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da Silva Pereira ENG, Franco RLC, Santos RDCD, Daliry A. Statins and non-alcoholic fatty liver disease: A concise review. Biomed Pharmacother 2025; 183:117805. [PMID: 39755024 DOI: 10.1016/j.biopha.2024.117805] [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: 10/16/2024] [Revised: 12/12/2024] [Accepted: 12/28/2024] [Indexed: 01/06/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common hepatic manifestation of metabolic syndrome affecting 20-30 % of the adult population worldwide. This disease, which includes simple steatosis and non-alcoholic steatohepatitis, poses a significant risk for cardiovascular and metabolic diseases. Lifestyle modifications are crucial in the treatment of NAFLD; however, patient adherence remains challenging. As there is no specific treatment, drug repositioning is being researched as an alternative strategy. Statins, which are known for their cholesterol-lowering effects, are considered potential interventions for NAFLD. This review aimed to present the current understanding of the effects of statins on liver physiology in the context of NAFLD. The pathophysiology of NAFLD includes steatosis, inflammation, and fibrosis, which are exacerbated by dyslipidemia and insulin resistance. Statins, which inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, have pleiotropic effects beyond cholesterol-lowering and affect pathways related to inflammation, fibrogenesis, oxidative stress, and microcirculation. Although clinical guidelines support the use of statins for dyslipidemia in patients with NAFLD, more studies are needed to demonstrate their efficacy in liver disease. This comprehensive review serves as a foundation for future studies on the therapeutic potential of statins in NAFLD.
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Affiliation(s)
| | - Rafaela Luiza Costa Franco
- Laboratory of Clinical and Experimental Physiopathology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | - Rafaele Dantas Cruz Dos Santos
- Laboratory of Clinical and Experimental Physiopathology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | - Anissa Daliry
- Laboratory of Clinical and Experimental Physiopathology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
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Rabiu L, Zhang P, Afolabi LO, Saliu MA, Dabai SM, Suleiman RB, Gidado KI, Ige MA, Ibrahim A, Zhang G, Wan X. Immunological dynamics in MASH: from landscape analysis to therapeutic intervention. J Gastroenterol 2024; 59:1053-1078. [PMID: 39400718 DOI: 10.1007/s00535-024-02157-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/01/2024] [Indexed: 10/15/2024]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH), previously known as nonalcoholic steatohepatitis (NASH), is a multifaceted liver disease characterized by inflammation and fibrosis that develops from simple steatosis. Immune and inflammatory pathways have a central role in the pathogenesis of MASH, yet, how to target immune pathways to treat MASH remains perplexed. This review emphasizes the intricate role that immune cells play in the etiology and pathophysiology of MASH and highlights their significance as targets for therapeutic approaches. It discusses both current strategies and novel therapies aimed at modulating the immune response in MASH. It also highlights challenges in liver-specific drug delivery, potential off-target effects, and difficulties in targeting diverse immune cell populations within the liver. This review is a comprehensive resource that integrates current knowledge with future perspectives in the evolving field of MASH, with the goal of driving forward progress in medical therapies designed to treat this complex liver disease.
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Affiliation(s)
- Lawan Rabiu
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
- Federal University Dutse, Jigawa, Nigeria
| | - Pengchao Zhang
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Lukman O Afolabi
- Department of Pediatrics, Indiana University School of Medicine, 1234 Notre Dame Ave, S Bend, IN, 46617, USA
| | - Muhammad A Saliu
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Salisu M Dabai
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Rabiatu B Suleiman
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Khalid I Gidado
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Mark A Ige
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Abdulrahman Ibrahim
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Guizhong Zhang
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China.
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China.
| | - Xiaochun Wan
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China.
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China.
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3
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Maino C, Vernuccio F, Cannella R, Cristoferi L, Franco PN, Carbone M, Cortese F, Faletti R, De Bernardi E, Inchingolo R, Gatti M, Ippolito D. Non-invasive imaging biomarkers in chronic liver disease. Eur J Radiol 2024; 181:111749. [PMID: 39317002 DOI: 10.1016/j.ejrad.2024.111749] [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: 07/28/2024] [Revised: 08/20/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
Chronic liver disease (CLD) is a global and worldwide clinical challenge, considering that different underlying liver entities can lead to hepatic dysfunction. In the past, blood tests and clinical evaluation were the main noninvasive tools used to detect, diagnose and follow-up patients with CLD; in case of clinical suspicion of CLD or unclear diagnosis, liver biopsy has been considered as the reference standard to rule out different chronic liver conditions. Nowadays, noninvasive tests have gained a central role in the clinical pathway. Particularly, liver stiffness measurement (LSM) and cross-sectional imaging techniques can provide transversal information to clinicians, helping them to correctly manage, treat and follow patients during time. Cross-sectional imaging techniques, namely computed tomography (CT) and magnetic resonance imaging (MRI), have plenty of potential. Both techniques allow to compute the liver surface nodularity (LSN), associated with CLDs and risk of decompensation. MRI can also help quantify fatty liver infiltration, mainly with the proton density fat fraction (PDFF) sequences, and detect and quantify fibrosis, especially thanks to elastography (MRE). Advanced techniques, such as intravoxel incoherent motion (IVIM), T1- and T2- mapping are promising tools for detecting fibrosis deposition. Furthermore, the injection of hepatobiliary contrast agents has gained an important role not only in liver lesion characterization but also in assessing liver function, especially in CLDs. Finally, the broad development of radiomics signatures, applied to CT and MR, can be considered the next future approach to CLDs. The aim of this review is to provide a comprehensive overview of the current advancements and applications of both invasive and noninvasive imaging techniques in the evaluation and management of CLD.
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Affiliation(s)
- Cesare Maino
- Department of Diagnostic Radiology, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi 33, 20900 Monza, MB, Italy.
| | - Federica Vernuccio
- Section of Radiology - Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, Via del Vespro 129, Palermo 90127, Italy
| | - Roberto Cannella
- Section of Radiology - Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, Via del Vespro 129, Palermo 90127, Italy
| | - Laura Cristoferi
- Department of Gastroenterlogy, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi 33, 20900 Monza, MB, Italy
| | - Paolo Niccolò Franco
- Department of Diagnostic Radiology, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi 33, 20900 Monza, MB, Italy
| | - Marco Carbone
- Department of Gastroenterlogy, ASST Grande Ospedale Metropolitano Niguarda, Pizza dell'Ospedale Maggiore 3, 20100 Milano, MI, Italy
| | - Francesco Cortese
- Interventional Radiology Unit, "F. Miulli" General Hospital, Acquaviva delle Fonti 70021, Italy
| | - Riccardo Faletti
- Department of Surgical Sciences, University of Turin, Turin 10126, Italy
| | - Elisabetta De Bernardi
- Department of Medicine and Surgery - University of Milano Bicocca, Via Cadore 33, 20090 Monza, MB, Italy
| | - Riccardo Inchingolo
- Interventional Radiology Unit, "F. Miulli" General Hospital, Acquaviva delle Fonti 70021, Italy
| | - Marco Gatti
- Department of Surgical Sciences, University of Turin, Turin 10126, Italy
| | - Davide Ippolito
- Department of Diagnostic Radiology, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi 33, 20900 Monza, MB, Italy; Department of Medicine and Surgery - University of Milano Bicocca, Via Cadore 33, 20090 Monza, MB, Italy
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Zheng C, Nie H, Pan M, Fan W, Pi D, Liang Z, Liu D, Wang F, Yang Q, Zhang Y. Chaihu Shugan powder influences nonalcoholic fatty liver disease in rats in remodeling microRNAome and decreasing fatty acid synthesis. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:116967. [PMID: 37506783 DOI: 10.1016/j.jep.2023.116967] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/14/2023] [Accepted: 07/24/2023] [Indexed: 07/30/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chaihu Shugan powder (CSP) plays an important role in the prevention and treatment of nonalcoholic fatty liver disease (NAFLD) through a variety of biological mechanisms. However, whether the mechanism involves microRNA (miRNA) regulation remains unknown. AIM OF THE STUDY To investigate the effects of CSP on the miRNA expression profile of rats with NAFLD induced by high-fat diet (HFD), and to explore the mechanism of CSP in the treatment of NAFLD. METHODS NAFLD rat models were established by an 8-week HFD. The therapeutic effects of CSP on NAFLD were evaluated by physiological, biochemical and pathological analysis and hepatic surface microcirculation perfusion test. MicroRNA sequencing was used to study the effect of CSP on the miRNA expression profile of NAFLD rats, and the target genes of differentially expressed (DE) miRNAs were predicted for further function enrichment analysis. Next, targets of CSP and NAFLD were collected by a network pharmacological approach, and Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis were performed for the common target genes of CSP, NAFLD and DE miRNAs, and the expression levels of key genes and proteins were verified by quantitative Real-time PCR and Western blot. Finally, a network among formula-herb-compound-miRNA-target-biological processes-disease was established to explained the complex regulation mechanism of CSP on NAFLD. RESULTS The results showed that CSP significantly improved liver lipid accumulation, serum lipid and transaminase levels and liver surface microcirculation disturbance in HFD-induced NAFLD rats. The intervention of CSP reversed the high expression of 15 miRNAs in liver tissues induced by HFD, including miR-34a-5p, miR-146a-5p, miR-20b-5p and miR-142-3p. The results of pathway and functional enrichment analysis showed that, CSP might play an anti-NAFLD role via regulating DE miRNAs related to fatty acid metabolic process. Combined with the network pharmacological analysis, it was found that the DE miRNAs might affected the fatty acid biosynthesis pathway in the treatment of NAFLD by CSP. Molecular biology experiments have conformed the decreased the gene and protein levels of acetyl-CoA carboxylase alpha (ACACA), fatty acid synthase (FASN) and other fatty acid biosynthesis related enzymes on NAFLD rats after intervention of CSP. CONCLUSIONS CSP can significantly reduce hepatic lipid accumulation of NAFLD rat model induced by HFD, and its mechanism may be through the action of 15 miRNAs such as miR-34a-5p, miR-146a-5p, miR-20b-5p and miR-142-3p. Reduce the gene and protein expression levels of ACACA, FASN and other fatty acid biosynthesis related enzymes, thus reducing fatty acid biosynthesis. Based on an epigenetic perspective, this study explains the key anti-NAFLD mechanism of CSP via combination of microRNA sequencing and network pharmacological analysis, providing a new reference for the modernization of traditional Chinese medicine.
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Affiliation(s)
- Chuiyang Zheng
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
| | - Huan Nie
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
| | - Maoxing Pan
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
| | - Wen Fan
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
| | - Dajin Pi
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
| | - Zheng Liang
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
| | - Dongdong Liu
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
| | - Fengzhen Wang
- Accreditation Center of TCM Physician State Administration of Traditional Chinese Medicine, Beijing, China.
| | - Qinhe Yang
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
| | - Yupei Zhang
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
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5
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Kwanten W(WJ, Francque SM. The liver sinusoid in chronic liver disease: NAFLD and NASH. SINUSOIDAL CELLS IN LIVER DISEASES 2024:263-284. [DOI: 10.1016/b978-0-323-95262-0.00012-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Mitten EK, Portincasa P, Baffy G. Portal Hypertension in Nonalcoholic Fatty Liver Disease: Challenges and Paradigms. J Clin Transl Hepatol 2023; 11:1201-1211. [PMID: 37577237 PMCID: PMC10412712 DOI: 10.14218/jcth.2023.00029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/04/2023] [Accepted: 05/17/2023] [Indexed: 07/03/2023] Open
Abstract
Portal hypertension in cirrhosis is defined as an increase in the portal pressure gradient (PPG) between the portal and hepatic veins and is traditionally estimated by the hepatic venous pressure gradient (HVPG), which is the difference in pressure between the free-floating and wedged positions of a balloon catheter in the hepatic vein. By convention, HVPG≥10 mmHg indicates clinically significant portal hypertension, which is associated with adverse clinical outcomes. Nonalcoholic fatty liver disease (NAFLD) is a common disorder with a heterogeneous clinical course, which includes the development of portal hypertension. There is increasing evidence that portal hypertension in NAFLD deserves special considerations. First, elevated PPG often precedes fibrosis in NAFLD, suggesting a bidirectional relationship between these pathological processes. Second, HVPG underestimates PPG in NAFLD, suggesting that portal hypertension is more prevalent in this condition than currently believed. Third, cellular mechanoresponses generated early in the pathogenesis of NAFLD provide a mechanistic explanation for the pressure-fibrosis paradigm. Finally, a better understanding of liver mechanobiology in NAFLD may aid in the development of novel pharmaceutical targets for prevention and management of this disease.
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Affiliation(s)
- Emilie K. Mitten
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Piero Portincasa
- Division of Internal Medicine and Department of Precision and Regenerative Medicine and Ionian Area, University ‘Aldo Moro’ Medical School, Bari, Italy
| | - György Baffy
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Section of Gastroenterology, Department of Medicine, VA Boston Healthcare System, Boston, MA, USA
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7
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Morsy MHE, Nabil ZI, Darwish ST, Al-Eisa RA, Mehana AE. Anti-Diabetic and Anti-Adipogenic Effect of Harmine in High-Fat-Diet-Induced Diabetes in Mice. Life (Basel) 2023; 13:1693. [PMID: 37629550 PMCID: PMC10455780 DOI: 10.3390/life13081693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 07/31/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
One of the most important health issues facing the world today is obesity. It is an important independent risk factor for developing type 2 diabetes. Harmine offers various pharmacological effects, such as anti-inflammatory and anti-tumor effects. The current study aims to investigate Harmine's anti-diabetic and anti-adipogenic properties in albino mice after inducing low-grade inflammation with a high-fat diet (HFD). About forty-eight male albino mice were divided into four groups. Group 1: control mice were injected with daily saline and fed a normal chow diet of 21% protein for 5 months. Group 2: mice were treated daily with IP-injected Harmine (30 mg/kg body weight) and were fed a normal chow diet for 5 months. Group 3: mice were fed HFD to induce type 2 Diabetes Mellitus (T2DM) for 5 months. Group 4: mice were fed HFD for 14 weeks and treated with Harmine for the last 6 weeks. A figh-fat diet caused a significant increase in body and organ weight, lipid profiles, and destructive changes within the pancreas, kidney, and liver tissue. The administration of Harmine led to a remarkable improvement in the histological and ultrastructural changes induced by HFD. The findings indicate that mice cured using Harmine had lower oxidative stress, a higher total antioxidant capacity, and a reduced lipid profile compared to HFD mice. Harmine led to the hepatocytes partly restoring their ordinary configuration. Furthermore, it was noticed that the pathological incidence of damage in the structure of both the kidney and pancreas sections reduced in comparison with the diabetic group. Additional research will be required to fully understand Harmine and its preventive effects on the two forms of diabetes.
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Affiliation(s)
- Menna H E Morsy
- Department of Zoology, Faculty of Science, Arish University, Arish 45511, Egypt
- Department of Zoology, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
| | - Zohour I Nabil
- Department of Zoology, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
| | - Samah T Darwish
- Department of Zoology, Faculty of Science, Arish University, Arish 45511, Egypt
| | - Rasha A Al-Eisa
- Department of Biology, College of Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Amir E Mehana
- Department of Zoology, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
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Li D, Janmey PA, Wells RG. Local fat content determines global and local stiffness in livers with simple steatosis. FASEB Bioadv 2023; 5:251-261. [PMID: 37287868 PMCID: PMC10242205 DOI: 10.1096/fba.2022-00134] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/09/2023] [Accepted: 04/04/2023] [Indexed: 06/09/2023] Open
Abstract
Fat accumulation during liver steatosis precedes inflammation and fibrosis in fatty liver diseases, and is associated with disease progression. Despite a large body of evidence that liver mechanics play a major role in liver disease progression, the effect of fat accumulation by itself on liver mechanics remains unclear. Thus, we conducted ex vivo studies of liver mechanics in rodent models of simple steatosis to isolate and examine the mechanical effects of intrahepatic fat accumulation, and found that fat accumulation softens the liver. Using a novel adaptation of microindentation to permit association of local mechanics with microarchitectural features, we found evidence that the softening of fatty liver results from local softening of fatty regions rather than uniform softening of the liver. These results suggest that fat accumulation itself exerts a softening effect on liver tissue. This, along with the localized heterogeneity of softening within the liver, has implications in what mechanical mechanisms are involved in the progression of liver steatosis to more severe pathologies and disease. Finally, the ability to examine and associate local mechanics with microarchitectural features is potentially applicable to the study of the role of heterogeneous mechanical microenvironments in both other liver pathologies and other organ systems.
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Affiliation(s)
- David Li
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- NSF Science and Technology Center for Engineering MechanoBiologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Paul A. Janmey
- NSF Science and Technology Center for Engineering MechanoBiologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Institute for Medicine and EngineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of PhysiologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Rebecca G. Wells
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- NSF Science and Technology Center for Engineering MechanoBiologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
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Esparza J, Shrestha U, Kleiner DE, Crawford JM, Vanatta J, Satapathy S, Tipirneni-Sajja A. Automated Segmentation and Morphological Characterization of Hepatic Steatosis and Correlation with Histopathology. J Clin Exp Hepatol 2023; 13:468-478. [PMID: 37250872 PMCID: PMC10213977 DOI: 10.1016/j.jceh.2022.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 12/02/2022] [Indexed: 05/31/2023] Open
Abstract
BACKGROUND/OBJECTIVES Prevalence of nonalcoholic fatty liver disease (NAFLD) has increased to 25% of the world population. Hepatic steatosis is a hallmark feature of NAFLD and is assessed histologically using visual and ordinal fat grading criteria (0-3) from the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) scoring system. The purpose of this study is to automatically segment and extract morphological characteristics and distributions of fat droplets (FDs) on liver histology images and find associations with severity of steatosis. METHODS A previously published human cohort of 68 NASH candidates was graded for steatosis by an experienced pathologist using the Fat CRN grading system. The automated segmentation algorithm quantified fat fraction (FF) and fat-affected hepatocyte ratio (FHR), extracted fat morphology by calculating radius and circularity of FDs, and examined FDs distribution and heterogeneity using nearest neighbor distance and regional isotropy. RESULTS Regression analysis and Spearman correlation (ρ) yielded high correlations for radius (R2 = 0.86, ρ = 0.72), nearest neighbor distance (R2 = 0.82, ρ = -0.82), regional isotropy (R2 = 0.84, ρ = 0.74), and FHR (R2 = 0.90, ρ = 0.85), and low correlation for circularity (R2 = 0.48, ρ = -0.32) with FF and pathologist grades, respectively. FHR showed a better distinction between pathologist Fat CRN grades compared to conventional FF measurements, making it a potential surrogate measure for Fat CRN scores. Our results showed variation in distribution of morphological features and steatosis heterogeneity within the same patient's biopsy sample as well as between patients of similar FF. CONCLUSIONS The fat percentage measurements, specific morphological characteristics, and patterns of distribution quantified with the automated segmentation algorithm showed associations with steatosis severity; however, future studies are warranted to evaluate the clinical significance of these steatosis features in progression of NAFLD and NASH.
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Affiliation(s)
- Juan Esparza
- Department of Biomedical Engineering, The University of Memphis, Memphis, TN, USA
| | - Utsav Shrestha
- Department of Biomedical Engineering, The University of Memphis, Memphis, TN, USA
| | - David E. Kleiner
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institute to Health, Bethesda, MD, USA
| | - James M. Crawford
- Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Jason Vanatta
- Department of Surgery, University of Tennessee Health and Science Center, Memphis, TN, USA
| | - Sanjaya Satapathy
- Liver Transplantation, North Shore University Hospital/Northwell Health, Manhasset, NY, USA
| | - Aaryani Tipirneni-Sajja
- Department of Biomedical Engineering, The University of Memphis, Memphis, TN, USA
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, TN, USA
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10
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Zhang X, Ohayon-Steckel L, Coppin E, Johny E, Dasari A, Florentin J, Vasamsetti S, Dutta P. Epidermal Growth Factor Receptor in Hepatic Endothelial Cells Suppresses MCP-1-Dependent Monocyte Recruitment in Diabetes. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:1363-1371. [PMID: 36946774 PMCID: PMC10121888 DOI: 10.4049/jimmunol.2200557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 02/27/2023] [Indexed: 03/23/2023]
Abstract
Insulin resistance is a compromised response to insulin in target tissues such as liver. Emerging evidence shows that vascular endothelial cells (ECs) are critical in mediating glucose metabolism. However, how liver ECs can regulate inflammation in the setting of insulin resistance is still unknown. Using genome-wide transcriptome analysis of ECs isolated from diabetic mice, we found enrichment of the genes involved in epidermal growth factor receptor (Egfr) signaling. In line with this, hepatic sinusoidal ECs in diabetic mice had elevated levels of Egfr expression. Interestingly, we found an increased number of hepatic myeloid cells, especially macrophages, and systemic glucose intolerance in Cdh5Cre/+Egfrfl/fl mice lacking Egfr in ECs compared with littermate control mice with type II diabetes. Egfr deficiency upregulated the expression of MCP-1 in hepatic sinusoidal ECs. This resulted in augmented monocyte recruitment and macrophage differentiation in Cdh5Cre/+Egfrfl/fl mice compared with littermate control mice as determined by a mouse model of parabiosis. Finally, MCP-1 neutralization and hepatic macrophage depletion in Cdh5Cre/+Egfrfl/fl mice resulted in a reduced number of hepatic macrophages and ameliorated glucose intolerance compared with the control groups. Collectively, these results demonstrate a protective endothelial Egfr signaling in reducing monocyte-mediated hepatic inflammation and glucose intolerance in type II diabetic mice.
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Affiliation(s)
- Xinyi Zhang
- Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Lee Ohayon-Steckel
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Emilie Coppin
- Regeneration in Hematopoiesis, Institute for Immunology, TU Dresden, Dresden, Germany
- Immunology of Aging, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany
| | - Ebin Johny
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Ankush Dasari
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Jonathan Florentin
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Sathish Vasamsetti
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Partha Dutta
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Pittsburgh VA Medical Center-University Drive, University Drive C, Pittsburgh, PA, 15213
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11
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CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease. Pharmaceuticals (Basel) 2023; 16:ph16010106. [PMID: 36678603 PMCID: PMC9863901 DOI: 10.3390/ph16010106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/07/2023] [Accepted: 01/08/2023] [Indexed: 01/12/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the common metabolic diseases characterized by hepatic lipid accumulation. Insulin resistance and microcirculation dysfunction are strongly associated with NAFLD. CX08005, an inhibitor of PTP1B with the IC50 of 0.75 ± 0.07 μM, has been proven to directly enhance insulin sensitivity. The present study aimed to investigate the effects of CX08005 on hepatic lipid accumulation and microcirculation dysfunction in both KKAy mice and diet-induced obesity (DIO) mice. Hepatic lipid accumulation was evaluated by hepatic triglyceride determination and B-ultrasound analysis in KKAy mice. Insulin sensitivity and blood lipids were assessed by insulin tolerance test (ITT) and triglyceride (TG)/total cholesterol (TC) contents, respectively. In addition, the hepatic microcirculation was examined in DIO mice by in vivo microscopy. The results showed that CX08005 intervention significantly reduced the TG and echo-intensity attenuation coefficient in the livers of KKAy mice. Furthermore, we found that CX08005 treatment significantly enhanced insulin sensitivity, and decreased plasma TG and/or TC contents in KKAy and DIO mice, respectively. In addition, CX08005 treatment ameliorated hepatic microcirculation dysfunction in DIO mice, as evidenced by increased RBCs velocity and shear rate of the blood flow in central veins and in the interlobular veins, as well as enhanced rate of perfused hepatic sinusoids in central vein area. Additionally, CX08005 administration decreased the adhered leukocytes both in the center veins and in the hepatic sinusoids area. Taken together, CX08005 exhibited beneficial effects on hepatic lipid accumulation and microcirculation dysfunction associated with NAFLD, which was involved with modulating insulin sensitivity and leukocyte recruitment, as well as restoration of normal microcirculatory blood flow.
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12
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Eriksen PL, Thomsen KL, Hamilton-Dutoit S, Vilstrup DMSH, Sørensen M. Experimental non-alcoholic fatty liver disease causes regional liver functional deficits as measured by the capacity for galactose metabolism while whole liver function is preserved. BMC Gastroenterol 2022; 22:541. [PMID: 36575375 PMCID: PMC9793673 DOI: 10.1186/s12876-022-02574-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 11/09/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Increasing incidence of non-alcoholic fatty liver disease (NAFLD) calls for improved understanding of how the disease affects metabolic liver function. AIMS To investigate in vivo effects of different NAFLD stages on metabolic liver function, quantified as regional and total capacity for galactose metabolism in a NAFLD model. METHODS Male Sprague Dawley rats were fed a high-fat, high-cholesterol diet for 1 or 12 weeks, modelling early or late NAFLD, respectively. Each NAFLD group (n = 8 each) had a control group on standard chow (n = 8 each). Metabolic liver function was assessed by 2-[18F]fluoro-2-deoxy-D-galactose positron emission tomography; regional galactose metabolism was assessed as standardised uptake value (SUV). Liver tissue was harvested for histology and fat quantification. RESULTS Early NAFLD had median 18% fat by liver volume. Late NAFLD had median 32% fat and varying features of non-alcoholic steatohepatitis (NASH). Median SUV reflecting regional galactose metabolism was reduced in early NAFLD (9.8) and more so in late NAFLD (7.4; p = 0.02), both significantly lower than in controls (12.5). In early NAFLD, lower SUV was quantitatively explained by fat infiltration. In late NAFLD, the SUV decrease was beyond that attributable to fat; probably related to structural NASH features. Total capacity for galactose elimination was intact in both groups, which in late NAFLD was attained by increased fat-free liver mass to 21 g, versus 15 g in early NAFLD and controls (both p ≤ 0.002). CONCLUSION Regional metabolic liver function was compromised in NAFLD by fat infiltration and structural changes. Still, whole liver metabolic function was preserved in late NAFLD by a marked increase in the fat-free liver mass.
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Affiliation(s)
- Peter Lykke Eriksen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200, Aarhus N, Denmark. .,Department of Internal Medicine, Randers Regional Hospital, Skovlyvej 15, 8930, Randers, Denmark.
| | - Karen Louise Thomsen
- grid.154185.c0000 0004 0512 597XDepartment of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark
| | - Stephen Hamilton-Dutoit
- grid.154185.c0000 0004 0512 597XDepartment of Pathology, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark
| | - DMSc Hendrik Vilstrup
- grid.154185.c0000 0004 0512 597XDepartment of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark
| | - Michael Sørensen
- grid.154185.c0000 0004 0512 597XDepartment of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark ,grid.154185.c0000 0004 0512 597XDepartment of Nuclear Medicine & PET, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark ,grid.416838.00000 0004 0646 9184Department of Internal Medicine, Viborg Regional Hospital, Heibergs Alle 5A, 8800 Viborg, Denmark
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13
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Nababan SHH, Lesmana CRA. Portal Hypertension in Nonalcoholic Fatty Liver Disease: From Pathogenesis to Clinical Practice. J Clin Transl Hepatol 2022; 10:979-985. [PMID: 36304507 PMCID: PMC9547264 DOI: 10.14218/jcth.2021.00593] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/05/2022] [Accepted: 06/06/2022] [Indexed: 12/04/2022] Open
Abstract
Portal hypertension in nonalcoholic fatty liver disease (NAFLD) mostly occur in cirrhotic stage. However, several experimental and clinical studies showed evidence of portal hypertension in NAFLD without significant or advance fibrosis. This early development of portal hypertension in NAFLD is associated with liver sinusoidal contraction by hepatocellular lipid accumulation and ballooning, which is also accompanied by capillarization and dysfunction of liver sinusoidal endothelial cells. Both of these impaired mechanical and molecular components can cause an increase in intrahepatic vascular resistance which lead to the increase of portal pressure in the absence of significant liver fibrosis. Extrahepatic factors such as insulin resistance and gut dysbiosis may also contribute to liver sinusoidal endothelial dysfunction and early portal hypertension in NAFLD. The clinical impact of early portal hypertension in NAFLD is still unclear. However, clinical tools for diagnosis and monitoring of portal hypertension in NAFLD are being investigated to predict high-risk patients and to guide therapy.
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Affiliation(s)
- Saut Horas H. Nababan
- Hepatobiliary Division, Department of Internal Medicine, Dr Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
- Gastrointestinal Cancer Center, MRCCC Siloam Semanggi Hospital, Jakarta, Indonesia
| | - Cosmas Rinaldi Adithya Lesmana
- Hepatobiliary Division, Department of Internal Medicine, Dr Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
- Gastrointestinal Cancer Center, MRCCC Siloam Semanggi Hospital, Jakarta, Indonesia
- Digestive Disease & GI Oncology Center, Medistra Hospital, Jakarta, Indonesia
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14
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Liu B, Tian Y, He J, Gu Q, Jin B, Shen H, Li W, Shi L, Yu H, Shan G, Cai X. The potential of mecciRNA in hepatic stellate cell to regulate progression of nonalcoholic hepatitis. J Transl Med 2022; 20:393. [PMID: 36058953 PMCID: PMC9441041 DOI: 10.1186/s12967-022-03595-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) occupies a substantial proportion of chronic liver disease worldwide, of which pathogenesis needs further research. Recent studies have demonstrated the significant roles of circular RNAs (circRNAs) in NASH, while the function of a novel type of circRNAs, namely mitochondria-encoded circRNAs (mecciRNAs), remains elusive. Therefore, we aimed to investigate their potential to regulate the progression of NASH in this study. METHODS GSE134146 was used to screen for differentially expressed mecciRNAs in NASH, while GSE46300 was used to identify NASH-related genes. To establish the mecciRNA-miRNA-mRNA networks, circMINE and miRNet databases were used for predicting downstream targets. Then, consensus clustering analysis was used to determine immune subtypes of NASH. Finally, we successfully validated our findings in vitro (LPS-treated hepatic stellate cells [HSCs]) and in vivo (MCD-diet mice) NASH models. RESULTS We confirmed that circRNomics balance is disrupted in HSCs of NASH, while two mecciRNAs (hsa_circ_0089761 and hsa_circ_0089763) could function as competing for endogenous RNAs (ceRNAs) to regulate fibrosis-related signals. Furthermore, we constructed two ceRNA networks based on mecciRNAs for the first time. Cell and animal NASH models validated our findings that c-MYC and SMAD2/3 were upregulated in HSCs, while THBS1 and p-STAT3 were upregulated in hepatocytes. Moreover, we identified 21 core genes by overlapping the differentially expressed genes (NASH vs. Normal) with mecciRNA-targeted genes. According to their expression profiles, NASH patients could be divided in 2 different clusters, in which proinflammatory signals (TNF and IL-17 pathways) are significantly activated in Cluster 1. CONCLUSION We successfully established two novel mecciRNA-miRNA-mRNA networks in HSCs and hepatocytes, which were further confirmed by in vitro and in vivo models. Meanwhile, the novel immunotyping model revealed the heterogeneity of NASH, thereby might guiding treatment options. Altogether, our study brought a distinct perspective on the relationship between mecciRNAs and NASH.
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Affiliation(s)
- Boqiang Liu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Yuanshi Tian
- Department of Diagnostic Ultrasound & Echocardiography, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Jing He
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Qiuxia Gu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Binghan Jin
- Department of Endocrinology, The Children's Hospital, School of Medicine, National Clinical Research Center for Child Health, Zhejiang University, Hangzhou, 310053, China
| | - Hao Shen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Weiqi Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Liang Shi
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Hong Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Ge Shan
- Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China. .,Department of Pulmonary and Critical Care Medicine, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. .,Department of Clinical Laboratory, First Affiliated Hospital of the USTC, Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China (UTSC), Hefei, 230027, China.
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. .,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China. .,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China. .,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China. .,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China.
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15
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Nasiri-Ansari N, Androutsakos T, Flessa CM, Kyrou I, Siasos G, Randeva HS, Kassi E, Papavassiliou AG. Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review. Cells 2022; 11:2511. [PMID: 36010588 PMCID: PMC9407007 DOI: 10.3390/cells11162511] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/07/2022] [Accepted: 08/10/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. It is strongly associated with obesity, type 2 diabetes (T2DM), and other metabolic syndrome features. Reflecting the underlying pathogenesis and the cardiometabolic disorders associated with NAFLD, the term metabolic (dysfunction)-associated fatty liver disease (MAFLD) has recently been proposed. Indeed, over the past few years, growing evidence supports a strong correlation between NAFLD and increased cardiovascular disease (CVD) risk, independent of the presence of diabetes, hypertension, and obesity. This implies that NAFLD may also be directly involved in the pathogenesis of CVD. Notably, liver sinusoidal endothelial cell (LSEC) dysfunction appears to be implicated in the progression of NAFLD via numerous mechanisms, including the regulation of the inflammatory process, hepatic stellate activation, augmented vascular resistance, and the distortion of microcirculation, resulting in the progression of NAFLD. Vice versa, the liver secretes inflammatory molecules that are considered pro-atherogenic and may contribute to vascular endothelial dysfunction, resulting in atherosclerosis and CVD. In this review, we provide current evidence supporting the role of endothelial cell dysfunction in the pathogenesis of NAFLD and NAFLD-associated atherosclerosis. Endothelial cells could thus represent a "golden target" for the development of new treatment strategies for NAFLD and its comorbid CVD.
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Affiliation(s)
- Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
| | - Gerasimos Siasos
- Third Department of Cardiology, ‘Sotiria’ Thoracic Diseases General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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16
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The Potential Hepatoprotective Effect of Paeoniae Radix Alba in Thioacetamide-Induced Acute Liver Injury in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:7904845. [PMID: 35126604 PMCID: PMC8816603 DOI: 10.1155/2022/7904845] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 12/23/2022]
Abstract
Aim Acute liver injury (ALI) can occur for various reasons by induced inflammation and apoptosis of liver cells including hepatocytes, Kupffer cells, and hepatic stellate cells. Thioacetamide (TAA), which is a classic hepatotoxin, causes oxidative stress, membrane damage, and accumulation of lipid droplets and subsequently provokes consecutive liver injury. In the current study, we tested whether Paeoniae Radix Alba (PR) could alleviate TAA-induced ALI. Methods Thirty-five male rats were equally separated into five groups. The first group was the normal group, which received distilled water only. The remaining four groups received intraperitoneal TAA (200 mg/kg) for 3 days to induce ALI. The four groups were divided into the control group (no treatment), silymarin-treated, 100 mg/kg PR-treated, and 200 mg/kg PR-treated. The efficacy of PR against hepatotoxicity was evaluated in terms of the serum biochemical index and protein expression associated with inflammation and apoptosis. Moreover, the dissected livers were analyzed by hematoxylin and eosin stain. Results PR alleviated liver dysfunction as evidenced by decreased levels of aspartate aminotransferase, alanine aminotransferase, and ammonia. Phosphorylated AMP-activated protein kinase (AMPK) and Sirtuin 1 (Sirt1) levels were obviously decreased in the TAA control group, whereas PR reversed these changes. PR also prevented deteriorative effects through inhibition of inflammation and apoptosis via nuclear transcription factor-kappa Bp65 (NF-κBp65) inactivation. Moreover, we found that the hepatoprotective effect of PR pretreatment was mediated by restoration of histopathological changes. Conclusion PR efficiently blocked both the inflammatory response and apoptosis through activating the AMPK/Sirt1/NF-κBp65 pathway. Therefore, PR is considered a potential therapeutic agent against ALI.
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Simvastatin Improves Microcirculatory Function in Nonalcoholic Fatty Liver Disease and Downregulates Oxidative and ALE-RAGE Stress. Nutrients 2022; 14:nu14030716. [PMID: 35277075 PMCID: PMC8838100 DOI: 10.3390/nu14030716] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 01/11/2022] [Accepted: 01/14/2022] [Indexed: 12/12/2022] Open
Abstract
Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product–receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat–high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.
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18
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van der Graaff D, Chotkoe S, De Winter B, De Man J, Casteleyn C, Timmermans JP, Pintelon I, Vonghia L, Kwanten WJ, Francque S. Vasoconstrictor antagonism improves functional and structural vascular alterations and liver damage in rats with early NAFLD. JHEP Rep 2022; 4:100412. [PMID: 35036886 PMCID: PMC8749167 DOI: 10.1016/j.jhepr.2021.100412] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND & AIMS Intrahepatic vascular resistance is increased in early non-alcoholic fatty liver disease (NAFLD), potentially leading to tissue hypoxia and triggering disease progression. Hepatic vascular hyperreactivity to vasoconstrictors has been identified as an underlying mechanism. This study investigates vasoconstrictive agonism and antagonism in 2 models of early NAFLD and in non-alcoholic steatohepatitis (NASH). METHODS The effects of endothelin-1 (ET-1), angiotensin II (ATII) and thromboxane A2 (TxA2) agonism and antagonism were studied by in situ ex vivo liver perfusion and preventive/therapeutic treatment experiments in a methionine-choline-deficient diet model of steatosis. Furthermore, important results were validated in Zucker fatty rats after 4 or 8 weeks of high-fat high-fructose diet feeding. In vivo systemic and portal pressures, ex vivo transhepatic pressure gradients (THPG) and transaminase levels were measured. Liver tissue was harvested for structural and mRNA analysis. RESULTS The THPG and consequent portal pressure were significantly increased in both models of steatosis and in NASH. ET-1, ATII and TxA2 increased the THPG even further. Bosentan (ET-1 receptor antagonist), valsartan (ATII receptor blocker) and celecoxib (COX-2 inhibitor) attenuated or even normalised the increased THPG in steatosis. Simultaneously, bosentan and valsartan treatment improved transaminase levels. Moreover, bosentan was able to mitigate the degree of steatosis and restored the disrupted microvascular structure. Finally, beneficial vascular effects of bosentan endured in NASH. CONCLUSIONS Antagonism of vasoconstrictive mediators improves intrahepatic vascular function. Both ET-1 and ATII antagonists showed additional benefit and bosentan even mitigated steatosis and structural liver damage. In conclusion, vasoconstrictive antagonism is a potentially promising therapeutic option for the treatment of early NAFLD. LAY SUMMARY In non-alcoholic fatty liver disease (NAFLD), hepatic blood flow is impaired and the blood pressure in the liver blood vessels is increased as a result of an increased response of the liver vasculature to vasoconstrictors. Using drugs to block the constriction of the intrahepatic vasculature, the resistance of the liver blood vessels decreases and the increased portal pressure is reduced. Moreover, blocking the vasoconstrictive endothelin-1 pathway restored parenchymal architecture and reduced disease severity.
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Key Words
- ALT, alanine aminotransferase
- ARB, angiotensin receptor blocker
- AST, aspartate aminotransferase
- ATII, angiotensin II
- COX, cyclooxygenase
- ET, endothelin
- HFHFD, high-fat high-fructose diet
- IHVR, intrahepatic vascular resistance
- Jak2, Janus-kinase-2
- MCD, methionine-choline deficient diet
- Mx, methoxamine
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NO, nitric oxide
- PP, portal pressure
- PR, pulse rate
- SEM, scanning electron microscopy
- TBW, total body weight
- TEM, transmission electron microscopy
- TXAS, thromboxane synthase
- TxA2, thromboxane A2
- ZFR, Zucker fatty rats
- angiotensin II
- endothelin-1
- non-alcoholic fatty liver disease
- portal hypertension
- thromboxane A2
- transhepatic pressure gradient
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Affiliation(s)
- Denise van der Graaff
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- European Reference Network Rare Hepatic Diseases (ERN RARE-LIVER)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Shivani Chotkoe
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- European Reference Network Rare Hepatic Diseases (ERN RARE-LIVER)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Benedicte De Winter
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- European Reference Network Rare Hepatic Diseases (ERN RARE-LIVER)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Joris De Man
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Christophe Casteleyn
- Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium
- Department of Applied Veterinary Morphology, Faculty of Veterinary Medicine, University of Antwerp, Antwerp, Belgium
| | - Jean-Pierre Timmermans
- Laboratory of Cell Biology and Histology, Antwerp Centre for Advanced Microscopy (ACAM), University of Antwerp, Antwerp, Belgium
| | - Isabel Pintelon
- Laboratory of Cell Biology and Histology, Antwerp Centre for Advanced Microscopy (ACAM), University of Antwerp, Antwerp, Belgium
| | - Luisa Vonghia
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- European Reference Network Rare Hepatic Diseases (ERN RARE-LIVER)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Wilhelmus J. Kwanten
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- European Reference Network Rare Hepatic Diseases (ERN RARE-LIVER)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- European Reference Network Rare Hepatic Diseases (ERN RARE-LIVER)
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
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19
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Baffy G, Bosch J. Overlooked subclinical portal hypertension in non-cirrhotic NAFLD: Is it real and how to measure it? J Hepatol 2022; 76:458-463. [PMID: 34606912 DOI: 10.1016/j.jhep.2021.09.029] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 09/21/2021] [Accepted: 09/26/2021] [Indexed: 12/12/2022]
Abstract
Clinical and experimental advances related to the detection, magnitude and pathobiology of subclinical portal hypertension in non-alcoholic fatty liver disease (NAFLD), primarily observed in the presence of non-alcoholic steatohepatitis (NASH), prompt us to revisit current disease paradigms. Hepatic venous pressure gradient (HVPG) has been reported to underestimate portal pressure in NASH-related cirrhosis, while inaccuracy is more likely in non-cirrhotic livers, indicating a potential need for new and preferably non-invasive methods of measurement. Although clinically significant portal hypertension (HVPG ≥10 mmHg) retains its prognostic significance in NASH, subclinical portal hypertension (HVPG 6.0-9.5 mmHg) has been repeatedly detected in patients with NAFLD in the absence of cirrhosis or even significant fibrosis whereas the impact of these findings on disease outcomes remains unclear. Mechanocrine signalling pathways in various types of liver cell reveal a molecular basis for the adverse effects of subclinical portal hypertension and suggest a bidirectional relationship between portal pressure and fibrosis. These findings may guide efforts to improve risk assessment and identify novel therapeutic targets in NAFLD.
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Affiliation(s)
- Gyorgy Baffy
- Department of Medicine, VA Boston Healthcare System and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
| | - Jaume Bosch
- Department of Biomedical Research, University of Bern, Bern, Switzerland; Institut d'Investigacions Biomediques August Pi i Sunyer and CIBERehd, University of Barcelona, Spain
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20
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NALBANT A, ŞAKUL BU, YÜCEL F. Investigation of Changes in Liver Microanatomy in the Steatosis Model Created by Permanent Canula in Rats. CLINICAL AND EXPERIMENTAL HEALTH SCIENCES 2021. [DOI: 10.33808/clinexphealthsci.948391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Objective: The knowledge of nonalcoholic fatty liver disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH) is limited to the findings from available suitable models for this disease. A number of rodent models have been described in which relevant liver pathology develops in an appropriate metabolic context. In this experimental study, it was aimed to create a new liver fat model by giving fat from the portal vein of rats and to visualize the changes in the liver with advanced microscopic techniques.
Methods: 28 female rats were used in the study. Permanent intraabdominal cannulas were inserted into the portal vein of the rats. Rats were randomly divided four group. Intralipid 20% substance was injected through cannula to the experimental groups during the test period. Control group received saline at the same rate. At the end of the experiment, the animals were visualized with a laser speckle microscope and livers were divided into sections according to the stereological method. The sections were painted with Hematoxylin-Eosin, Oil red o, Masson trichoma, Bodipy, Nile red. Sections were evaluated under a microscope.
Results: Ballooning, inflammation and fibrosis were observed in the 2 week intralipid group. In the 1 week intralipid group, the rate of parenchyma decreased while the sinusoid rate increased, and sinusoid rate increased significantly in the 2 week intralipid (p˂0.05).
Conclusion: According to the findings, steatohepatitis was detected in the 2 week intralipid, whereas only steatosis was observed in the 1 week intralipid. Thus, it was concluded that the newly formed rat model causes steatosis.
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21
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Maeda H, Ishima Y, Saruwatari J, Mizuta Y, Minayoshi Y, Ichimizu S, Yanagisawa H, Nagasaki T, Yasuda K, Oshiro S, Taura M, McConnell MJ, Oniki K, Sonoda K, Wakayama T, Kinoshita M, Shuto T, Kai H, Tanaka M, Sasaki Y, Iwakiri Y, Otagiri M, Watanabe H, Maruyama T. Nitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH. J Control Release 2021; 341:457-474. [PMID: 34856227 DOI: 10.1016/j.jconrel.2021.11.039] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 02/07/2023]
Abstract
Kupffer cells are a key source of reactive oxygen species (ROS) and are implicated in the development of steatohepatitis and fibrosis in nonalcoholic steatohepatitis (NASH). We recently developed a polythiolated and mannosylated human serum albumin (SH-Man-HSA), a nano-antioxidant that targets Kupffer cells, in which the mannosyl units on albumin allows their specific uptake by Kupffer cells via the mannose receptor C type 1 (MRC1), and in which the polythiolation confers antioxidant activity. The aim of this study was to investigate the therapeutic potential of SH-Man-HSA in NASH model mice. In livers from mice and/or patients with NASH, we observed a reduced blood flow in the liver lobes and the down-regulation in MRC1 expression in Kupffer cells, and SH-Man-HSA alone failed to improve the pathological phenotype in NASH. However, the administration of a nitric oxide (NO) donor restored hepatic blood flow and increased the expression of the mannose receptor C type 2 (MRC2) instead of MRC1. Consequently, treatment with a combination of SH-Man-HSA and an NO donor improved oxidative stress-associated pathology. Finally, we developed a hybrid type of nano-antioxidant (SNO-Man-HSA) via the S-nitrosation of SH-Man-HSA. This nanomedicine efficiently delivered both NO and thiol groups to the liver, with a hepatoprotective effect that was comparable to the combination therapy of SH-Man-HSA and an NO donor. These findings suggest that SNO-Man-HSA has the potential for functioning as a novel nano-therapy for the treatment of NASH.
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Affiliation(s)
- Hitoshi Maeda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Department of Internal Medicine, Sections of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Yu Ishima
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Junji Saruwatari
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuki Mizuta
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuki Minayoshi
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shota Ichimizu
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroki Yanagisawa
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Taisei Nagasaki
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kengo Yasuda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shun Oshiro
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Manabu Taura
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA; Laboratory of Bioresponse Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Matthew J McConnell
- Department of Internal Medicine, Sections of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Kentaro Oniki
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kayoko Sonoda
- Department of Histology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Tomohiko Wakayama
- Department of Histology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Manabu Kinoshita
- Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan
| | - Tsuyoshi Shuto
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hirofumi Kai
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Motohiko Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yutaka Sasaki
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yasuko Iwakiri
- Department of Internal Medicine, Sections of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Masaki Otagiri
- Faculty of Pharmaceutical Sciences and DDS Research Institute, Sojo University, Kumamoto, Japan
| | - Hiroshi Watanabe
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
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22
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Nour OA, Ghoniem HA, Nader MA, Suddek GM. Impact of protocatechuic acid on high fat diet-induced metabolic syndrome sequelae in rats. Eur J Pharmacol 2021; 907:174257. [PMID: 34129881 DOI: 10.1016/j.ejphar.2021.174257] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/02/2021] [Accepted: 06/11/2021] [Indexed: 01/03/2023]
Abstract
The study aimed to assess the possible protective impact of protocatechuic acid (PCA) on high fat diet (HFD)-induced metabolic syndrome (Mets) sequelae in rats. Forty-two male Sprague-Dawley (SD) rats were randomly grouped as follows: CTR group; PCA group; HFD group; HFD-PCA group and HFD-MET group. Rats were fed on standard diet or HFD for 14 weeks. HFD-fed rats exhibited significant decreases in food intake and adiponectin (ADP) level; yet, body weight and anthropometrical parameters were significantly increased. Moreover, insulin sensitivity was impaired as indicated by significant elevation in glucose AUC during oral glucose tolerance test (OGTT), fasting serum glucose, fasting serum insulin and homeostasis model assessment of insulin resistance (HOMA-IR) index. Furthermore, chronic HFD feeding elicited significant increases in serum lipid profile and free fatty acids (FFAs) with concomitant hepatic steatosis. Additionally, serum C-reactive protein (CRP), interleukin 1b (Il-1b) and monocyte chemoattractant protein 1(MCP-1) levels were increased. Also, HFD-fed rats exhibited an increase in MDA level, while superoxide dismutase (SOD) and glutathione (GSH) activities were decreased. Moreover, the insulin-signaling pathway was markedly impaired in soleus muscles as indicated by a decrease in insulin-induced AKT phosphorylation. Histopathologically, adipose tissues showed significant increase in adipocyte size. Also, flow cytometry analysis of adipose tissue confirmed a significant increase in the percentage of number of CD68+ cells. PCA administration succeeded to attenuate HFD-induced obesity, insulin resistance, oxidative stress and inflammation. In conclusion, PCA administration could protect against HFD-induced Mets, possibly via its hypoglycemic, insulin-sensitizing, anti-oxidant and anti-inflammatory effects.
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Affiliation(s)
- Omnia A Nour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
| | - Hamdy A Ghoniem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Manar A Nader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Ghada M Suddek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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23
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Wisse E, Braet F, Shami GJ, Zapotoczny B, Vreuls C, Verhaegh P, Frederik P, Peters PJ, Olde Damink S, Koek G. Fat causes necrosis and inflammation in parenchymal cells in human steatotic liver. Histochem Cell Biol 2021; 157:27-38. [PMID: 34524512 PMCID: PMC8755686 DOI: 10.1007/s00418-021-02030-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 02/07/2023]
Abstract
Adapted fixation methods for electron microscopy allowed us to study liver cell fine structure in 217 biopsies of intact human livers over the course of 10 years. The following novel observations and concepts arose: single fat droplets in parenchymal cells can grow to a volume four times larger than the original cell, thereby extremely marginalizing the cytoplasm with all organelles. Necrosis of single parenchymal cells, still containing one huge fat droplet, suggests death by fat in a process of single-cell steatonecrosis. In a later stage of single-cell steatonecrosis, neutrophils and erythrocytes surround the single fat droplet, forming an inflammatory fat follicle indicating the apparent onset of inflammation. Also, fat droplets frequently incorporate masses of filamentous fragments and other material, most probably representing Mallory substance. No other structure or material was found that could possibly represent Mallory bodies. We regularly observe the extrusion of huge fat droplets, traversing the peripheral cytoplasm of parenchymal cells, the Disse space and the endothelium. These fat droplets fill the sinusoid as a sinusoidal lipid embolus. In conclusion, adapted methods of fixation applied to human liver tissue revealed that single, huge fat droplets cause necrosis and inflammation in single parenchymal cells. Fat droplets also collect Mallory substance and give rise to sinusoidal fat emboli. Therefore, degreasing of the liver seems to be an essential therapeutic first step in the self-repairing of non-alcoholic fatty liver disease. This might directly reduce single-cell steatotic necrosis and inflammation as elements in non-alcoholic steatohepatitis progression.
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Affiliation(s)
- Eddie Wisse
- Division of Nanoscopy, University of Maastricht Multimodal Molecular Imaging Institute, Maastricht, 6229, The Netherlands.
| | - Filip Braet
- School of Medical Sciences (Discipline of Anatomy and Histology) & Australian Centre for Microscopy & Microanalysis, The University of Sydney, Sydney, NSW, 2006, Australia.
| | - Gerald J Shami
- School of Medical Sciences (Discipline of Anatomy and Histology) & Australian Centre for Microscopy & Microanalysis, The University of Sydney, Sydney, NSW, 2006, Australia
| | | | - Celien Vreuls
- Department of Pathology, Utrecht University Medical Centre, Utrtecht, The Netherlands
| | - Pauline Verhaegh
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center, 6229 HX, Maastricht, The Netherlands
| | - Peter Frederik
- Emeritus of Maastricht University, Jekerstraat 39, 6211 NS, Maastricht, The Netherlands
| | - Peters J Peters
- Division of Nanoscopy, University of Maastricht Multimodal Molecular Imaging Institute, Maastricht, 6229, The Netherlands
| | - Steven Olde Damink
- Department of Surgery, Maastricht University Medical Center, 6229 HX, Maastricht, The Netherlands
| | - Ger Koek
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center, 6229 HX, Maastricht, The Netherlands
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24
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Große-Segerath L, Lammert E. Role of vasodilation in liver regeneration and health. Biol Chem 2021; 402:1009-1019. [PMID: 33908220 DOI: 10.1515/hsz-2021-0155] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/12/2021] [Indexed: 12/14/2022]
Abstract
Recently, we have shown that an enhanced blood flow through the liver triggers hepatocyte proliferation and thereby liver growth. In this review, we first explain the literature on hepatic blood flow and its changes after partial hepatectomy (PHx), before we present the different steps of liver regeneration that take place right after the initial hemodynamic changes induced by PHx. Those parts of the molecular mechanisms governing liver regeneration, which are directly associated with the hepatic vascular system, are subsequently reviewed. These include β1 integrin-dependent mechanotransduction in liver sinusoidal endothelial cells (LSECs), triggering mechanically-induced activation of the vascular endothelial growth factor receptor-3 (VEGFR3) and matrix metalloproteinase-9 (MMP9) as well as release of growth-promoting angiocrine signals. Finally, we speculate how advanced age and obesity negatively affect the hepatic vasculature and thus liver regeneration and health, and we conclude our review with some recent technical progress in the clinic that employs liver perfusion. In sum, the mechano-elastic properties and alterations of the hepatic vasculature are key to better understand and influence liver health, regeneration, and disease.
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Affiliation(s)
- Linda Große-Segerath
- Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, D-85764 Neuherberg, Germany
| | - Eckhard Lammert
- Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, D-85764 Neuherberg, Germany
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25
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Carr RM. VCAM-1: closing the gap between lipotoxicity and endothelial dysfunction in nonalcoholic steatohepatitis. J Clin Invest 2021; 131:147556. [PMID: 33720049 DOI: 10.1172/jci147556] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) results in the accumulation of fat in the liver and can progress as an inflammatory disorder with considerable vascular endothelial dysfunction known as nonalcoholic steatohepatitis (NASH). Inflammatory signals can trigger the expression of vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells. VCAM-1 is a surface protein that induces adherence and extravasation of monocytes to blood vessels. In this issue of the JCI, Furuta et al. report on their sequencing of RNA transcripts from the livers of mice fed a NASH-inducing diet. VCAM-1 was upregulated in the whole liver as well as liver sinusoidal endothelial cells (LSECs). When the researchers incubated LSECs with palmitate, a toxic lipid, VCAM-1 was upregulated. Notably, inhibiting VCAM-1 in the NASH model reduced VCAM-1 expression, lessened infiltrating macrophages, and mitigated fibrosis. This study connects steatosis to endothelial dysfunction and inflammation and suggests that targeting VCAM-1 may address fibrosis in patients with NASH.
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26
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Effect of Adrenergic Agonists on High-Fat Diet-Induced Hepatic Steatosis in Mice. Int J Mol Sci 2020; 21:ijms21249392. [PMID: 33321735 PMCID: PMC7764675 DOI: 10.3390/ijms21249392] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/07/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
The autonomic nervous system, consisting of sympathetic and parasympathetic branches, plays an important role in regulating metabolic homeostasis. The sympathetic nervous system (SNS) regulates hepatic lipid metabolism by regulating adrenergic receptor activation, resulting in the stimulation of hepatic very-low-density lipoprotein-triglyceride (TG) production in vivo. However, only a few studies on the relationship between SNS and hepatic steatosis have been reported. Here, we investigate the effect of adrenergic receptor agonists on hepatic steatosis in mice fed a high-fat diet (HFD). The α-adrenergic receptor agonist phenylephrine (10 mg/kg/d) or the β-adrenergic receptor agonist isoproterenol (30 mg/kg/d) was coadministered with HFD to male mice. After five weeks, hepatic steatosis, TG levels, and hepatic fat metabolism-related biomarkers were examined. HFD treatment induced hepatic steatosis, and cotreatment with phenylephrine, but not isoproterenol, attenuated this effect. Phenylephrine administration upregulated the mRNA levels of hepatic peroxisome proliferator-activated receptor alpha and its target genes (such as carnitine palmitoyltransferase 1) and increased hepatic β-hydroxybutyrate levels. Additionally, phenylephrine treatment increased the expression of the autophagosomal marker LC3-II but decreased that of p62, which is selectively degraded during autophagy. These results indicate that phenylephrine inhibits hepatic steatosis through stimulation of β-oxidation and autophagy in the liver.
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27
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Preguiça I, Alves A, Nunes S, Fernandes R, Gomes P, Viana SD, Reis F. Diet-induced rodent models of obesity-related metabolic disorders-A guide to a translational perspective. Obes Rev 2020; 21:e13081. [PMID: 32691524 DOI: 10.1111/obr.13081] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/12/2020] [Accepted: 05/28/2020] [Indexed: 12/12/2022]
Abstract
Diet is a critical element determining human health and diseases, and unbalanced food habits are major risk factors for the development of obesity and related metabolic disorders. Despite technological and pharmacological advances, as well as intensification of awareness campaigns, the prevalence of metabolic disorders worldwide is still increasing. Thus, novel therapeutic approaches with increased efficacy are urgently required, which often depends on cellular and molecular investigations using robust animal models. In the absence of perfect rodent models, those induced by excessive consumption of fat and sugars better replicate the key aspects that are the root causes of human metabolic diseases. However, the results obtained using these models cannot be directly compared, particularly because of the use of different dietary protocols, and animal species and strains, among other confounding factors. This review article revisits diet-induced models of obesity and related metabolic disorders, namely, metabolic syndrome, prediabetes, diabetes and nonalcoholic fatty liver disease. A critical analysis focused on the main pathophysiological features of rodent models, as opposed to the criteria defined for humans, is provided as a practical guide with a translational perspective for the establishment of animal models of obesity-related metabolic diseases.
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Affiliation(s)
- Inês Preguiça
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal
| | - André Alves
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal
| | - Sara Nunes
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal
| | - Rosa Fernandes
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal
| | - Pedro Gomes
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal.,Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.,Center for Health Technology and Services Research (CINTESIS), University of Porto, Porto, Portugal
| | - Sofia D Viana
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal.,ESTESC-Coimbra Health School, Pharmacy, Polytechnic Institute of Coimbra, Coimbra, Portugal
| | - Flávio Reis
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal
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28
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Miyachi Y, Yagi S, Hirata M, Iwamura S, Yao S, Shirai H, Okumura S, Iida T, Ito T, Uozumi R, Kaido T, Uemoto S. Etiology of Liver Steatosis Influences the Severity of Ischemia/Reperfusion Injury and Survival After Liver Transplantation in Rats. Liver Transpl 2020; 26:1504-1515. [PMID: 32511857 DOI: 10.1002/lt.25814] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/27/2020] [Accepted: 05/21/2020] [Indexed: 01/13/2023]
Abstract
Liver steatosis is a leading cause of graft disposal in liver transplantation, though the degree of steatosis is often the single factor determining acceptability of the graft. We investigated how the cause of liver steatosis affects graft function in rat orthotopic liver transplantation (OLT). OLT was performed using 2 types of steatotic liver grafts: the fasting and hyperalimentation (FHA) model and the methionine- and choline-deficient diet models. The FHA and 4-week feeding of a methionine- and choline-deficient diet (MCDD4wk) groups showed similar liver triglyceride levels without signs of steatohepatitis. Therefore, the 2 groups were compared in the following experiment. With 6-hour cold storage, the 7-day survival rate after OLT was far worse in the FHA than in the MCDD4wk group (0% versus 100%, P = 0.002). With 1-hour cold storage, the FHA group showed higher aspartate aminotransferase and alanine aminotransferase levels and histological injury scores in zones 1 and 2 at 24 hours after reperfusion than the normal liver and MCDD4wk groups. Intrahepatic microcirculation and tissue adenosine triphosphate levels were significantly lower in the FHA group after reperfusion. Hepatocyte necrosis, sinusoidal endothelial cell injury, and abnormal swelling of the mitochondria were also found in the FHA group after reperfusion. Tissue malondialdehyde levels were higher in the MCDD4wk group before and after reperfusion. However, the grafts up-regulated several antioxidant enzymes soon after reperfusion. Even though the degree of steatosis was equivalent, the 2 liver steatosis models possessed quite unique basal characteristics and showed completely different responses against ischemia/reperfusion injury and survival after transplantation. Our results demonstrate that the degree of fat accumulation is not a single determinant for the usability of steatotic liver grafts.
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Affiliation(s)
- Yosuke Miyachi
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Shintaro Yagi
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Masaaki Hirata
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Sena Iwamura
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Siyuan Yao
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Hisaya Shirai
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Shinya Okumura
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Taku Iida
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Takashi Ito
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Ryuji Uozumi
- Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshimi Kaido
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan
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Özkan A, Stolley D, Cressman ENK, McMillin M, DeMorrow S, Yankeelov TE, Rylander MN. The Influence of Chronic Liver Diseases on Hepatic Vasculature: A Liver-on-a-chip Review. MICROMACHINES 2020; 11:E487. [PMID: 32397454 PMCID: PMC7281532 DOI: 10.3390/mi11050487] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/02/2020] [Accepted: 05/04/2020] [Indexed: 12/13/2022]
Abstract
In chronic liver diseases and hepatocellular carcinoma, the cells and extracellular matrix of the liver undergo significant alteration in response to chronic injury. Recent literature has highlighted the critical, but less studied, role of the liver vasculature in the progression of chronic liver diseases. Recent advancements in liver-on-a-chip systems has allowed in depth investigation of the role that the hepatic vasculature plays both in response to, and progression of, chronic liver disease. In this review, we first introduce the structure, gradients, mechanical properties, and cellular composition of the liver and describe how these factors influence the vasculature. We summarize state-of-the-art vascularized liver-on-a-chip platforms for investigating biological models of chronic liver disease and their influence on the liver sinusoidal endothelial cells of the hepatic vasculature. We conclude with a discussion of how future developments in the field may affect the study of chronic liver diseases, and drug development and testing.
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Affiliation(s)
- Alican Özkan
- Department of Mechanical Engineering, The University of Texas, Austin, TX 78712, USA
| | - Danielle Stolley
- Department of Biomedical Engineering, The University of Texas, Austin, TX 78712, USA
| | - Erik N K Cressman
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Matthew McMillin
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX 78713, USA
- Central Texas Veterans Health Care System, Temple, TX 76504, USA
| | - Sharon DeMorrow
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX 78713, USA
- Central Texas Veterans Health Care System, Temple, TX 76504, USA
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA
| | - Thomas E Yankeelov
- Department of Biomedical Engineering, The University of Texas, Austin, TX 78712, USA
- Oden Institute for Computational Engineering and Sciences, The University of Texas, Austin, TX 78712, USA
- Departments of Diagnostic Medicine, The University of Texas, Austin, TX 78712, USA
- Department of Oncology, The University of Texas, Austin, TX 78712, USA
- Livestrong Cancer Institutes, Dell Medical School, The University of Texas, Austin, TX 78712, USA
| | - Marissa Nichole Rylander
- Department of Mechanical Engineering, The University of Texas, Austin, TX 78712, USA
- Department of Biomedical Engineering, The University of Texas, Austin, TX 78712, USA
- Oden Institute for Computational Engineering and Sciences, The University of Texas, Austin, TX 78712, USA
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Hammoutene A, Biquard L, Lasselin J, Kheloufi M, Tanguy M, Vion AC, Mérian J, Colnot N, Loyer X, Tedgui A, Codogno P, Lotersztajn S, Paradis V, Boulanger CM, Rautou PE. A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis. J Hepatol 2020; 72:528-538. [PMID: 31726115 DOI: 10.1016/j.jhep.2019.10.028] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 10/15/2019] [Accepted: 10/28/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Previous studies demonstrated that autophagy is protective in hepatocytes and macrophages, but detrimental in hepatic stellate cells in chronic liver diseases. The role of autophagy in liver sinusoidal endothelial cells (LSECs) in non-alcoholic steatohepatitis (NASH) is unknown. Our aim was to analyze the potential implication of autophagy in LSECs in NASH and liver fibrosis. METHODS We analyzed autophagy in LSECs from patients using transmission electron microscopy. We determined the consequences of a deficiency in autophagy: (a) on LSEC phenotype, using primary LSECs and an LSEC line; (b) on early stages of NASH and on advanced stages of liver fibrosis, using transgenic mice deficient in autophagy specifically in endothelial cells and fed a high-fat diet or chronically treated with carbon tetrachloride, respectively. RESULTS Patients with NASH had half as many LSECs containing autophagic vacuoles as patients without liver histological abnormalities, or with simple steatosis. LSECs from mice deficient in endothelial autophagy displayed an upregulation of genes implicated in inflammatory pathways. In the LSEC line, deficiency in autophagy enhanced inflammation (Ccl2, Ccl5, Il6 and VCAM-1 expression), features of endothelial-to-mesenchymal transition (α-Sma, Tgfb1, Col1a2 expression) and apoptosis (cleaved caspase-3). In mice fed a high-fat diet, deficiency in endothelial autophagy induced liver expression of inflammatory markers (Ccl2, Ccl5, Cd68, Vcam-1), liver cell apoptosis (cleaved caspase-3) and perisinusoidal fibrosis. Mice deficient in endothelial autophagy treated with carbon tetrachloride also developed more perisinusoidal fibrosis. CONCLUSIONS A defect in autophagy in LSECs occurs in patients with NASH. Deficiency in endothelial autophagy promotes the development of liver inflammation, features of endothelial-to-mesenchymal transition, apoptosis and liver fibrosis in the early stages of NASH, but also favors more advanced stages of liver fibrosis. LAY SUMMARY Autophagy is a physiological process controlling endothelial homeostasis in vascular beds outside the liver. This study demonstrates that autophagy is defective in the liver endothelial cells of patients with non-alcoholic steatohepatitis. This defect promotes liver inflammation and fibrosis at early stages of non-alcoholic steatohepatitis, but also at advanced stages of chronic liver disease.
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Affiliation(s)
- Adel Hammoutene
- Université de Paris, PARCC, INSERM, F-75015, Paris, France; Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75018, Paris, France
| | - Louise Biquard
- Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75018, Paris, France
| | | | | | - Marion Tanguy
- Université de Paris, PARCC, INSERM, F-75015, Paris, France; Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75018, Paris, France
| | | | - Jules Mérian
- Université de Paris, PARCC, INSERM, F-75015, Paris, France
| | - Nathalie Colnot
- Service d'Anatomie Pathologique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France
| | - Xavier Loyer
- Université de Paris, PARCC, INSERM, F-75015, Paris, France
| | - Alain Tedgui
- Université de Paris, PARCC, INSERM, F-75015, Paris, France
| | - Patrice Codogno
- Université de Paris, INEM, INSERM, F-75014, Paris, France; CNRS UMR-8253, 75014, Paris, France
| | - Sophie Lotersztajn
- Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75018, Paris, France
| | - Valérie Paradis
- Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75018, Paris, France; Service d'Anatomie Pathologique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France
| | | | - Pierre-Emmanuel Rautou
- Université de Paris, PARCC, INSERM, F-75015, Paris, France; Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75018, Paris, France; Service d'Hépatologie, DHU Unity, DMU Digest, Hôpital Beaujon, AP-HP, Clichy, France; Centre de Référence des Maladies Vasculaires du Foie, French Network for Rare Liver Diseases (FILFOIE), European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
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Pereira ENGDS, Silvares RR, Flores EEI, Rodrigues KL, Daliry A. Pyridoxamine improves metabolic and microcirculatory complications associated with nonalcoholic fatty liver disease. Microcirculation 2020; 27:e12603. [PMID: 31876010 DOI: 10.1111/micc.12603] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE We investigated the protective effects of pyridoxamine against metabolic and microcirculatory complications in nonalcoholic fatty liver disease. METHODS Nonalcoholic fatty liver disease was established by a high-fat diet administration over 28 weeks. Pyridoxamine was administered between weeks 20 and 28. The recruitment of leukocytes and the number of vitamin A-positive hepatic stellate cells were examined by in vivo microscopy. Laser speckle contrast imaging was used to evaluate microcirculatory hepatic perfusion. Thiobarbituric acid reactive substances measurement and RT-PCR were used for oxidative stress and inflammatory parameters. advanced glycation end products were evaluated by fluorescence spectroscopy. RESULTS The increase in body, liver, and fat weights, together with steatosis and impairment in glucose metabolism observed in the nonalcoholic fatty liver disease group were attenuated by pyridoxamine treatment. Regarding the hepatic microcirculatory parameters, rats with high-fat diet-induced nonalcoholic fatty liver disease showed increased rolling and adhesion of leukocytes, increased hepatic stellate cells activation, and decreased tissue perfusion, which were reverted by pyridoxamine. Pyridoxamine protected against the increased hepatic lipid peroxidation observed in the nonalcoholic fatty liver disease group. Pyridoxamine treatment was associated with increased levels of tumor necrosis factor alpha (TNF-α) mRNA transcripts in the liver. CONCLUSION Pyridoxamine modulates oxidative stress, advanced glycation end products, TNF-α transcripts levels, and metabolic disturbances, being a potential treatment for nonalcoholic fatty liver disease-associated microcirculatory and metabolic complications.
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Affiliation(s)
| | - Raquel Rangel Silvares
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | | | - Karine Lino Rodrigues
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Anissa Daliry
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
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Hobeika C, Ronot M, Beaufrere A, Paradis V, Soubrane O, Cauchy F. Metabolic syndrome and hepatic surgery. J Visc Surg 2019; 157:231-238. [PMID: 31866269 DOI: 10.1016/j.jviscsurg.2019.11.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In Europe, the prevalence of metabolic syndrome (MS) has reached the endemic rate of 25%. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of MS. Its definition is histological, bringing together the different lesions associated with hepatic steatosis (fat deposits on more than 5% of hepatocytes) without alcohol consumption and following exclusion of other causes. MS and NAFLD are implicated in the carcinogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). At present, HCC and ICC involving MS represent 15-20% and 20-30% respectively of indications for hepatic resection in HCC and ICC. Moreover, in the industrialized nations NAFLD is tending to become the most frequent indication for liver transplantation. MS patients combine the operative risk associated with their general condition and comorbidities and the risk associated with the presence and/or severity of NAFLD. Following hepatic resection in cases of HCC and ICC complicating MS, the morbidity rate ranges from 20 to 30%, and due to cardiovascular and infectious complications, post-transplantation mortality is heightened. The operative risk incurred by MS patients necessitates appropriate management including: (i) precise characterization of the subjacent liver; (ii) an accurately targeted approach privileging detection and optimization of treatment taking into account the relevant cardiovascular risk factors; (iii) a surgical strategy adapted to the histology of the underlying liver, with optimization of the volume of the remaining (postoperative) liver.
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Affiliation(s)
- C Hobeika
- Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, Hôpital Beaujon, AP-HP et Université de Paris, 100, boulevard du Général Leclerc, 92110, Clichy, France
| | - M Ronot
- Service de radiologie, Hôpital Beaujon, AP-HP et Université de Paris, 100, boulevard du Général Leclerc, 92110, Clichy, France
| | - A Beaufrere
- Service d'anatomo-pathologie, Hôpital Beaujon, AP-HP et Université de Paris, 100, boulevard du Général Leclerc, 92110, Clichy, France
| | - V Paradis
- Service d'anatomo-pathologie, Hôpital Beaujon, AP-HP et Université de Paris, 100, boulevard du Général Leclerc, 92110, Clichy, France
| | - O Soubrane
- Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, Hôpital Beaujon, AP-HP et Université de Paris, 100, boulevard du Général Leclerc, 92110, Clichy, France
| | - F Cauchy
- Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, Hôpital Beaujon, AP-HP et Université de Paris, 100, boulevard du Général Leclerc, 92110, Clichy, France.
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Li C, Ye J, Peng Y, Dou W, Shang S, Wu J, Jafari R, Gillen KM, Wang Y, Prince M, Luo X. Evaluation of diffusion kurtosis imaging in stratification of nonalcoholic fatty liver disease and early diagnosis of nonalcoholic steatohepatitis in a rabbit model. Magn Reson Imaging 2019; 63:267-273. [PMID: 31445117 DOI: 10.1016/j.mri.2019.08.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 08/19/2019] [Accepted: 08/21/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE To examine the feasibility of MR diffusion kurtosis imaging (DKI) for characterizing nonalcoholic fatty liver disease (NAFLD) and diagnosing nonalcoholic steatohepatitis (NASH). METHODS Thirty-two rabbits on high fat diet with different severities of NAFLD were imaged at 3 T MR including diffusion weighted imaging (DWI) and DKI using b values of 0, 400, 800 s/mm2 with 15 diffusion directions at each b value. Apparent diffusion coefficient (ADC) was derived from the linear exponential DWI model. Mean diffusion (MD) and mean kurtosis (MK) were derived from the quadratic exponential model of DKI. Correlations between MR parameters and hepatic pathology determined by the NAFLD activity scoring system were analyzed by Spearman rank correlation analysis. Receiver operating characteristic analyses were applied to determine the cutoff values of MD, MK as well as ADC in distinguishing NASH from non-NASH. The diagnostic efficacies of MD and MK in detecting NASH were compared with that of ADC. RESULTS Values for ADC and MD significantly decreased as the severity of NAFLD increased (ρ = -0.529, -0.904, respectively; P < 0.05). MK values significantly increased as the severity of NAFLD increased (ρ = 0.761; P < 0.05). In addition, both MD and MK values were significantly different between borderline NASH and NASH groups (MD: 1.729 ± 0.144 vs. 1.458 ± 0.240[×10-3 mm2/s]; MK: 1.096 ± 0.079 vs. 1.237 ± 0.180; P < 0.05). Moreover, there was a significantly higher area under the curve (AUC) for both MD (0.955) and MK (0.905), as compared to ADC (0.736). CONCLUSION Diffusion kurtosis imaging was feasible for stratifying NAFLD, and more accurately discriminated NASH from non-NASH when compared with DWI.
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Affiliation(s)
- Chang Li
- Department of Radiology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, No. 98 Nantong West Road, Yangzhou 225001, China; Xiangya School of Medicine, Central South University, No. 172 Tongzipo Road, Changsha 410013, China
| | - Jing Ye
- Department of Radiology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, No. 98 Nantong West Road, Yangzhou 225001, China
| | - Yun Peng
- Department of Radiology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, No. 98 Nantong West Road, Yangzhou 225001, China; Xiangya School of Medicine, Central South University, No. 172 Tongzipo Road, Changsha 410013, China
| | - Weiqiang Dou
- GE Healthcare, MR Research China, Beijing, China
| | - Songan Shang
- Department of Radiology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, No. 98 Nantong West Road, Yangzhou 225001, China; Xiangya School of Medicine, Central South University, No. 172 Tongzipo Road, Changsha 410013, China
| | - Jingtao Wu
- Department of Radiology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, No. 98 Nantong West Road, Yangzhou 225001, China
| | - Ramin Jafari
- Department of Radiology, Weill Medical College of Cornell University, 407 E 61st Street, New York, NY 10065, USA
| | - Kelly McCabe Gillen
- Department of Radiology, Weill Medical College of Cornell University, 407 E 61st Street, New York, NY 10065, USA
| | - Yi Wang
- Department of Radiology, Weill Medical College of Cornell University, 407 E 61st Street, New York, NY 10065, USA; Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - Martin Prince
- Department of Radiology, Weill Medical College of Cornell University, 407 E 61st Street, New York, NY 10065, USA
| | - Xianfu Luo
- Department of Radiology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, No. 98 Nantong West Road, Yangzhou 225001, China.
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Layman JI, Pereira DL, Chellan N, Huisamen B, Kotzé SH. A histomorphometric study on the hepatoprotective effects of a green rooibos extract in a diet-induced obese rat model. Acta Histochem 2019; 121:646-656. [PMID: 31153588 DOI: 10.1016/j.acthis.2019.05.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 05/21/2019] [Accepted: 05/21/2019] [Indexed: 12/17/2022]
Abstract
Obesity, type two diabetes mellitus and insulin resistance are associated with increased oxidative stress and inflammation. Unfermented green rooibos is an aspalathin rich variant of traditional fermented rooibos (Aspalathus linearis) and has a high polyphenol content. The present study aimed to determine the histologically observable effects of a commercially produced, aspalathin-rich green rooibos extract, Afriplex GRT™ (GRE) in a diet-induced obese rat model. Male Wistar rats (N = 28) were randomly assigned to four study groups (n = 7): control (C), green rooibos (GRT), high-fat diet (HFD) and experimental (HFD-GRT) group. Body mass was determined prior to euthanasia and liver mass was determined after death. The left lateral lobe of the liver was processed to wax and stained using haematoxylin and eosin (H & E), Masson's trichrome stain, Gordons and Sweet's reticulin impregnation and periodic acid-Schiff stain. Frozen liver tissue sections were used for Oil red O staining. Morphometric quantification of steatosis, semiquantitative pathology grading and scoring were performed and verified by a veterinary histopathologist. A significant increase in body and liver mass was observed in the HFD groups while co-treatment with green rooibos significantly reduced both. The volume and area of steatosis were significantly increased in the HFD groups while the area of steatosis significantly reduced with green rooibos co-treatment. The percentage, location and type of steatosis as well as presence of inflammation and hepatocellular injury were reduced in the HFD group co-treated with GRE. These findings suggest that a GRE has potential as an anti-steatotic, anti-inflammatory and weight reducing agent in vivo.
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Affiliation(s)
- J I Layman
- Division of Clinical Anatomy, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
| | - D L Pereira
- Division of Clinical Anatomy, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
| | - N Chellan
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
| | - B Huisamen
- Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa; Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
| | - S H Kotzé
- Division of Clinical Anatomy, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.
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Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 2019; 16:411-428. [PMID: 31028350 DOI: 10.1038/s41575-019-0145-7] [Citation(s) in RCA: 949] [Impact Index Per Article: 158.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Caloric excess and sedentary lifestyle have led to a global epidemic of obesity and metabolic syndrome. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), is estimated to affect up to one-third of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Owing to the high prevalence of NAFLD, especially in industrialized countries but also worldwide, and the consequent burden of progressive liver disease, there is mounting epidemiological evidence that NAFLD has rapidly become a leading aetiology underlying many cases of hepatocellular carcinoma (HCC). In this Review, we discuss NAFLD-associated HCC, including its epidemiology, the key features of the hepatic NAFLD microenvironment (for instance, adaptive and innate immune responses) that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities. The challenges and future directions of research will also be discussed, including clinically relevant biomarkers for early detection, treatment stratification and monitoring as well as approaches to therapies for both prevention and treatment in those at risk or presenting with NAFLD-associated HCC.
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Affiliation(s)
- Quentin M Anstee
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- The Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
| | - Helen L Reeves
- The Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
- Northern Institute for Cancer Research, Medical School, Newcastle upon Tyne, UK
- Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Elena Kotsiliti
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Olivier Govaere
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Eriksen PL, Thomsen KL, Larsen LP, Grønbaek H, Vilstrup H, Sørensen M. Non-alcoholic steatohepatitis, but not simple steatosis, disturbs the functional homogeneity of the liver - a human galactose positron emission tomography study. Aliment Pharmacol Ther 2019; 50:84-92. [PMID: 31099410 DOI: 10.1111/apt.15293] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 02/12/2019] [Accepted: 04/18/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND The disease severity of non-alcoholic fatty liver disease (NAFLD) and the distinction between simple steatosis and non-alcoholic steatohepatitis (NASH) are based on the pathohistological presence of steatosis, inflammation, ballooning and fibrosis. However, little is known about the relation between such structural changes and the function of the afflicted liver. AIMS To investigate in vivo effects of hepatic fat fraction, ballooning and fibrosis on regional and whole liver metabolic function assessed by galactose elimination in NASH and simple steatosis. METHODS Twenty-five biopsy-proven, nondiabetic patients with NAFLD (13 NASH with low-grade fibrosis, 12 simple steatosis with no fibrosis) underwent 2-[18 F]fluoro-2-deoxy-d-galactose positron emission tomography and magnetic resonance imaging-derived proton density fat fraction of the liver. Nine healthy persons were included as controls. RESULTS In the NASH patients, the standardised hepatic uptake of 2-[18 F]fluoro-2-deoxy-d-galactose was reduced to 13.5 (95% confidence interval, 12.1-14.9) as compared with both simple steatosis and controls (16.4 (15.6-17.1), P < 0.001). Thus, the NASH patients had reduced regional metabolic liver function. The liver fat fraction diluted the standardised uptake equally in NASH and simple steatosis but the fibrosis and ballooning of NASH were associated with a further decrease. Moreover, the NASH livers exhibited increased variation in their standardised uptake values (coefficient of variation 13.8% vs 11.6% in simple steatosis and 10.2% in controls, P = 0.02), reflecting an increased functional heterogeneity. CONCLUSIONS In NASH, the regional metabolic liver function was lower and more heterogeneous than in both simple steatosis and healthy controls. Thus, NASH disturbs the normal homogeneous metabolic function of the liver.
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Affiliation(s)
- Peter Lykke Eriksen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Karen Louise Thomsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Lars Peter Larsen
- Department of Radiology, Aarhus University Hospital, Aarhus N, Denmark
| | - Henning Grønbaek
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
| | - Michael Sørensen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark.,Department of Nuclear Medicine & PET-Centre, Aarhus University Hospital, Aarhus N, Denmark
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Wang X, Li L, Wang H, Xiao F, Ning Q. Epoxyeicosatrienoic acids alleviate methionine‐choline‐deficient diet–induced non‐alcoholic steatohepatitis in mice. Scand J Immunol 2019; 90:e12791. [PMID: 31132306 DOI: 10.1111/sji.12791] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 05/14/2019] [Accepted: 05/17/2019] [Indexed: 12/26/2022]
Affiliation(s)
- Xiaojing Wang
- Department and Institute of Infectious Disease Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Lan Li
- Department and Institute of Infectious Disease Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Hongwu Wang
- Department and Institute of Infectious Disease Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Fang Xiao
- Department and Institute of Infectious Disease Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Qin Ning
- Department and Institute of Infectious Disease Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
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Jiang M, Wu N, Chen X, Wang W, Chu Y, Liu H, Li W, Chen D, Li X, Xu B. Pathogenesis of and major animal models used for nonalcoholic fatty liver disease. J Int Med Res 2019; 47:1453-1466. [PMID: 30871397 PMCID: PMC6460620 DOI: 10.1177/0300060519833527] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and its pathologically more severe form, nonalcoholic steatohepatitis (NASH), have become prevalent worldwide and carry an increased risk of developing hepatocellular carcinoma and other metabolic diseases. Diverse animal models have been proposed to replicate particular characteristics of NAFLD and NASH and have provided significant clues to the critical molecular targets of NASH treatment. In this review, we summarize the histopathology, pathogenesis, and molecular basis of NAFLD progression and discuss the benchmark animal models of NAFLD/NASH.
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Affiliation(s)
- Mingzuo Jiang
- 1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, The Air-Force Military Medical University, Xi'an, Shaanxi, China
| | - Nan Wu
- 2 Laboratory of Tissue Engineering, Faculty of Life Science, Northwest University, Xi'an, Shaanxi, China
| | - Xi Chen
- 3 Department of Surgical Anesthesiology, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi'an, Shaanxi, China
| | - Weijie Wang
- 1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, The Air-Force Military Medical University, Xi'an, Shaanxi, China
| | - Yi Chu
- 1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, The Air-Force Military Medical University, Xi'an, Shaanxi, China
| | - Hao Liu
- 1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, The Air-Force Military Medical University, Xi'an, Shaanxi, China
| | - Wenjiao Li
- 1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, The Air-Force Military Medical University, Xi'an, Shaanxi, China
| | - Di Chen
- 1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, The Air-Force Military Medical University, Xi'an, Shaanxi, China.,5 Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaowei Li
- 4 Department of Gastroenterology, PLA Navy General Hospital, Beijing, China.,5 Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Bing Xu
- 5 Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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The potential role of vascular alterations and subsequent impaired liver blood flow and hepatic hypoxia in the pathophysiology of non-alcoholic steatohepatitis. Med Hypotheses 2018; 122:188-197. [PMID: 30593409 DOI: 10.1016/j.mehy.2018.11.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 11/21/2018] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disease ranging from steatosis to steatohepatitis (NASH) and fibrosis, but the underlying pathophysiological mechanisms remain largely unknown. As there is currently no approved pharmacological therapy and the prevalence of NAFLD keeps increasing, understanding of its pathophysiology is crucial. We hypothesise that vascular alterations in early NAFLD play a role in the progression of the disease by inducing an increased intrahepatic vascular resistance and consequently relative hypoxia in the liver. Evidence of the detrimental effects of hypoxia in NAFLD has already been observed in liver surgery, where the outcomes of steatotic livers after ischaemia-reperfusion are worse than in healthy livers, and in obstructive sleep apnoea, which is an independent risk factor of NAFLD. Moreover, early histological damage in NAFLD is situated in the pericentral zone, which is also the first zone to be affected by a decreased oxygen tension because of the unique hepatic vacsular anatomy that causes the pericentral oxygen tension to be the lowest. Angiogenesis is also a characteristic of NAFLD, driven by hypoxia-induced mechanisms, as demonstrated in both animal models and in humans with NAFLD. Relative hypoxia is most probably induced by impaired blood flow to the liver, caused by increased intrahepatic vascular resistance. An increased intrahepatic vascular resistance early in the development of disease has been convincingly demonstrated in several animal models of NAFLD, whereas an increased portal pressure, a consequence of increased intrahepatic vascular resistance, has been proven in patients with NAFLD. Animal studies demonstrated a decreased intrahepatic effect of vasodilators and an increased reactivity to vasoconstrictors that results in an increased intrahepatic vascular resistance, thus the presence of a functional component. Pharmacological products that target vasoregulation can hence improve the intrahepatic vascular resistance and this might prevent or reverse progression of NAFLD, representing an important therapeutic option to study. Some of the drugs currently under evaluation in clinical trials for NASH have interesting properties related to the hepatic vasculature. Some other interesting drugs have been tested in animal models but further study in patients with NAFLD is warranted. In summary, in this paper we summarise the evidence that leads to the hypothesis that an increased intrahepatic vascular resistance and subsequent parenchymal hypoxia in early NAFLD is an important pathophysiological driving mechanism for the progression of the disease.
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Fujii T, Kuriyama N, Hayasaki A, Iizawa Y, Tanemura A, Kato H, Murata Y, Azumi Y, Kishiwada M, Mizuno S, Usui M, Sakurai H, Isaji S. Recombinant Human Soluble Thrombomodulin Attenuates Hepatic Ischemia and/or Reperfusion Injury by Inhibiting Leukocyte Accumulation in Mice With Normal and Fatty Liver. Transplant Proc 2018; 50:2807-2814. [PMID: 30401402 DOI: 10.1016/j.transproceed.2018.03.044] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 03/06/2018] [Indexed: 12/12/2022]
Abstract
UNLABELLED In an attempt to increase the number of donor livers, there has been an increased use of marginal donor livers, such as steatotic (fatty) livers that increase susceptibility to ischemia and reperfusion injury (IRI). Inflammatory cell accumulation has a greater role in IRI in steatotic liver than in normal liver. Although the recombinant human soluble thrombomodulin (rhsTM) attracts attention as a new treatment for disseminated intravascular coagulation, the therapeutic efficacy of rhsTM in hepatic IRI remains uncertain, especially in fatty livers. We aimed to demonstrate the effect of rhsTM on hepatic IRI using well-established in vivo experimental models with steatotic liver. METHODS C57/BL6 mice were divided into 2 groups: normal liver (NL) group and fatty liver (FL) group, in which the steatotic liver was induced by high-fat diet for 9 weeks. The mice in the NL and FL groups were premedicated with venous injection of rhsTM (TM) or saline (Control) as control groups. All 4 groups (NL-Control vs NL-TM, FL-Control vs FL-TM) were subjected to partial hepatic warm ischemia followed by reperfusion. RESULTS rhsTM significantly attenuated liver injury in the FL group as well as the NL group, as evidenced by transaminase levels and histologic finding after hepatic IRI. rhsTM remarkably decreased the accumulation of inflammatory cells, such as macrophages and neutrophils, in both NL and FL tissue after IRI. Furthermore, rhsTM depressed mRNA and protein expressions of adhesion molecules such as intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both NL and FL groups after IRI. CONCLUSION Our results demonstrate that rhsTM has a protective effect on fatty liver as well as normal liver after hepatic IRI. They also suggest that rhsTM contributes to attenuation of leukocyte accumulation caused by depressing expressions of adhesion molecules that facilitate accumulation of leukocytes in liver tissue in hepatic IRI.
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Affiliation(s)
- T Fujii
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan.
| | - N Kuriyama
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - A Hayasaki
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Y Iizawa
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - A Tanemura
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - H Kato
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Y Murata
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Y Azumi
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - M Kishiwada
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - S Mizuno
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - M Usui
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - H Sakurai
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - S Isaji
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
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Roh YS, Kim JW, Park S, Shon C, Kim S, Eo SK, Kwon JK, Lim CW, Kim B. Toll-Like Receptor-7 Signaling Promotes Nonalcoholic Steatohepatitis by Inhibiting Regulatory T Cells in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:2574-2588. [PMID: 30125542 DOI: 10.1016/j.ajpath.2018.07.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 06/09/2018] [Accepted: 07/10/2018] [Indexed: 12/17/2022]
Abstract
Toll-like receptor 7 (TLR7) signaling regulates the production of type 1 interferons (IFNs) and proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, implicated in the control of regulatory T (Treg) cell activity. However, the mechanistic interplay between TLR7 signaling and Treg cells in nonalcoholic steatohepatitis (NASH) has not been elucidated. Our aim was to clarify the role of TLR7 signaling in the pathogenesis of NASH. Steatohepatitis was induced in wild-type (WT), TLR7-deficient, IFN-α/β receptor 1-deficient, and Treg cell-depleted mice. TLR7-deficient and IFN-α/β receptor 1-deficient mice were more protective to steatohepatitis than WT mice. Of interest, both TNF-α and type 1 IFN promoted apoptosis of Treg cells involved in the prevention of NASH. Indeed, Treg cell-depleted mice had aggravated steatohepatitis compared with WT mice. Finally, treatment with immunoregulatory sequence 661, an antagonist of TLR7, efficiently ameliorated NASH in vivo. These results demonstrate that TLR7 signaling can induce TNF-α production in Kupffer cells and type I IFN production in dendritic cells. These cytokines subsequently induce hepatocyte death and inhibit Treg cells activities, leading to the progression of NASH. Thus, manipulating the TLR7-Treg cell axis might be used as a novel therapeutic strategy to treat NASH.
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Ultrasonographic measurement of liver, portal vein, hepatic vein and perivisceral adipose tissue in high-yielding dairy cows with fatty liver during the transition period. J DAIRY RES 2018; 85:431-438. [PMID: 30295210 DOI: 10.1017/s0022029918000754] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The aim of the present study was to evaluate the potential for diagnosis of fatty liver by means of ultrasonographic measurement of liver and perivisceral adipose tissue as an alternative to blood indicators of lipomobilization and liver biopsy in periparturient high-yielding dairy cows. Thirty cows were enrolled and divided into two groups. The evaluation of body condition score (BCS), non-esterified fatty acids (NEFA), β-hydroxybutyrate (BHB), liver and perivisceral adipose tissue ultrasonographic measurement and histological liver lipid content (GdL) was performed at 15 ± 5 d prepartum (T0), 10 ± 2 d postpartum (T1), 30 ± 2 d postpartum (T2) and 50 ± 2 d postpartum (T3). Mesenteric fat thickness (the thickness of the perivascular adipose tissue) measured on ultrasound was shown to be an independent determinant of fatty liver. The cut-off of the ultrasonographic evaluation of the liver may be useful as a first and practical approach in identifying fatty liver. In conclusion, a non-invasive and reliable diagnostic method for predicting the risk of fatty liver in high yielding dairy cows has been demonstrated.
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Van der Graaff D, Kwanten WJ, Couturier FJ, Govaerts JS, Verlinden W, Brosius I, D'Hondt M, Driessen A, De Winter BY, De Man JG, Michielsen PP, Francque SM. Severe steatosis induces portal hypertension by systemic arterial hyporeactivity and hepatic vasoconstrictor hyperreactivity in rats. J Transl Med 2018; 98:1263-1275. [PMID: 29326427 DOI: 10.1038/s41374-017-0018-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 11/30/2017] [Accepted: 12/13/2017] [Indexed: 12/27/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. The presence of portal hypertension has been demonstrated in NAFLD prior to development of inflammation or fibrosis, and is a result of extrahepatic and intrahepatic factors, principally driven by vascular dysfunction. An increased intrahepatic vascular resistance potentially contributes to progression of NAFLD via intralobular hypoxia. However, the exact mechanisms underlying vascular dysfunction in NAFLD remain unknown. This study investigates systemic hemodynamics and both aortic and intrahepatic vascular reactivity in a rat model of severe steatosis. Wistar rats were fed a methionine-choline-deficient diet, inducing steatosis, or control diet for 4 weeks. In vivo hemodynamic measurements, aortic contractility studies, and in situ liver perfusion experiments were performed. The mean arterial blood pressure was lower and portal blood pressure was higher in steatosis compared to controls. The maximal contraction force in aortic rings from steatotic rats was markedly reduced compared to controls. While blockade of nitric oxide (NO) production did not reveal any differences, cyclooxygenase (COX) blockade reduced aortic reactivity in both controls and steatosis, whereas effects were more pronounced in controls. Effects could be attributed to COX-2 iso-enzyme activity. In in situ liver perfusion experiments, exogenous NO donation or endogenous NO stimulation reduced the transhepatic pressure gradient (THPG), whereas NO synthase blockade increased the THPG only in steatosis, but not in controls. Alpha-1-adrenergic stimulation and endothelin-1 induced a significantly more pronounced increase in THPG in steatosis compared to controls. Our results demonstrate that severe steatosis, without inflammation or fibrosis, induces portal hypertension and signs of a hyperdynamic circulation, accompanied by extrahepatic arterial hyporeactivity and intrahepatic vascular hyperreactivity. The arterial hyporeactivity seems to be NO-independent, but appears to be mediated by specific COX-2-related mechanisms. Besides, the increased intrahepatic vascular resistance in steatosis appears not to be NO-related but rather to vasoconstrictor hyperreactivity.
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Affiliation(s)
- Denise Van der Graaff
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Wilhelmus J Kwanten
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Filip J Couturier
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Jesse S Govaerts
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Wim Verlinden
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Isabel Brosius
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Michiel D'Hondt
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Ann Driessen
- Department of Pathology, Antwerp University Hospital, Laboratory of Pathology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Benedicte Y De Winter
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Joris G De Man
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Peter P Michielsen
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Sven M Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
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Vanadium(IV)-chlorodipicolinate alleviates hepatic lipid accumulation by inducing autophagy via the LKB1/AMPK signaling pathway in vitro and in vivo. J Inorg Biochem 2018; 183:66-76. [PMID: 29558683 DOI: 10.1016/j.jinorgbio.2018.03.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 03/06/2018] [Accepted: 03/11/2018] [Indexed: 12/16/2022]
Abstract
Numerous studies have demonstrated that vanadium compounds are able to improve lipemia and triglyceridemia in both humans and animals. However, the molecular mechanism remains elusive. The present study was conducted to investigate the anti-hyperlipidemic effect of vanadium(IV) complex with 4-chlorodipicolinic acid (VOdipic-Cl)-induced autophagy on hepatic lipid accumulation. To explore the possible underlying mechanisms, primary rat hepatocytes, human hepatoma cell line HepG2, and liver tissue from C57BL/6 mice fed a high-fat diet (HFD) were used. In vitro, cultured primary rat hepatocytes were treated with palmitate (0.25, 0.5 and 0.75 mM) prior to VOdipic-Cl (50, 100, and 200 μM) for 24 h, respectively. In vivo, C57BL/6 mice were fed with high-fat diet for 16 weeks. VOdipic-Cl (10 mg V/kg body weight) was given by daily gavage for 4 weeks. In vitro results showed that VOdipic-Cl significantly inhibited lipid droplet formation by increasing the level of conversion and punctuation of microtubule-associated proteins light chain 3 (LC3) in a dose-dependent manner, and activated liver kinase B-1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Confocal microscopy images also showed that VOdipic-Cl induced sequestration of lipid droplets (LDs) by autophagy. In vivo, VOdipic-Cl attenuated the increase in serum and liver triglyceride levels in the mice fed with high-fat diet, while significantly increased autophagy induction and activated LKB1 and AMPK phosphorylation in the liver. Taken together, these results suggest that VOdipic-Cl reduces hepatic lipid accumulation by inducing autophagy via the activation of LKB1/AMPK-dependent signaling pathway.
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[ 18F]-BMS-747158-02PET imaging for evaluating hepatic mitochondrial complex 1dysfunction in a mouse model of non-alcoholic fatty liver disease. EJNMMI Res 2017; 7:96. [PMID: 29209997 PMCID: PMC5716959 DOI: 10.1186/s13550-017-0345-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 11/21/2017] [Indexed: 12/17/2022] Open
Abstract
Background Mitochondrial dysfunction is one of the main causes of non-alcohol fatty liver disease (NAFLD). [18F]-BMS-747158-02 (18F-BMS) which was originally developed as a myocardial perfusion imaging agent was reported to bind mitochondrial complex-1 (MC-1). The aim of this study was to investigate the potential use of 18F-BMS for evaluating hepatic MC-1 activity in mice fed a methionine- and choline-deficient (MCD) diet. Male C57BL/6J mice were fed a MCD diet for up to 2 weeks. PET scans with 18F-BMS were performed after 1 and 2 weeks of the MCD diet. 18F-BMS was intravenously injected into mice, and the uptake (standardized uptake value (SUV)) in the liver was determined. The binding specificity for MC-1 was assessed by pre-administration of rotenone, a specific MC-1 inhibitor. Hepatic MC-1 activity was measured using liver homogenates generated after each positron emission tomography (PET) scan. Blood biochemistry and histopathology were also assessed. Results In control mice, hepatic 18F-BMS uptake was significantly inhibited by the pre-injection of rotenone. The uptake of 18F-BMS was significantly decreased after 2 weeks of the MCD diet. The SUV at 30–60 min was well correlated with hepatic MC-1 activity (r = 0.73, p < 0.05). Increases in plasma ALT and AST levels were also noted at 1 and 2 weeks. Mild hepatic steatosis with or without minimal inflammation was histopathologically observed at 1 and 2 weeks in mice liver on the MCD diet. However, inflammation was observed only at 2 weeks in mice on the MCD diet. Conclusions The present study demonstrated that 18F-BMS is a potential PET probe for quantitative imaging of hepatic MC-1 activity and its mitochondrial dysfunction induced by steatosis and inflammation, such as in NAFLD.
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Liebig M, Hassanzada A, Kämmerling M, Genz B, Vollmar B, Abshagen K. Microcirculatory disturbances and cellular changes during progression of hepatic steatosis to liver tumors. Exp Biol Med (Maywood) 2017; 243:1-12. [PMID: 29065724 DOI: 10.1177/1535370217738730] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease is closely associated with metabolic syndrome and comprises a pathological spectrum of liver disease ranging from steatosis to steatohepatitis and can progress to fibrosis/cirrhosis and hepatocellular carcinoma. In 2013, a mouse model was described that mimics non-alcoholic fatty liver disease progression from steatohepatitis to tumors in a short time span and with high incidence. As microcirculatory disturbances play a crucial role in liver disease, the suitability of the steatosis-inflammation-tumor model for microcirculatory studies was assessed. Herein, we present a comprehensive view on morphological, microvascular, cellular, and functional aspects of non-alcoholic fatty liver disease progression in the steatosis-inflammation-tumor model using intravital microscopy, biochemical, and histological techniques. Mice develop steatohepatitis, mild fibrosis, and liver tumors at ages of 6, 12, and 20 weeks, respectively. Non-alcoholic fatty liver disease progression was accompanied by several general aspects of disease severity like increasing liver/body weight index, non-alcoholic fatty liver disease activity score, and hepatocellular apoptosis. Intravital microscopic analysis revealed significant changes in hepatic microcirculation with increasing structural alterations, elevated leukocyte adherence, and impaired nutritive perfusion. Non-alcoholic fatty liver disease was further characterized by a lower sinusoidal density with a striking rise at 20 weeks. The characteristic microcirculatory changes make the model a convenient tool for analysis of microcirculation during progression from steatosis to liver tumor. Impact statement Significant alterations of microcirculation contribute to progression of NAFLD, a chronic liver disease with increasing medical and socio-economic impact. Characterization of microcirculation in a NAFLD model reflecting all relevant stages of disease progression was still missing. Thus, we evaluated microcirculatory and cellular changes in a steatosis-inflammation-tumor model using in vivo microscopy. Analyses revealed increasing structural alterations, elevated leukocyte-endothelial interaction, and impaired nutritive perfusion. Thus, this model is suitable for further studies investigating therapeutic approaches targeting these progressive microcirculatory disturbances.
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Affiliation(s)
- Marie Liebig
- 1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany
| | - Alireza Hassanzada
- 1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany
| | - Malte Kämmerling
- 1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany
| | - Berit Genz
- 1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany.,2 QIMR Berghofer Medical Research Institute, Brisbane QLD 4006, Australia
| | - Brigitte Vollmar
- 1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany
| | - Kerstin Abshagen
- 1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany
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Traussnigg S, Kienbacher C, Gajdošík M, Valkovič L, Halilbasic E, Stift J, Rechling C, Hofer H, Steindl‐Munda P, Ferenci P, Wrba F, Trattnig S, Krššák M, Trauner M. Ultra-high-field magnetic resonance spectroscopy in non-alcoholic fatty liver disease: Novel mechanistic and diagnostic insights of energy metabolism in non-alcoholic steatohepatitis and advanced fibrosis. Liver Int 2017; 37:1544-1553. [PMID: 28544208 PMCID: PMC5638103 DOI: 10.1111/liv.13451] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS With the rising prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) non-invasive tools obtaining pathomechanistic insights to improve risk stratification are urgently needed. We therefore explored high- and ultra-high-field magnetic resonance spectroscopy (MRS) to obtain novel mechanistic and diagnostic insights into alterations of hepatic lipid, cell membrane and energy metabolism across the spectrum of NAFLD. METHODS MRS and liver biopsy were performed in 30 NAFLD patients with NAFL (n=8) or NASH (n=22). Hepatic lipid content and composition were measured using 3-Tesla proton (1 H)-MRS. 7-Tesla phosphorus (31 P)-MRS was applied to determine phosphomonoester (PME) including phosphoethanolamine (PE), phosphodiester (PDE) including glycerophosphocholine (GPC), phosphocreatine (PCr), nicotinamide adenine dinucleotide phosphate (NADPH), inorganic phosphate (Pi), γ-ATP and total phosphorus (TP). Saturation transfer technique was used to quantify hepatic ATP flux. RESULTS Hepatic steatosis in 1 H-MRS highly correlated with histology (P<.001) showing higher values in NASH than NAFL (P<.001) without differences in saturated or unsaturated fatty acid indices. PE/TP ratio increased with advanced fibrosis (F3/4) (P=.002) whereas GPC/PME+PDE decreased (P=.05) compared to no/mild fibrosis (F0-2). γ-ATP/TP was lower in advanced fibrosis (P=.049), while PCr/TP increased (P=.01). NADPH/TP increased with higher grades of ballooning (P=.02). Pi-to-ATP exchange rate constant (P=.003) and ATP flux (P=.001) were lower in NASH than NAFL. CONCLUSIONS Ultra-high-field MRS, especially saturation transfer technique uncovers changes in energy metabolism including dynamic ATP flux in inflammation and fibrosis in NASH. Non-invasive profiling by MRS appears feasible and may assist further mechanistic and therapeutic studies in NAFLD/NASH.
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Affiliation(s)
- Stefan Traussnigg
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Christian Kienbacher
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Martin Gajdošík
- High‐Field MR CenterDepartment of Biomedical Imaging and Image‐guided TherapyMedical University of ViennaViennaAustria
- Christian Doppler Laboratory for Clinical Molecular MR ImagingViennaAustria
| | - Ladislav Valkovič
- High‐Field MR CenterDepartment of Biomedical Imaging and Image‐guided TherapyMedical University of ViennaViennaAustria
- Christian Doppler Laboratory for Clinical Molecular MR ImagingViennaAustria
- Department of Imaging MethodsInstitute of Measurement ScienceSlovak Academy of SciencesBratislavaSlovakia
| | - Emina Halilbasic
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Judith Stift
- Department of Clinical PathologyMedical University of ViennaViennaAustria
| | - Christian Rechling
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Harald Hofer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Petra Steindl‐Munda
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Peter Ferenci
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Fritz Wrba
- Department of Clinical PathologyMedical University of ViennaViennaAustria
| | - Siegfried Trattnig
- High‐Field MR CenterDepartment of Biomedical Imaging and Image‐guided TherapyMedical University of ViennaViennaAustria
- Christian Doppler Laboratory for Clinical Molecular MR ImagingViennaAustria
| | - Martin Krššák
- High‐Field MR CenterDepartment of Biomedical Imaging and Image‐guided TherapyMedical University of ViennaViennaAustria
- Christian Doppler Laboratory for Clinical Molecular MR ImagingViennaAustria
- Division of Endocrinology and MetabolismDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
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Influence of nicotine on choline-deficient, L-amino acid-defined diet-induced non-alcoholic steatohepatitis in rats. PLoS One 2017; 12:e0180475. [PMID: 28662136 PMCID: PMC5491261 DOI: 10.1371/journal.pone.0180475] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 06/15/2017] [Indexed: 01/12/2023] Open
Abstract
Nicotine, a major compound in cigarette smoke, decreases food intake and body weight gain in mammals; however, the influence of nicotine on the progression of non-alcoholic steatohepatitis (NASH) remains controversial. This study aimed to investigate the effect of nicotine on NASH in rat models. Male Wistar rats were fed choline-deficient, l-amino acid-defined (CDAA) diet and treated with nicotine or saline. Food intake, body weight gain, presence of hepatic steatosis, inflammation, and fibrosis were assessed 6 weeks after the rats were fed CDAA diet. Hepatic branch vagotomy was performed to elucidate the mechanism through which nicotine affected steatohepatitis. CDAA diet induced hepatic steatosis, inflammation, and fibrosis, as well as increased the expression of inflammation-related genes. Conversely, nicotine significantly attenuated food intake, body weight gain, and inhibited the CDAA-diet-induced hepatic steatosis, inflammation, and fibrosis, together with increased expression of inflammation-related genes. Hepatic branch vagotomy by itself decreased food intake, body weight gain, and attenuated the CDAA-diet-induced hepatic steatosis, but not inflammation. However, nicotine did not change the food intake, body weight gain, and CDAA diet-induced hepatic steatosis and inflammation in vagotomized rats. These results suggest that nicotine attenuates the CDAA-diet-induced hepatic steatosis and inflammation through the hepatic branch of the vagus nerve in rats.
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Anavi S, Madar Z, Tirosh O. Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers. Redox Biol 2017; 13:386-392. [PMID: 28667907 PMCID: PMC5493836 DOI: 10.1016/j.redox.2017.06.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Revised: 06/18/2017] [Accepted: 06/20/2017] [Indexed: 12/29/2022] Open
Abstract
Nonalcoholic fatty liver diseases (NAFLD) is one of the most common chronic liver disease in Western countries. Oxygen is a central component of the cellular microenvironment, which participate in the regulation of cell survival, differentiation, functions and energy metabolism. Accordingly, sufficient oxygen supply is an important factor for tissue durability, mainly in highly metabolic tissues, such as the liver. Accumulating evidence from the past few decades provides strong support for the existence of interruptions in oxygen availability in fatty livers. This outcome may be the consequence of both, impaired systemic microcirculation and cellular membrane modifications which occur under steatotic conditions. This review summarizes current knowledge regarding the main factors which can affect oxygen supply in fatty liver.
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Affiliation(s)
- Sarit Anavi
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel; Peres Academic Center, Rehovot, Israel
| | - Zecharia Madar
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel
| | - Oren Tirosh
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel.
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