalam Alhalmi
- Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, Yemen
- Correspondence: Abdulsalam Alhalmi, Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, Yemen, Email
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20
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Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer 2021; 21:541-557. [PMID: 34326518 DOI: 10.1038/s41568-021-00383-9] [Citation(s) in RCA: 313] [Impact Index Per Article: 78.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/18/2021] [Indexed: 02/07/2023]
Abstract
The liver is the sixth most common site of primary cancer in humans, and generally arises in a background of cirrhosis and inflammation. Moreover, the liver is frequently colonized by metastases from cancers of other organs (particularly the colon) because of its anatomical location and organization, as well as its unique metabolic and immunosuppressive environment. In this Review, we discuss how the hepatic microenvironment adapts to pathologies characterized by chronic inflammation and metabolic alterations. We illustrate how these immunological or metabolic changes alter immunosurveillance and thus hinder or promote the development of primary liver cancer. In addition, we describe how inflammatory and metabolic niches affect the spreading of cancer metastases into or within the liver. Finally, we review the current therapeutic options in this context and the resulting challenges that must be surmounted.
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Affiliation(s)
- Xin Li
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Pierluigi Ramadori
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dominik Pfister
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marco Seehawer
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tuebingen, Germany
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Lars Zender
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany
- German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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21
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Serrano A, Ribot J, Palou A, Bonet ML. Long-term programming of skeletal muscle and liver lipid and energy metabolism by resveratrol supplementation to suckling mice. J Nutr Biochem 2021; 95:108770. [PMID: 34000411 DOI: 10.1016/j.jnutbio.2021.108770] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 03/04/2021] [Accepted: 04/29/2021] [Indexed: 02/07/2023]
Abstract
Metabolic programming by dietary chemicals consumed in early life stages is receiving increasing attention. We here studied long-term effects of mild resveratrol (RSV) supplementation during lactation on muscular and hepatic lipid metabolism in adulthood. Newborn male mice received RSV or vehicle from day 2-20 of age, were weaned onto a chow diet on day 21, and were assigned to either a high-fat diet (HFD) or a normal-fat diet on day 90 of age for 10 weeks. RSV-treated mice showed in adulthood protection against HFD-induced triacylglycerol accumulation in skeletal muscle, enhanced muscular capacities for fat oxidation and mitochondria activity, signs of enhanced sirtuin 1 and AMP-dependent protein kinase signaling in muscle, and increased fat oxidation capacities and a decreased capacity for lipogenesis in liver compared with controls. Thus, RSV supplementation in early postnatal life may help preventing later diet-related disorders linked to ectopic lipid accumulation in muscle and liver tissues.
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Affiliation(s)
- Alba Serrano
- Grup de Recerca Nutrigenòmica i Obesitat, Laboratori de Biologia Molecular, Nutrició i Biotecnologia (LBNB), Universitat de les Illes Balears, Palma de Mallorca, Spain
| | - Joan Ribot
- Grup de Recerca Nutrigenòmica i Obesitat, Laboratori de Biologia Molecular, Nutrició i Biotecnologia (LBNB), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Palma de Mallorca, Spain.
| | - Andreu Palou
- Grup de Recerca Nutrigenòmica i Obesitat, Laboratori de Biologia Molecular, Nutrició i Biotecnologia (LBNB), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Palma de Mallorca, Spain
| | - M Luisa Bonet
- Grup de Recerca Nutrigenòmica i Obesitat, Laboratori de Biologia Molecular, Nutrició i Biotecnologia (LBNB), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Palma de Mallorca, Spain
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22
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Gu Y, Liu X, Liao L, Gao Y, Shi Y, Ni J, He G. Relationship between lipid metabolism and Hedgehog signaling pathway. J Steroid Biochem Mol Biol 2021; 209:105825. [PMID: 33529733 DOI: 10.1016/j.jsbmb.2021.105825] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/28/2020] [Accepted: 01/13/2021] [Indexed: 02/08/2023]
Abstract
The Hedgehog (Hh) signaling pathway is highly conserved signaling pathway in cells. Steroids was found to play a vital role in Hh signaling pathway and aberrant Hh signaling was found to lead a series of disease correlate with abnormal lipid metabolism. This paper aimed to elucidate the relationship between lipid metabolism and Hedgehog signaling pathway.
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Affiliation(s)
- Yuan Gu
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Hunan 410011, PR China
| | - Xiaochen Liu
- University of Toledo Medical Center 3000 Arlington Ave. Toledo, OH 43614, USA
| | - Lele Liao
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Hunan 410011, PR China
| | - Yongquan Gao
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Hunan 410011, PR China
| | - Yu Shi
- West China School of Stomatology, Sichuan University, Chengdu 610041, PR China; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Jiangdong Ni
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Hunan 410011, PR China
| | - Guangxu He
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Hunan 410011, PR China.
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23
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Freag MS, Namgung B, Reyna Fernandez ME, Gherardi E, Sengupta S, Jang HL. Human Nonalcoholic Steatohepatitis on a Chip. Hepatol Commun 2021; 5:217-233. [PMID: 33553970 PMCID: PMC7850303 DOI: 10.1002/hep4.1647] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 10/29/2020] [Accepted: 11/02/2020] [Indexed: 02/04/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH), an advanced stage of nonalcoholic fatty liver disease (NAFLD), is a rapidly growing and global health problem compounded by the current absence of specific treatments. A major limiting factor in the development of new NASH therapies is the absence of models that capture the unique cellular structure of the liver microenvironment and recapitulate the complexities of NAFLD progression to NASH. Organ-on-a-chip platforms have emerged as a powerful approach to dynamically model diseases and test drugs. Herein, we describe a NASH-on-a-chip platform. Four main types of human primary liver cells (hepatocytes [HCs], Kupffer cells, liver sinusoidal endothelial cells, and hepatic stellate cells [HSCs]) were cocultured under microfluidic dynamics. Our chip-based model successfully recapitulated a functional liver cellular microenvironment with stable albumin and urea secretion for at least 2 weeks. Exposing liver chips to a lipotoxic environment led to gradual development of NASH phenotypic characteristics, including intracellular lipid accumulation, hepatocellular ballooning, HSC activation, and elevation of inflammatory and profibrotic markers. Further, exposure of the chip to elafibranor, a drug under study for the therapy of NASH, inhibited the development of NASH-specific hallmarks, causing an ~8-fold decrease in intracellular lipids, a 3-fold reduction in number of ballooned HCs, a significant reduction in HSC activation, and a significant decrease in the levels of inflammatory and profibrotic markers compared with controls. Conclusion: We have successfully developed a microfluidic NASH-on-a-chip platform that recapitulates the main NASH histologic endpoints in a single chip and that can emerge as a powerful noninvasive, human-relevant, in vitro platform to study disease pathogenesis and develop novel anti-NASH drugs.
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Affiliation(s)
- May S Freag
- Center for Engineered TherapeuticsDivision of Engineering in MedicineDepartment of MedicineBrigham and Women's HospitalHarvard Medical SchoolBostonMAUSA.,Division of Health Sciences and TechnologyHarvard-Massachusetts Institute of TechnologyMassachusetts Institute of TechnologyBostonMAUSA
| | - Bumseok Namgung
- Center for Engineered TherapeuticsDivision of Engineering in MedicineDepartment of MedicineBrigham and Women's HospitalHarvard Medical SchoolBostonMAUSA.,Division of Health Sciences and TechnologyHarvard-Massachusetts Institute of TechnologyMassachusetts Institute of TechnologyBostonMAUSA
| | - Maria E Reyna Fernandez
- Center for Engineered TherapeuticsDivision of Engineering in MedicineDepartment of MedicineBrigham and Women's HospitalHarvard Medical SchoolBostonMAUSA.,Division of Health Sciences and TechnologyHarvard-Massachusetts Institute of TechnologyMassachusetts Institute of TechnologyBostonMAUSA
| | - Ermanno Gherardi
- Unit of Immunology and General PathologyDepartment of Molecular MedicineUniversity of PaviaPaviaItaly
| | - Shiladitya Sengupta
- Center for Engineered TherapeuticsDivision of Engineering in MedicineDepartment of MedicineBrigham and Women's HospitalHarvard Medical SchoolBostonMAUSA.,Division of Health Sciences and TechnologyHarvard-Massachusetts Institute of TechnologyMassachusetts Institute of TechnologyBostonMAUSA.,Dana Farber Cancer InstituteBostonMAUSA
| | - Hae Lin Jang
- Center for Engineered TherapeuticsDivision of Engineering in MedicineDepartment of MedicineBrigham and Women's HospitalHarvard Medical SchoolBostonMAUSA
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24
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Ow JR, Cadez MJ, Zafer G, Foo JC, Li HY, Ghosh S, Wollmann H, Cazenave-Gassiot A, Ong CB, Wenk MR, Han W, Choi H, Kaldis P. Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division. eLife 2020; 9:63835. [PMID: 33345777 PMCID: PMC7771968 DOI: 10.7554/elife.63835] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 12/19/2020] [Indexed: 12/13/2022] Open
Abstract
Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, hepatocyte proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid metabolism and the consequent impact on whole-body physiology, we performed lipidomics, metabolomics, and RNA-seq analyses on a mouse model. We observed reduced triacylglycerides in liver of young mice, caused by oxidative stress that activated FOXO1 to promote the expression of Pnpla2/ATGL. Additionally, we discovered that hepatocytes displayed malfunctioning β-oxidation, reflected by increased acylcarnitines (ACs) and reduced β-hydroxybutyrate. This led to elevated plasma free fatty acids (FFAs), which were transported to the adipose tissue for storage and triggered greater insulin secretion. Upon aging, chronic hyperinsulinemia resulted in insulin resistance and hepatic steatosis through activation of LXR. Here, we demonstrate that loss of hepatocyte proliferation is not only an outcome but also possibly a causative factor for liver pathology.
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Affiliation(s)
- Jin Rong Ow
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
| | - Matias J Cadez
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Gözde Zafer
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Juat Chin Foo
- Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore (NUS), Singapore, Singapore
| | - Hong Yu Li
- Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium (SBIC), A*STAR, Singapore, Singapore
| | - Soumita Ghosh
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Heike Wollmann
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
| | - Amaury Cazenave-Gassiot
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.,Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore (NUS), Singapore, Singapore
| | - Chee Bing Ong
- Biological Resource Centre (BRC), A*STAR, Singapore, Singapore
| | - Markus R Wenk
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.,Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore (NUS), Singapore, Singapore
| | - Weiping Han
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.,Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium (SBIC), A*STAR, Singapore, Singapore
| | - Hyungwon Choi
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Philipp Kaldis
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.,Department of Clinical Sciences, Lund University, Clinical Research Centre (CRC), Malmö, Sweden
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25
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Rives C, Fougerat A, Ellero-Simatos S, Loiseau N, Guillou H, Gamet-Payrastre L, Wahli W. Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants. Biomolecules 2020; 10:E1702. [PMID: 33371482 PMCID: PMC7767499 DOI: 10.3390/biom10121702] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor candidates in NAFLD. At the molecular level, several models have been proposed for the pathogenesis of NAFLD. Most importantly, oxidative stress and mitochondrial damage have been reported to be causative in NAFLD initiation and progression. The aim of this review is to provide an overview of the contribution of nutrients and food contaminants, especially pesticides, to oxidative stress and how they may influence NAFLD pathogenesis.
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Affiliation(s)
- Clémence Rives
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
| | - Anne Fougerat
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
| | - Sandrine Ellero-Simatos
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
| | - Nicolas Loiseau
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
| | - Hervé Guillou
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
| | - Laurence Gamet-Payrastre
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
| | - Walter Wahli
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, EVT, INP-Purpan, UPS, 31300 Toulouse, France; (C.R.); (A.F.); (S.E.-S.); (N.L.); (H.G.)
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232, Singapore
- Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland
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26
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Baek J, Poul SS, Swanson TA, Tuthill T, Parker KJ. Scattering Signatures of Normal versus Abnormal Livers with Support Vector Machine Classification. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:3379-3392. [PMID: 32917469 PMCID: PMC9386788 DOI: 10.1016/j.ultrasmedbio.2020.08.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/30/2020] [Accepted: 08/06/2020] [Indexed: 05/14/2023]
Abstract
Fifty years of research on the nature of backscatter from tissues has resulted in a number of promising diagnostic parameters. We recently introduced two analyses tied directly to the biophysics of ultrasound scattering: the H-scan, based on a matched filter approach to distinguishing scattering transfer functions, and the Burr distribution for quantification of speckle patterns. Together, these analyses can produce at least five parameters that are directly linked to the mathematics of ultrasound in tissue. These have been measured in vivo in 35 rat livers under normal conditions and after exposure to compounds that induce inflammation, fibrosis, and steatosis in varying combinations. A classification technique, the support vector machine, is employed to determine clusters of the five parameters that are signatures of the different liver conditions. With the multiparametric measurement approach and determination of clusters, the different types of liver pathology can be discriminated with 94.6% accuracy.
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Affiliation(s)
- Jihye Baek
- Department of Electrical and Computer Engineering, University of Rochester, Rochester, New York, USA
| | - Sedigheh S Poul
- Department of Mechanical Engineering, University of Rochester, Rochester, New York, USA
| | | | | | - Kevin J Parker
- Department of Electrical and Computer Engineering, University of Rochester, Rochester, New York, USA.
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27
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Ronda OAHO, van de Heijning BJM, de Bruin A, Thomas RE, Martini I, Koehorst M, Gerding A, Koster MH, Bloks VW, Jurdzinski A, Mulder NL, Havinga R, van der Beek EM, Reijngoud DJ, Kuipers F, Verkade HJ. Spontaneous liver disease in wild-type C57BL/6JOlaHsd mice fed semisynthetic diet. PLoS One 2020; 15:e0232069. [PMID: 32956351 PMCID: PMC7505464 DOI: 10.1371/journal.pone.0232069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 08/16/2020] [Indexed: 11/19/2022] Open
Abstract
Mouse models are frequently used to study mechanisms of human diseases. Recently, we observed a spontaneous bimodal variation in liver weight in C57BL/6JOlaHsd mice fed a semisynthetic diet. We now characterized the spontaneous variation in liver weight and its relationship with parameters of hepatic lipid and bile acid (BA) metabolism. In male C57BL/6JOlaHsd mice fed AIN-93G from birth to postnatal day (PN)70, we measured plasma BA, lipids, Very low-density lipoprotein (VLDL)-triglyceride (TG) secretion, and hepatic mRNA expression patterns. Mice were sacrificed at PN21, PN42, PN63 and PN70. Liver weight distribution was bimodal at PN70. Mice could be subdivided into two nonoverlapping groups based on liver weight: 0.6 SD 0.1 g (approximately one-third of mice, small liver; SL), and 1.0 SD 0.1 g (normal liver; NL; p<0.05). Liver histology showed a higher steatosis grade, inflammation score, more mitotic figures and more fibrosis in the SL versus the NL group. Plasma BA concentration was 14-fold higher in SL (p<0.001). VLDL-TG secretion rate was lower in SL mice, both absolutely (-66%, p<0.001) and upon correction for liver weight (-44%, p<0.001). Mice that would later have the SL-phenotype showed lower food efficiency ratios during PN21-28, suggesting the cause of the SL phenotype is present at weaning (PN21). Our data show that approximately one-third of C57BL/6JOlaHsd mice fed semisynthetic diet develop spontaneous liver disease with aberrant histology and parameters of hepatic lipid, bile acid and lipoprotein metabolism. Study designs involving this mouse strain on semisynthetic diets need to take the SL phenotype into account. Plasma lipids may serve as markers for the identification of the SL phenotype.
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Affiliation(s)
- Onne A. H. O. Ronda
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Alain de Bruin
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Rachel E. Thomas
- Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Ingrid Martini
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Martijn Koehorst
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Albert Gerding
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Mirjam H. Koster
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Vincent W. Bloks
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Angelika Jurdzinski
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Niels L. Mulder
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rick Havinga
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Eline M. van der Beek
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Danone Nutricia Research, Uppsalalaan, Utrecht, The Netherlands
| | - Dirk-Jan Reijngoud
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Folkert Kuipers
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Henkjan J. Verkade
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- * E-mail:
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Cartland SP, Tamer N, Patil MS, Di Bartolo BA, Kavurma MM. A "Western Diet" promotes symptoms of hepatic steatosis in spontaneously hypertensive rats. Int J Exp Pathol 2020; 101:152-161. [PMID: 32783310 DOI: 10.1111/iep.12369] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 06/15/2020] [Accepted: 07/02/2020] [Indexed: 12/23/2022] Open
Abstract
Systemic hypertension, characterized by elevated blood pressure ≥140/90 mm Hg, is a major modifiable risk factor for cardiovascular disease. Hypertension also associates with non-alcoholic fatty liver disease (NAFLD), which is becoming common due to a modern diet and lifestyle. The aim of the present study was to examine whether a high-fat "Western" diet had effects on hypertension and associated NAFLD. Normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were placed on a normal chow or high-fat diet for 8 weeks; blood pressure was measured fortnightly and body weight recorded weekly. As expected, SHR had elevated blood pressure compared to WKY. Diet did not influence blood pressure. Compared to SHR, WKY rats gained more weight, associating with increased white adipose tissue weight. Normotensive rats also had higher plasma cholesterol and triglycerides in response to a "Western" diet, with no changes in plasma glucose levels. Neither strain developed atherosclerosis. Interestingly, high-fat diet-fed SHR had increased liver weight, associating with a significant level of hepatic lipid accumulation not observed in WKY. Further, they exhibited hepatocellular ballooning and increased hepatic inflammation, indicative of steatohepatitis. These findings suggest that a high-fat "Western" diet promotes features of NAFLD in SHR, but not WKY rats. Importantly, the high-fat diet had no effect on blood pressure.
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Affiliation(s)
- Siân P Cartland
- Heart Research Institute, Sydney, NSW, Australia.,Faculty of Health and Medicine, University of Sydney, Sydney, NSW, Australia
| | - Nicole Tamer
- Heart Research Institute, Sydney, NSW, Australia
| | | | - Belinda A Di Bartolo
- Heart Research Institute, Sydney, NSW, Australia.,Faculty of Health and Medicine, University of Sydney, Sydney, NSW, Australia.,Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia
| | - Mary M Kavurma
- Heart Research Institute, Sydney, NSW, Australia.,Faculty of Health and Medicine, University of Sydney, Sydney, NSW, Australia
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29
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Mujawdiya PK, Sharma P, Sharad S, Kapur S. Reversal of Increase in Intestinal Permeability by Mangifera indica Seed Kernel Extract in High-Fat Diet-Induced Obese Mice. Pharmaceuticals (Basel) 2020; 13:ph13080190. [PMID: 32796561 PMCID: PMC7464080 DOI: 10.3390/ph13080190] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/28/2020] [Accepted: 07/30/2020] [Indexed: 12/17/2022] Open
Abstract
Obesity and hyper-intestinal permeability are interconnected. This study is designed to evaluate the ability of Mangifera indica seed kernel extract (MESK) in restoring the intestinal barrier and preventing obesity and associated metabolic complications in a high-fat diet-induced obese mouse model. Four groups of Swiss albino mice: (1) normal diet (ND), (2) high-fat diet (HFD), (3) HFD + Orlistat (100 µg/kg), and (4) HFD + MESK (75 µg/kg), were used to monitor various biochemical parameters associated with metabolic syndrome (glucose, total cholesterol, triglycerides) and body weight in an eight-week-long study. In vivo intestinal permeability was determined by the FITC-dextran method. Interestingly, MESK significantly reduced HFD-induced body weight gain, hepatic lipid accumulation, hepatic fibrosis, hyperglycemia, and dyslipidemia. Additionally, MESK treatment restored the expression of tight junction protein Zonula Occludens-1 (ZO-1) and Claudin-1 and hence prevented increased intestinal permeability induced by a high-fat diet. Moreover, it also increased the expression of potent satiety molecule Nesfatin-1 in the mouse jejunum. Our results, for the first time, establish MESK as a nutraceutical which prevents disruption of the intestinal barrier and thereby intercepts the adverse consequences of compromised intestinal permeability such as obesity, hyperglycemia, dyslipidemia, and systemic inflammation.
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Affiliation(s)
- Pavan Kumar Mujawdiya
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Hyderabad 500078, India;
| | - Pravesh Sharma
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Hyderabad 500078, India;
| | - Shashwat Sharad
- Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, MD 20814, USA;
| | - Suman Kapur
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Hyderabad 500078, India;
- Correspondence:
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30
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Wallert M, Börmel L, Lorkowski S. Inflammatory Diseases and Vitamin E-What Do We Know and Where Do We Go? Mol Nutr Food Res 2020; 65:e2000097. [PMID: 32692879 DOI: 10.1002/mnfr.202000097] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 06/26/2020] [Indexed: 12/14/2022]
Abstract
Inflammation-driven diseases and related comorbidities, such as the metabolic syndrome, obesity, fatty liver disease, and cardiovascular diseases cause significant global burden. There is a growing body of evidence that nutrients alter inflammatory responses and can therefore make a decisive contribution to the treatment of these diseases. Recently, the inflammasome, a cytosolic multiprotein complex, has been identified as a key player in inflammation and the development of various inflammation-mediated disorders, with nucleotide-binding domain and leucine-rich repeat pyrin domain (NLRP) 3 being the inflammasome of interest. Here an overview about the cellular signaling pathways underlying nuclear factor "kappa-light-chain-enhancer" of activated B-cells (NF-κB)- and NLRP3-mediated inflammatory processes, and the pathogenesis of the inflammatory diseases atherosclerosis and non-alcoholic fatty liver disease (NAFLD) is provided; next, the current state of knowledge for drug-based and dietary-based interventions for treating cardiovascular diseases and NAFLD is discussed. To date, one of the most important antioxidants in the human diet is vitamin E. Various in vitro and in vivo studies suggest that the different forms of vitamin E and also their derivatives have anti-inflammatory activity. Recent publications suggest that vitamin E-and possibly metabolites of vitamin E-are a promising therapeutic approach for treating inflammatory diseases such as NAFLD.
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Affiliation(s)
- Maria Wallert
- Department of Nutritional Biochemistry and Physiology, Institute of Nutritional Science, Friedrich Schiller University Jena, Jena, 07743, Germany.,Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany
| | - Lisa Börmel
- Department of Nutritional Biochemistry and Physiology, Institute of Nutritional Science, Friedrich Schiller University Jena, Jena, 07743, Germany.,Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany
| | - Stefan Lorkowski
- Department of Nutritional Biochemistry and Physiology, Institute of Nutritional Science, Friedrich Schiller University Jena, Jena, 07743, Germany.,Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany
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31
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Schwabe RF, Tabas I, Pajvani UB. Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis. Gastroenterology 2020; 158:1913-1928. [PMID: 32044315 PMCID: PMC7682538 DOI: 10.1053/j.gastro.2019.11.311] [Citation(s) in RCA: 409] [Impact Index Per Article: 81.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 11/18/2019] [Accepted: 11/20/2019] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease is the most prevalent liver disease worldwide, affecting 20%-25% of the adult population. In 25% of patients, nonalcoholic fatty liver disease progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of cirrhosis, liver failure, and hepatocellular carcinoma. In patients with NASH, liver fibrosis is the main determinant of mortality. Here, we review how interactions between different liver cells culminate in fibrosis development in NASH, focusing on triggers and consequences of hepatocyte-macrophage-hepatic stellate cell (HSC) crosstalk. We discuss pathways through which stressed and dead hepatocytes instigate the profibrogenic crosstalk with HSC and macrophages, including the reactivation of developmental pathways such as TAZ, Notch, and hedgehog; how clearance of dead cells in NASH via efferocytosis may affect inflammation and fibrogenesis; and insights into HSC and macrophage heterogeneity revealed by single-cell RNA sequencing. Finally, we summarize options to therapeutically interrupt this profibrogenic hepatocyte-macrophage-HSC network in NASH.
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Affiliation(s)
- Robert F Schwabe
- Department of Medicine, Columbia University, New York, New York; Institute of Human Nutrition, Columbia University, New York, New York.
| | - Ira Tabas
- Department of Medicine, Columbia University, New York, New York; Institute of Human Nutrition, Columbia University, New York, New York; Department of Physiology and Cellular Biophysics, Columbia University, New York, New York
| | - Utpal B Pajvani
- Department of Medicine, Columbia University, New York, New York; Institute of Human Nutrition, Columbia University, New York, New York
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Pirmoazen AM, Khurana A, El Kaffas A, Kamaya A. Quantitative ultrasound approaches for diagnosis and monitoring hepatic steatosis in nonalcoholic fatty liver disease. Theranostics 2020; 10:4277-4289. [PMID: 32226553 PMCID: PMC7086372 DOI: 10.7150/thno.40249] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 02/14/2020] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease is a major global health concern with increasing prevalence, associated with obesity and metabolic syndrome. Recently, quantitative ultrasound-based imaging techniques have dramatically improved the ability of ultrasound to detect and quantify hepatic steatosis. These newer ultrasound techniques possess many inherent advantages similar to conventional ultrasound such as universal availability, real-time capability, and relatively low cost along with quantitative rather than a qualitative assessment of liver fat. In addition, quantitative ultrasound-based imaging techniques are less operator dependent than traditional ultrasound. Here we review several different emerging quantitative ultrasound-based approaches used for detection and quantification of hepatic steatosis in patients at risk for nonalcoholic fatty liver disease. We also briefly summarize other clinically available imaging modalities for evaluating hepatic steatosis such as MRI, CT, and serum analysis.
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Affiliation(s)
- Amir M. Pirmoazen
- Department of Radiology, School of Medicine, Stanford University, Stanford, California
| | - Aman Khurana
- Department of Radiology, University of Kentucky, Lexington, Kentucky
| | - Ahmed El Kaffas
- Department of Radiology, Molecular Imaging Program at Stanford, School of Medicine, Stanford University, Stanford, California
| | - Aya Kamaya
- Department of Radiology, School of Medicine, Stanford University, Stanford, California
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33
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Hepatic gene expression explains primary drug toxicity in bipolar disorder. Transl Psychiatry 2019; 9:331. [PMID: 31819046 PMCID: PMC6901567 DOI: 10.1038/s41398-019-0666-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 10/23/2019] [Accepted: 11/06/2019] [Indexed: 11/16/2022] Open
Abstract
In bipolar disorder (BPD), long-term psychotropic drug treatment is often necessary to prevent relapse or recurrence. Nevertheless, adverse drug effects including disturbances in hepatic metabolism are observed and still poorly understood. Here, the association between hepatic gene expression and histopathological changes of the liver was investigated. By the use of microarrays (Affymetrix U133 plus2.0), a genome-wide expression study was performed on BPD patients with psychotropic drug treatment (n = 29) compared to unaffected controls (n = 20) and validated by quantitative real-time PCR. WebGestalt was used to identify over-represented functional pathways of the Reactome database. Association analyses between histopathological changes and differentially expressed genes comprised in the over-represented functional pathways were performed using regression analyses, from which feature-expression heatmaps were drawn. The majority of identified genes were underexpressed and involved in energy supply, metabolism of lipids and proteins, and the innate immune system. Positive associations were found for genes involved in all pathways and degenerative changes. The strongest negative association was observed between genes involved in energy supply and hepatic activity, as well as inflammation. In summary, we found a possible association between gene expression involved in various biological pathways and histopathological changes of the liver in BPD. Further, we found support for the probable primary toxic effect of psychotropic drugs on hepatic injury in BPD. Even if the safety of psychotropic drugs improves, adverse effects especially on hepatic function should not be underestimated.
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34
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Cho Y, Lim SK, Joo SK, Jeong DH, Kim JH, Bae JM, Park JH, Chang MS, Lee DH, Jung YJ, Kim BG, Kim D, Lee KL, Kim W. Nonalcoholic steatohepatitis is associated with a higher risk of advanced colorectal neoplasm. Liver Int 2019; 39:1722-1731. [PMID: 31162812 DOI: 10.1111/liv.14163] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 05/23/2019] [Accepted: 05/29/2019] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is known to increase the risk of adenomatous colonic polyps. However, the role of screening colonoscopy in patients with biopsy-proven NAFLD in detecting advanced colorectal neoplasm is not clearly evidence-based. Therefore, we investigated whether the histological severity of NAFLD is associated with advanced colorectal neoplasm. METHODS This study included patients ≥18 years old who underwent screening colonoscopy between 2013 and 2018 within a biopsy-evaluated prospective NAFLD cohort. Advanced colorectal neoplasm was defined as an adenomatous polyp greater than 10 mm in diameter and/or with villous histology and/or with high-grade dysplasia or adenocarcinoma. RESULTS Among the 476 patients with clinically suspected NAFLD, 379 patients were diagnosed with biopsy-proven NAFLD and 97 patients had no evidence of NAFLD histologically, who were analyzed as healthy controls. The prevalence of advanced colorectal neoplasm was 11.1% (n = 53). Patients with advanced colorectal neoplasm had higher grade of steatosis (P = 0.004) and higher stage of hepatic fibrosis (P = 0.044) than those with normal colonoscopic findings or low-grade adenomatous polyp. Multivariable logistic regression analysis revealed that the presence of nonalcoholic steatohepatitis (NASH) was an independent risk factor for both colorectal polyp (odds ratio [OR], 2.08; 95% confidential interval [CI], 1.12-3.86; P = 0.020) and advanced colorectal neoplasm (OR, 2.81; 95% CI, 1.01-7.87; P = 0.049). CONCLUSIONS The presence of biopsy-proven NASH was significantly associated with an increased risk of advanced colorectal neoplasm among patients with NAFLD. This finding may alert physicians to conduct screening colonoscopy in patients with NASH to detect advanced colorectal neoplasm early.
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Affiliation(s)
- Yuri Cho
- Department of Internal Medicine, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, Korea
| | - Soo-Kyung Lim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Sae Kyung Joo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Dong-Hyong Jeong
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Jung Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
| | - Jeong Hwan Park
- Department of Pathology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
| | - Dong Hyeon Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Yong Jin Jung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Byeong Gwan Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Kook Lae Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
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Morikawa S, Sato A, Ezaki T. A simple, one-step polychromatic staining method for epoxy-embedded semithin tissue sections. Microscopy (Oxf) 2019; 67:331-344. [PMID: 30321369 PMCID: PMC6278751 DOI: 10.1093/jmicro/dfy037] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 08/30/2018] [Indexed: 12/25/2022] Open
Abstract
Although conventional toluidine blue staining is a common technique used for rapid observation of semithin sections prior to transmission electron microscopy, it is monochromatic and insufficient for accurate identification of different tissue components by light microscopy. Additionally, polychromatic staining methods generally require step-by-step processes involving different dyes, and it is often difficult to balance the color tone of each step. In this study, we developed a simple polychromatic staining method for epoxy-embedded tissue sections. We stained preheated sections with an aqueous ethanol solution of azure B and basic fuchsin, with the addition of sodium tetraborate to enhance the staining efficacy. We optimized various staining conditions to enable sufficient coloration easily and consistently in a single, rapid staining step, using a single staining-mixture solution. Our method enabled clear differentiation of various tissue structures according to color tone and stain intensity, thereby facilitating the detection of fine structural differences, including various organelle and inclusion bodies. This technique represents a simple polychrome-staining method to allow more informative and convincing histological investigation in various fields of research and education.
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Affiliation(s)
- Shunichi Morikawa
- Department of Anatomy and Developmental Biology, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku, Tokyo, Japan
| | - Azusa Sato
- Department of Chemistry, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku, Tokyo, Japan
| | - Taichi Ezaki
- Department of Anatomy and Developmental Biology, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku, Tokyo, Japan
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Lackner C, Tiniakos D. Fibrosis and alcohol-related liver disease. J Hepatol 2019; 70:294-304. [PMID: 30658730 DOI: 10.1016/j.jhep.2018.12.003] [Citation(s) in RCA: 185] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/06/2018] [Accepted: 12/07/2018] [Indexed: 02/06/2023]
Abstract
Histological fibrosis stage is one of the most important prognostic factors in compensated and decompensated alcohol-related liver disease (ALD). Morphological assessment of fibrosis is useful for patient stratification, enabling individualised management, and for evaluation of treatment effects in clinical studies. In contrast to most chronic liver diseases where fibrosis is portal-based, fatty liver disease (FLD) of alcoholic or non-alcoholic aetiology (NAFLD) is associated with a centrilobular pattern of injury which leads to perivenular fibrosis and/or pericellular fibrosis. Progression of FLD drives expansive pericellular fibrosis, linking vascular structures and paving the way for the development of cirrhosis. At the cirrhotic stage, ongoing tissue damage leads to increasing fibrosis severity due to parenchymal loss and proliferation of fibrous scars. Histologic fibrosis staging systems have been devised, based on topography and the extent of fibrosis, for most chronic liver diseases. The utility of histological staging is reflected in different risks associated with individual fibrosis stages which cannot be reliably distinguished by non-invasive fibrosis assessment. In contrast to NAFLD, ALD-specific staging systems that enable the standardised prognostication required for clinical management and trials are lacking. Although morphological similarities between NAFLD and ALD exist, differences in clinical and histological features may substantially limit the utility of established NAFLD-specific staging systems for prognostication in ALD. This review summarises morphological features of fibrosis in ALD and compares them to other chronic liver diseases, particularly NAFLD. ALD-related fibrosis is examined in the context of pathogenetic mechanisms of fibrosis progression, regression and clinical settings that need to be considered in future prognostically relevant ALD staging approaches.
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Affiliation(s)
- Carolin Lackner
- Institute of Pathology, Medical University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria.
| | - Dina Tiniakos
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; Dept of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Vas. Sofias Avenue 76, Athens 11528, Greece
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Disease Progression and Pharmacological Intervention in a Nutrient-Deficient Rat Model of Nonalcoholic Steatohepatitis. Dig Dis Sci 2019; 64:1238-1256. [PMID: 30511198 PMCID: PMC6548202 DOI: 10.1007/s10620-018-5395-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 11/22/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND There is a marked need for improved animal models of nonalcoholic steatohepatitis (NASH) to facilitate the development of more efficacious drug therapies for the disease. METHODS Here, we investigated the development of fibrotic NASH in male Wistar rats fed a choline-deficient L-amino acid-defined (CDAA) diet with or without cholesterol supplementation for subsequent assessment of drug treatment efficacy in NASH biopsy-confirmed rats. The metabolic profile and liver histopathology were evaluated after 4, 8, and 12 weeks of dieting. Subsequently, rats with biopsy-confirmed NASH were selected for pharmacological intervention with vehicle, elafibranor (30 mg/kg/day) or obeticholic acid (OCA, 30 mg/kg/day) for 5 weeks. RESULTS The CDAA diet led to marked hepatomegaly and fibrosis already after 4 weeks of feeding, with further progression of collagen deposition and fibrogenesis-associated gene expression during the 12-week feeding period. Cholesterol supplementation enhanced the stimulatory effect of CDAA on gene transcripts associated with fibrogenesis without significantly increasing collagen deposition. Pharmacological intervention with elafibranor, but not OCA, significantly reduced steatohepatitis scores, and fibrosis-associated gene expression, however, was unable to prevent progression in fibrosis scores. CONCLUSION CDAA-fed rats develop early-onset progressive NASH, which offers the opportunity to probe anti-NASH compounds with potential disease-modifying properties.
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38
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Parafati M, Lascala A, La Russa D, Mignogna C, Trimboli F, Morittu VM, Riillo C, Macirella R, Mollace V, Brunelli E, Janda E. Bergamot Polyphenols Boost Therapeutic Effects of the Diet on Non-Alcoholic Steatohepatitis (NASH) Induced by "Junk Food": Evidence for Anti-Inflammatory Activity. Nutrients 2018; 10:nu10111604. [PMID: 30388763 PMCID: PMC6267059 DOI: 10.3390/nu10111604] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 10/17/2018] [Accepted: 10/25/2018] [Indexed: 01/08/2023] Open
Abstract
Wrong alimentary behaviors and so-called “junk food” are a driving force for the rising incidence of non-alcoholic fatty liver disease (NAFLD) among children and adults. The “junk food” toxicity can be studied in “cafeteria” (CAF) diet animal model. Young rats exposed to CAF diet become obese and rapidly develop NAFLD. We have previously showed that bergamot (Citrus bergamia Risso et Poiteau) flavonoids, in the form of bergamot polyphenol fraction (BPF), effectively prevent CAF diet-induced NAFLD in rats. Here, we addressed if BPF can accelerate therapeutic effects of weight loss induced by a normocaloric standard chow (SC) diet. 21 rats fed with CAF diet for 16 weeks to induce NAFLD with inflammatory features (NASH) were divided into three groups. Two groups were switched to SC diet supplemented or not with BPF (CAF/SC±BPF), while one group continued with CAF diet (CAF/CAF) for 10 weeks. BPF had no effect on SC diet-induced weight loss, but it accelerated hepatic lipid droplets clearance and reduced blood triglycerides. Accordingly, BPF improved insulin sensitivity, but had little effect on leptin levels. Interestingly, the inflammatory parameters were still elevated in CAF/SC livers compared to CAF/CAF group after 10 weeks of dietary intervention, despite over 90% hepatic fat reduction. In contrast, BPF supplementation decreased hepatic inflammation by reducing interleukin 6 (Il6) mRNA expression and increasing anti-inflammatory Il10, which correlated with fewer Kupffer cells and lower inflammatory foci score in CAF/SC+BPF livers compared to CAF/SC group. These data indicate that BPF mediates a specific anti-inflammatory activity in livers recovering from NASH, while it boosts lipid-lowering and anti-diabetic effects of the dietary intervention.
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Affiliation(s)
- Maddalena Parafati
- Department of Health Sciences, Magna Graecia University, Campus Germaneto, 88100 Catanzaro, Italy.
- Interregional Research Center for Food Safety and Health, 88100 Catanzaro, Italy.
| | - Antonella Lascala
- Department of Health Sciences, Magna Graecia University, Campus Germaneto, 88100 Catanzaro, Italy.
- Interregional Research Center for Food Safety and Health, 88100 Catanzaro, Italy.
| | - Daniele La Russa
- Department of Health Sciences, Magna Graecia University, Campus Germaneto, 88100 Catanzaro, Italy.
- Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende (CS), Italy.
| | - Chiara Mignogna
- Department of Experimental and Clinical Medicine, Magna Graecia University, Campus Germaneto, 88100 Catanzaro, Italy.
| | - Francesca Trimboli
- Department of Health Sciences, Magna Graecia University, Campus Germaneto, 88100 Catanzaro, Italy.
| | - Valeria Maria Morittu
- Department of Health Sciences, Magna Graecia University, Campus Germaneto, 88100 Catanzaro, Italy.
| | - Concetta Riillo
- Department of Health Sciences, Magna Graecia University, Campus Germaneto, 88100 Catanzaro, Italy.
| | - Rachele Macirella
- Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende (CS), Italy.
| | - Vincenzo Mollace
- Department of Health Sciences, Magna Graecia University, Campus Germaneto, 88100 Catanzaro, Italy.
- Interregional Research Center for Food Safety and Health, 88100 Catanzaro, Italy.
| | - Elvira Brunelli
- Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende (CS), Italy.
| | - Elzbieta Janda
- Department of Health Sciences, Magna Graecia University, Campus Germaneto, 88100 Catanzaro, Italy.
- Interregional Research Center for Food Safety and Health, 88100 Catanzaro, Italy.
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Buckley AJ, Thomas EL, Lessan N, Trovato FM, Trovato GM, Taylor-Robinson SD. Non-alcoholic fatty liver disease: Relationship with cardiovascular risk markers and clinical endpoints. Diabetes Res Clin Pract 2018; 144:144-152. [PMID: 30170074 DOI: 10.1016/j.diabres.2018.08.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/08/2018] [Accepted: 08/14/2018] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common diagnosis and is increasing in prevalence worldwide. NAFLD is usually asymptomatic at presentation; progression of the disease is unpredictable, leading to the development of a variety of techniques for screening, diagnosis and risk stratification. Clinical methods in current use include serum biomarker panels, hepatic ultrasound, magnetic resonance imaging, and liver biopsy. NAFLD is strongly associated with the metabolic syndrome, and the most common cause of death for people with the condition is cardiovascular disease. Whether NAFLD is an independent cardiovascular risk factor needs exploration. NAFLD has been associated with surrogate markers of cardiovascular disease such as carotid intima-media thickness, the presence of carotid plaque, brachial artery vasodilatory responsiveness and CT coronary artery calcification score. There is no effective medical treatment for NAFLD and evidence is lacking regarding the efficacy of interventions in mitigating cardiovascular risk. Health care professionals managing patients with NAFLD should tackle the issue with early identification of risk factors and aggressive modification. Current management strategies therefore comprise lifestyle change, with close attention to known cardiovascular risk factors.
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Affiliation(s)
- Adam J Buckley
- Imperial College London, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine London, United Kingdom; Imperial College London Diabetes Centre, Research Department, Abu Dhabi, United Arab Emirates.
| | - E Louise Thomas
- University of Westminster, Department of Life Sciences, London, United Kingdom.
| | - Nader Lessan
- Imperial College London, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine London, United Kingdom; Imperial College London Diabetes Centre, Research Department, Abu Dhabi, United Arab Emirates.
| | - Francesca M Trovato
- University of Catania, Department of Clinical and Experimental Medicine, Catania, Italy
| | - Guglielmo M Trovato
- University of Catania, Department of Clinical and Experimental Medicine, Catania, Italy
| | - Simon D Taylor-Robinson
- Imperial College London, Division of Integrative Systems Medicine and Digestive Health, Department of Surgery and Cancer, London, United Kingdom.
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Alam S, Ghosh J, Mustafa G, Kamal M, Ahmad N. Effect of sitagliptin on hepatic histological activity and fibrosis of nonalcoholic steatohepatitis patients: a 1-year randomized control trial. Hepat Med 2018; 10:23-31. [PMID: 29740221 PMCID: PMC5931194 DOI: 10.2147/hmer.s158053] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background/purpose Dipeptidyl peptidase 4 (DPP-4) expression is directly associated with hepatic lipogenesis and liver injury in nonalcoholic steatohepatitis (NASH). This study has been designed to elucidate the histological improvement of NASH with the DPP-4 inhibitor sitagliptin. Materials and methods In this open-label randomized control trial, paired liver biopsy was taken from 40 NASH patients. Sitagliptin 100 mg was given once daily to the SL group and no sitagliptin was given to the L group for 1 year. Patients from both groups were encouraged to exercise moderately and advised to avoid saturated fat, excessive sugar, soft drinks, fast food, and refined carbohydrates to reduce weight. Results Steatosis improved in the SL group (from 2.3±0.6 to 1.2±0.8; P=0.000) and the L group (from 2.1±0.6 to 1.6±0.9; P=0.008), ballooning decreased from 1.8±0.6 to 1.3±06 (P=0.002) in the SL group, but not in the L group. Nonalcoholic fatty liver disease activity score (NAS) attenuated in both groups: the SL group (from 5.8±0.9 to 3.9±1.4; P=0.000) and the L group (from 5.3±0.6 to 4.6±1.2; P=0.009). NAS improvement was much higher in the SL group (1.9±1.4) than in the L group (0.7±1.1) (P=0.006), with NAS improving by ≥2 in 13 patients from the SL group and five patients from the L group (P=0.01). Improvement was irrespective of diabetes. Regression analysis explored that sitagliptin had odds of 6.38 and weight reduction had odds of 4.51 for NAS reduction. Conclusion Sitagliptin 100 mg once daily for 1 year ameliorates NAS by improving steatosis and ballooning, irrespective of diabetes. Sitagliptin has stronger efficacy than that of weight reduction.
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Affiliation(s)
| | | | | | - Mohammad Kamal
- Department of Pathology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
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Nascimbeni F, Ballestri S, Machado MV, Mantovani A, Cortez-Pinto H, Targher G, Lonardo A. Clinical relevance of liver histopathology and different histological classifications of NASH in adults. Expert Rev Gastroenterol Hepatol 2018; 12:351-367. [PMID: 29224471 DOI: 10.1080/17474124.2018.1415756] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 12/07/2017] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses simple steatosis and steatohepatitis (NASH) with or without fibrosis/cirrhosis and hepatocellular carcinoma. NAFLD occurs epidemically in most areas of the world, contributes to cardiovascular events and liver-related mortality and therefore exacts a major economic toll. Areas covered: Here we summarize what clinicians should know about NAFLD histopathology in adults. We report on the individual histological features and scoring systems of NAFLD: the NAFLD activity score (NAS) introduced by the NASH-Clinical Research Network, the 'Fatty Liver Inhibition of Progression' algorithm and Steatosis, Activity, and Fibrosis (SAF) score. Pros and cons of histological classifications in NASH are discussed. Special emphasis is given to liver histopathology in some high-risk patient groups, such as those with severe obesity and type 2 diabetes. Moreover, we also examine the relationship between liver histopathology and clinical features, and the impact of liver histopathology on the long-term prognosis of NAFLD. Finally, we propose an integrated diagnostic approach which utilizes both non-invasive tools and liver biopsy in those individual patients with suspected NAFLD. Expert commentary: Based on expert opinions, we conclude with a research agenda on NAFLD which focuses on the most burning topics to be addressed over the next five years.
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Affiliation(s)
- Fabio Nascimbeni
- a Ospedale Civile di Baggiovara , Azienda Ospedaliero-Universitaria , Modena , Italy
- b Department of Biomedical, Metabolic and Neural Sciences , University of Modena and Reggio Emilia , Modena , Italy
| | | | - Mariana Verdelho Machado
- d Departamento de Gastrenterologia e Hepatologia , Centro Hospitalar Lisboa Norte, Laboratório de Nutrição, Faculdade de Medicina de Lisboa , Lisboa , Portugal
| | - Alessandro Mantovani
- e Division of Endocrinology, Diabetes and Metabolism, Department of Medicine , University and Azienda Ospedaliera Universitaria Integrata of Verona , Verona , Italy
| | - Helena Cortez-Pinto
- d Departamento de Gastrenterologia e Hepatologia , Centro Hospitalar Lisboa Norte, Laboratório de Nutrição, Faculdade de Medicina de Lisboa , Lisboa , Portugal
| | - Giovanni Targher
- e Division of Endocrinology, Diabetes and Metabolism, Department of Medicine , University and Azienda Ospedaliera Universitaria Integrata of Verona , Verona , Italy
| | - Amedeo Lonardo
- a Ospedale Civile di Baggiovara , Azienda Ospedaliero-Universitaria , Modena , Italy
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Li H, Toth E, Cherrington NJ. Asking the Right Questions With Animal Models: Methionine- and Choline-Deficient Model in Predicting Adverse Drug Reactions in Human NASH. Toxicol Sci 2018; 161:23-33. [PMID: 29145614 PMCID: PMC6454421 DOI: 10.1093/toxsci/kfx253] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
In the past few decades, great conceptual and technological advances have been made in the field of toxicology, but animal model-based research still remains one of the most widely used and readily available tools for furthering our current knowledge. However, animal models are not perfect in predicting all systemic toxicity in humans. Extrapolating animal data to accurately predict human toxicities remains a challenge, and researchers are obligated to question the appropriateness of their chosen animal model. This paper provides an assessment of the utility of the methionine- and choline-deficient (MCD) diet fed animal model in reflecting human nonalcoholic steatohepatitis (NASH) and the potential risks of adverse drug reactions and toxicities that are associated with the disease. As a commonly used NASH model, the MCD model fails to exhibit most metabolic abnormalities in a similar manner to the human disease. The MCD model, on the other hand, closely resembles human NASH histology and reflects signatures of drug transporter alterations in humans. Due to the nature of the MCD model, it should be avoided in studies of NASH pathogenesis, metabolic parameter evaluation, and biomarker identification. But it can be used to accurately predict altered drug disposition due to NASH-associated transporter alterations.
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Affiliation(s)
- Hui Li
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721
| | - Erica Toth
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721
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Ibrahim SH, Hirsova P, Malhi H, Gores GJ. Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame. Dig Dis Sci 2016; 61:1325-36. [PMID: 26626909 PMCID: PMC4838538 DOI: 10.1007/s10620-015-3977-1] [Citation(s) in RCA: 162] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 11/23/2015] [Indexed: 02/07/2023]
Abstract
With the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become a public health problem with increasing prevalence. The mechanism of disease progression remains obscure and effective therapy is lacking. Therefore, there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies. To accomplish this goal, experimental animal models that recapitulate the human disease are necessary, especially, since causative mechanistic studies of NAFLD are more difficult or unethical to perform in humans. A large number of studies regarding the pathophysiology and treatment of nonalcoholic steatohepatitis (NASH) have been undertaken in mice to model human NAFLD and NASH. This review discusses the known dietary, genetic, and inflammation-based animal models of NASH described in recent years, with a focus on the major advances made in this field.
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Affiliation(s)
- Samar H Ibrahim
- Division of Pediatric Gastroenterology, Mayo Clinic, Rochester, MN, USA
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Lădaru A, Bălănescu P, Stan M, Codreanu I, Anca IA. Candidate proteomic biomarkers for non-alcoholic fatty liver disease (steatosis and non-alcoholic steatohepatitis) discovered with mass-spectrometry: a systematic review. Biomarkers 2015; 21:102-14. [PMID: 26632636 DOI: 10.3109/1354750x.2015.1118542] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
CONTEXT Non-alcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver which is accompanied by a series of metabolic deregulations. There are sustained research efforts focusing upon biomarker discovery for NAFLD diagnosis and its prognosis in order investigate and follow-up patients as minimally invasive as possible. OBJECTIVE The objective of this study is to critically review proteomic studies that used mass spectrometry techniques and summarize relevant proteomic NAFLD candidate biomarkers. METHODS Medline and Embase databases were searched from inception to December 2014. RESULTS A final number of 22 records were included that identified 251 candidate proteomic biomarkers. Thirty-three biomarkers were confirmed - 14 were found in liver samples, 21 in serum samples, and two from both serum and liver samples. CONCLUSION Some of the biomarkers identified have already been extensively studied regarding their diagnostic and prognostic capacity. However, there are also more potential biomarkers that still need to be addressed in future studies.
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Affiliation(s)
- Anca Lădaru
- a University of Medicine and Pharmacy "Carol Davila" , Pediatrics Chair , Bucharest , Romania .,b Institute for Mother and Child Care "Alfred Rusescu" , Bucharest , Romania
| | - Paul Bălănescu
- c Department of Clinical Immunology , CDPC Colentina Clinical Hospital , Bucharest , Romania , and.,d Clinical Research Unit RECIF (Réseau D' Epidémiologie Clinique International Francophone) , Bucharest , Romania
| | - Mihaela Stan
- a University of Medicine and Pharmacy "Carol Davila" , Pediatrics Chair , Bucharest , Romania .,b Institute for Mother and Child Care "Alfred Rusescu" , Bucharest , Romania
| | - Ioana Codreanu
- a University of Medicine and Pharmacy "Carol Davila" , Pediatrics Chair , Bucharest , Romania .,b Institute for Mother and Child Care "Alfred Rusescu" , Bucharest , Romania
| | - Ioana Alina Anca
- a University of Medicine and Pharmacy "Carol Davila" , Pediatrics Chair , Bucharest , Romania .,b Institute for Mother and Child Care "Alfred Rusescu" , Bucharest , Romania
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Khoury T, Ben Ya'acov A, Shabat Y, Zolotarovya L, Snir R, Ilan Y. Altered distribution of regulatory lymphocytes by oral administration of soy-extracts exerts a hepatoprotective effect alleviating immune mediated liver injury, non-alcoholic steatohepatitis and insulin resistance. World J Gastroenterol 2015; 21:7443-7456. [PMID: 26139990 PMCID: PMC4481439 DOI: 10.3748/wjg.v21.i24.7443] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 02/08/2015] [Accepted: 03/30/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the immune-modulatory and the hepatoprotective effects of oral administration of two soy extracts in immune mediated liver injury and non-alcoholic steatohepatitis (NASH). METHODS Two soy extracts, M1 and OS, were orally administered to mice with concanavalin A (ConA) immune-mediated hepatitis, to high-fat diet (HFD) mice and to methionine and choline reduced diet combined with HFD mice. Animals were followed for disease and immune biomarkers. RESULTS Oral administration of OS and M1 had an additive effect in alleviating ConA hepatitis manifested by a decrease in alanine aminotransferase and aspartate aminotransferase serum levels. Oral administration of the OS and M1 soy derived fractions, ameliorated liver injury in the high fat diet model of NASH, manifested by a decrease in hepatic triglyceride levels, improvement in liver histology, decreased serum cholesterol and triglycerides and improved insulin resistance. In the methionine and choline reduced diet combined with the high fat diet model, we noted a decrease in hepatic triglycerides and improvement in blood glucose levels and liver histology. The effects were associated with reduced serum tumor necrosis factor alpha and alteration of regulatory T cell distribution. CONCLUSION Oral administration of the combination of OS and M1 soy derived extracts exerted an adjuvant effect in the gut-immune system, altering the distribution of regulatory T cells, and alleviating immune mediated liver injury, hyperlipidemia and insulin resistance.
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Ikura Y. Transitions of histopathologic criteria for diagnosis of nonalcoholic fatty liver disease during the last three decades. World J Hepatol 2014; 6:894-900. [PMID: 25544876 PMCID: PMC4269908 DOI: 10.4254/wjh.v6.i12.894] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 10/09/2014] [Accepted: 10/28/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and is the most common type of chronic liver diseases in the majority of developed countries. NAFLD shows a wide spectrum of disorders including simple steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. While simple steatosis is recognized to be benign and stable, NASH is considered to be an aggressive form of the disease progressing to cirrhosis. Currently, differentiation between NASH and simple steatosis can be done only by liver biopsy. Despite many proposals and revisions, the histological criteria for the differentiation have not been perfected yet. In this review article, the changes in the histopathologic criteria of NAFLD during the last three decades are summarized, and perspectives of the future changes are demonstrated. The discussion focuses on how pathologists have been dealing with "hepatocellular ballooning". Loose criteria, in which hepatocellular ballooning was not required for the diagnosis of NASH, were applied in many clinical studies published in around 2000's, whereas a strict criterion based on the presence/absence of hepatocellular ballooning was approved recently. Hence, simple and reliable methods of identifying ballooned hepatocytes are being sought. Clinical and pathological predictors of NAFLD-related hepatocarcinogenesis will also be sought in the future.
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Affiliation(s)
- Yoshihiro Ikura
- Yoshihiro Ikura, Department of Pathology, Takatsuki General Hospital, Kosobecho, Takatsuki 569-1192, Japan
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Liang W, Menke AL, Driessen A, Koek GH, Lindeman JH, Stoop R, Havekes LM, Kleemann R, van den Hoek AM. Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology. PLoS One 2014; 9:e115922. [PMID: 25535951 PMCID: PMC4275274 DOI: 10.1371/journal.pone.0115922] [Citation(s) in RCA: 411] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 11/28/2014] [Indexed: 12/15/2022] Open
Abstract
Background and aims The recently developed histological scoring system for non-alcoholic fatty liver disease (NAFLD) by the NASH Clinical Research Network (NASH-CRN) has been widely used in clinical settings, but is increasingly employed in preclinical research as well. However, it has not been systematically analyzed whether the human scoring system can directly be converted to preclinical rodent models. To analyze this, we systematically compared human NAFLD liver pathology, using human liver biopsies, with liver pathology of several NAFLD mouse models. Based upon the features pertaining to mouse NAFLD, we aimed at establishing a modified generic scoring system that is applicable to broad spectrum of rodent models. Methods The histopathology of NAFLD was analyzed in several different mouse models of NAFLD to define generic criteria for histological assessment (preclinical scoring system). For validation of this scoring system, 36 slides of mouse livers, covering the whole spectrum of NAFLD, were blindly analyzed by ten observers. Additionally, the livers were blindly scored by one observer during two separate assessments longer than 3 months apart. Results The criteria macrovesicular steatosis, microvesicular steatosis, hepatocellular hypertrophy, inflammation and fibrosis were generally applicable to rodent NAFLD. The inter-observer reproducibility (evaluated using the Intraclass Correlation Coefficient) between the ten observers was high for the analysis of macrovesicular steatosis and microvesicular steatosis (ICC = 0.784 and 0.776, all p<0.001, respectively) and moderate for the analysis of hypertrophy and inflammation (ICC = 0.685 and 0.650, all p<0.001, respectively). The intra-observer reproducibility between the different observations of one observer was high for the analysis of macrovesicular steatosis, microvesicular steatosis and hypertrophy (ICC = 0.871, 0.871 and 0.896, all p<0.001, respectively) and very high for the analysis of inflammation (ICC = 0.931, p<0.001). Conclusions We established a simple NAFLD scoring system with high reproducibility that is applicable for different rodent models and for all stages of NAFLD etiology.
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Affiliation(s)
- Wen Liang
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
- Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Ann Driessen
- Department of Pathology, University Hospital Antwerp, University of Antwerp, Edegem, Belgium
| | - Ger H. Koek
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University Medical Center Maastricht, Maastricht, The Netherlands
| | - Jan H. Lindeman
- Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Reinout Stoop
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
| | - Louis M. Havekes
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
- Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - Robert Kleemann
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
| | - Anita M. van den Hoek
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
- * E-mail:
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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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Pournik O, Alavian SM, Ghalichi L, Seifizarei B, Mehrnoush L, Aslani A, Anjarani S, Eslami S. Inter-observer and Intra-observer Agreement in Pathological Evaluation of Non-alcoholic Fatty Liver Disease Suspected Liver Biopsies. HEPATITIS MONTHLY 2014; 14:e15167. [PMID: 24497882 PMCID: PMC3909644 DOI: 10.5812/hepatmon.15167] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 10/15/2013] [Accepted: 10/22/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Histopathologic assessment of liver tissue is an essential step in management and follow-up of non-alcoholic fatty liver disease (NAFLD) while inter- and intra-observer variations limit the accuracy of these assessments. OBJECTIVES The aim of this study was to assess the inter- and intra-observer reproducibility of histopathologic assessment of liver biopsies based on NAFLD activity score (NAS) scoring system. MATERIALS AND METHODS The anonymous liver biopsy samples of 100 consecutive NAFLD suspected adults were randomly assigned to four pathologists. Then, the samples were randomly reassigned to the pathologists for the second time in a way that each sample would be evaluated by two different pathologists. Biopsies were revisited by their first evaluator after two months. The results were reported based on NAS scoring system. RESULTS Inter-observer agreement of the pathology scores based on NAS scoring system was acceptable for steatosis, lobular inflammation, and fibrosis, but not for hepatocyte ballooning. The intra-observer agreement was acceptable in all scales, with lowest intra-class correlation observed for lobular inflammation. CONCLUSIONS NAS scoring system has good overall inter- and intra-observer agreement, but more attention should be given to defining the hepatocyte ballooning and lobular inflammation, and training the pathologists to improve the accuracy of pathology reports.
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Affiliation(s)
- Omid Pournik
- Department of Medical Informatics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran
- Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Middle East Liver Diseases Center (MELD), Tehran, IR Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallh University of Medical Sciences, Tehran, IR Iran
| | - Leila Ghalichi
- Mental Health Research Center, Iran University of Medical Sciences, Tehran, IR Iran
| | - Bahram Seifizarei
- School of Medicine, Shahid Beheshti Hospital, Hamedan University of Medical Sciences, Hamedan, IR Iran
| | | | - Azam Aslani
- Department of Medical Informatics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran
| | - Soghra Anjarani
- Reference Health Laboratories Research Center, Tehran, IR Iran
| | - Saeid Eslami
- Department of Medical Informatics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran
- Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, IR Iran
- Corresponding Author: Saeid Eslami, Department of Medical Informatics, Faculty of Medicine, Mashhad University of Medical Sciences, Azadi Sq., Mashhad, IR Iran. Tel/Fax: +98-5118827048, E-mail:
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Effect of metformin on ballooning degeneration in nonalcoholic steatohepatitis (NASH): when to use metformin in nonalcoholic fatty liver disease (NAFLD). Adv Ther 2014; 31:30-43. [PMID: 24385405 DOI: 10.1007/s12325-013-0084-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Indexed: 02/06/2023]
Abstract
The key histologic feature of nonalcoholic steatohepatitis (NASH) is hepatocellular ballooning (HB). It plays an important role in NASH progression and is an independent predictor of liver mortality. In this review, we identified all studies using metformin in the treatment of nonalcoholic fatty liver disease (NAFLD) that included pre- and post-treatment liver biopsies. We specifically reviewed the effects of metformin on HB. Improved HB was noted in pediatric populations and in those adult patients who were able to lose weight and improve or normalize transaminases during therapy. Previous studies have supported the beneficial effects of metformin in reduction of body weight, improvement of insulin resistance, prevention of complications related to diabetes and chemo-preventive benefits in reducing hepatocellular carcinoma. All these effects make it an attractive treatment consideration for patients with diabetes, and prediabetes who have co-existing NAFLD. Future studies are warranted in order to confirm this effect of metformin on HB and its association with improving long-term outcomes in patients with NAFLD.
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