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Xing XC, Liu ZY, Yang Q, Jia BW, Qiu L, Zhang LL, Gao W. Ac2-26 reduced the liver injury after cardiopulmonary bypass in rats via AKT1/GSK3β/eNOS pathway. J Cardiothorac Surg 2024; 19:312. [PMID: 38824570 PMCID: PMC11143710 DOI: 10.1186/s13019-024-02801-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 05/25/2024] [Indexed: 06/03/2024] Open
Abstract
OBJECTIVE About 10% of patients after cardiopulmonary bypass (CPB) would undergo acute liver injury, which aggravated the mortality of patients. Ac2-26 has been demonstrated to ameliorate organic injury by inhibiting inflammation. The present study aims to evaluate the effect and mechanism of Ac2-26 on acute liver injury after CPB. METHODS A total of 32 SD rats were randomized into sham, CPB, Ac, and Ac/AKT1 groups. The rats only received anesthesia, and rats in other groups received CPB. The rats in Ac/AKT1 were pre-injected with the shRNA to interfere with the expression of AKT1. The rats in CPB were injected with saline, and rats in Ac and Ac/AKT1 groups were injected with Ac2-26. After 12 h of CPB, all the rats were sacrificed and the peripheral blood and liver samples were collected to analyze. The inflammatory factors in serum and liver were detected. The liver function was tested, and the pathological injury of liver tissue was evaluated. RESULTS Compared with the sham group, the inflammatory factors, liver function, and pathological injury were worsened after CPB. Compared with the CPB group, the Ac2-26 significantly decreased the pro-inflammatory factors and increased the anti-inflammatory factor, improved liver function, and ameliorated the pathological injury. All the therapeutic effects of Ac2-26 were notably attenuated by the shRNA of AKT1. The Ac2-26 increased the GSK3β and eNOS, and this promotion was inhibited by the shRNA. CONCLUSION The Ac2-26 significantly treated the liver injury, inhibited inflammation, and improved liver function. The effect of Ac2-26 on liver injury induced by CPB was partly associated with the promotion of AKT1/GSK3β/eNOS.
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Affiliation(s)
- Xi-Chun Xing
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, 246Xuefu Road, Harbin, 150081, Heilongjiang, China
| | - Zi-Ying Liu
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, 246Xuefu Road, Harbin, 150081, Heilongjiang, China
| | - Qing Yang
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bao-Wei Jia
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, 246Xuefu Road, Harbin, 150081, Heilongjiang, China
| | - Lin Qiu
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, 246Xuefu Road, Harbin, 150081, Heilongjiang, China
| | - Lu-Lu Zhang
- Department of Cardiovascular Medicine, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Wei Gao
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, 246Xuefu Road, Harbin, 150081, Heilongjiang, China.
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Cespiati A, Coelho Rodrigues I, Santos I, Policarpo S, Carvalhana S, Fracanzani AL, Cortez-Pinto H. Effect of HCV eradication by DAAs on liver steatosis, carotid atherosclerosis, and associated metabolic comorbidities: A systematic review. Liver Int 2024; 44:1075-1092. [PMID: 38385567 DOI: 10.1111/liv.15876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 12/11/2023] [Accepted: 02/08/2024] [Indexed: 02/23/2024]
Abstract
BACKGROUND AND AIMS The beneficial effect of Hepatitis C virus (HCV) eradication by direct antiviral agents (DAAs) on liver fibrosis is well defined. Despite this, the impact of viral eradication in both hepatic and extra-hepatic metabolic features is underreached. This systematic review aimed to synthesize the evidence on the impact of HCV eradication by DAAs on liver steatosis, carotid atherosclerosis, glucidic impairment, dyslipidaemia, and weight gain. METHODS A systematic search of the existing literature (up to December 2022) identified 97 original studies that fulfilled the inclusion criteria. RESULTS Whereas total cholesterol and low-density lipoprotein (LDL) seem to increase after viral eradication, the cardiovascular damage expressed as carotid plaques and intima-media thickness seems to improve. Otherwise, the effect on liver steatosis, glucidic homeostasis, and weight seems to be strictly dependent on the presence of baseline metabolic disorders. CONCLUSION Despite high heterogeneity and relatively short follow-up of included studies, we can conclude that the presence of metabolic risk factors should be strictly evaluated due to their impact on liver steatosis, glucidic and lipid homeostasis, and on weight gain to better identify patients at risk of liver disease progression despite the virus eradication.
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Affiliation(s)
- Annalisa Cespiati
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Inês Coelho Rodrigues
- Departamento de Gastrenterologia, Centro Hospitalar Universitário Lisboa Norte, Departamento de Dietética e Nutrição, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Inês Santos
- Laboratório de Nutrição, Faculdade de Medicina, Centro Académico de Medicina de Lisboa, Universidade de Lisboa, Lisbon, Portugal
- Faculdade de Medicina, Instituto de Saúde Ambiental (ISAMB), Universidade de Lisboa, Lisbon, Portugal
| | - Sara Policarpo
- Laboratório de Nutrição, Faculdade de Medicina, Centro Académico de Medicina de Lisboa, Universidade de Lisboa, Lisbon, Portugal
- Serviço de Dietética e Nutrição, Centro Hospitalar Universitário Lisboa Norte, E.P.E., Lisbon, Portugal
| | - Sofia Carvalhana
- Departamento de Gastrenterologia, Centro Hospitalar Universitário Lisboa Norte, Departamento de Dietética e Nutrição, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Anna Ludovica Fracanzani
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Helena Cortez-Pinto
- Departamento de Gastrenterologia, Centro Hospitalar Universitário Lisboa Norte, Departamento de Dietética e Nutrição, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
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Chen Y, Pan Q, Liao W, Ai W, Yang S, Guo S. Transcription Factor Forkhead Box O1 Mediates Transforming Growth Factor-β1-Induced Apoptosis in Hepatocytes. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1143-1155. [PMID: 37263346 PMCID: PMC10477955 DOI: 10.1016/j.ajpath.2023.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/27/2023] [Accepted: 05/18/2023] [Indexed: 06/03/2023]
Abstract
Dysregulation of hepatocyte apoptosis is associated with several types of chronic liver diseases. Transforming growth factor-β1 (TGF-β1) is a well-known pro-apoptotic factor in the liver, which constitutes a receptor complex composed of TGF-β receptor I and II, along with transcription factor Smad proteins. As a member of the forkhead box O (Foxo) class of transcription factors, Foxo1 is a predominant regulator of hepatic glucose production and apoptosis. This study investigated the potential relationship between TGF-β1 signaling and Foxo1 in control of apoptosis in hepatocytes. TGF-β1 induced hepatocyte apoptosis in a Foxo1-dependent manner in hepatocytes isolated from both wild-type and liver-specific Foxo1 knockout mice. TGF-β1 activated protein kinase A through TGF-β receptor I-Smad3, followed by phosphorylation of Foxo1 at Ser273 in promotion of apoptosis in hepatocytes. Moreover, Smad3 overexpression in the liver of mice promoted the levels of phosphorylated Foxo1-S273, total Foxo1, and a Foxo1-target pro-apoptotic gene Bim, which eventually resulted in hepatocyte apoptosis. The study further demonstrated a crucial role of Foxo1-S273 phosphorylation in the pro-apoptotic effect of TGF-β1 by using hepatocytes isolated from Foxo1-S273A/A knock-in mice, in which the phosphorylation of Foxo1-S273 was disrupted. Taken together, this study established a novel role of TGF-β1→protein kinase A→Foxo1 signaling cascades in control of hepatocyte survival.
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Affiliation(s)
- Yunmei Chen
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Quan Pan
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Wang Liao
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Weiqi Ai
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Sijun Yang
- Institute of Animal Model for Human Disease, Wuhan University, Wuhan, China
| | - Shaodong Guo
- Department of Nutrition, Texas A&M University, College Station, Texas.
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Arora AS, Zafar S, Latif U, Llorens F, Sabine M, Kumar P, Tahir W, Thüne K, Shafiq M, Schmitz M, Zerr I. The role of cellular prion protein in lipid metabolism in the liver. Prion 2021; 14:95-108. [PMID: 32138593 PMCID: PMC7153832 DOI: 10.1080/19336896.2020.1729074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cellular prion protein (PrPC) is a plasma membrane glycophosphatidylinositol-anchored protein and it is involved in multiple functions, including neuroprotection and oxidative stress. So far, most of the PrPC functional research is done in neuronal tissue or cell lines; the role of PrPC in non-neuronal tissues such as liver is only poorly understood. To characterize the role of PrPC in the liver, a proteomics approach was applied in the liver tissue of PrPC knockout mice. The proteome analysis and biochemical validations showed an excessive fat accumulation in the liver of PrPC knockout mice with a change in mRNA expression of genes linked to lipid metabolism. In addition, the higher Bax to Bcl2 ratio, up-regulation of tgfb1 mRNA expression in PrPC knockout mice liver, further showed the evidences of metabolic disease. Over-expression of PrPC in fatty acid-treated AML12 hepatic cell line caused a reduction in excessive intracellular fat accumulation; shows association of PrPC levels and lipid metabolism. Therefore, based on observation of excessive fat globules in the liver of ageing PrPC knockout mice and the reduction of fat accumulation in AML12 cell line with PrPC over-expression, the role of PrPC in lipid metabolism is described.
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Affiliation(s)
- Amandeep Singh Arora
- Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Saima Zafar
- Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Umair Latif
- Departments of Gastroenterology Endocrinology, University Medical Center Göttingen, Göttingen, Germany
| | - Franc Llorens
- Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.,Network Center for Biomedical Research in Neurodegenerative Diseases, (CIBERNED), Institute Carlos III, Hospitalet De Llobregat, Spain
| | - Mihm Sabine
- Departments of Gastroenterology Endocrinology, University Medical Center Göttingen, Göttingen, Germany
| | - Prateek Kumar
- Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Waqas Tahir
- Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Katrin Thüne
- Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Mohsin Shafiq
- Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Matthias Schmitz
- Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Inga Zerr
- Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
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Al-Salihi M, Bornikoel A, Zhuang Y, Stachura P, Scheller J, Lang KS, Lang PA. The role of ADAM17 during liver damage. Biol Chem 2021; 402:1115-1128. [PMID: 34192832 DOI: 10.1515/hsz-2021-0149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 06/02/2021] [Indexed: 12/14/2022]
Abstract
A disintegrin and metalloprotease (ADAM) 17 is a membrane bound protease, involved in the cleavage and thus regulation of various membrane proteins, which are critical during liver injury. Among ADAM17 substrates are tumor necrosis factor α (TNFα), tumor necrosis factor receptor 1 and 2 (TNFR1, TNFR2), the epidermal growth factor receptor (EGFR) ligands amphiregulin (AR) and heparin-binding-EGF-like growth factor (HB-EGF), the interleukin-6 receptor (IL-6R) and the receptor for a hepatocyte growth factor (HGF), c-Met. TNFα and its binding receptors can promote liver injury by inducing apoptosis and necroptosis in liver cells. Consistently, hepatocyte specific deletion of ADAM17 resulted in increased liver cell damage following CD95 stimulation. IL-6 trans-signaling is critical for liver regeneration and can alleviate liver damage. EGFR ligands can prevent liver damage and deletion of amphiregulin and HB-EGF can result in increased hepatocyte death and reduced proliferation. All of which indicates that ADAM17 has a central role in liver injury and recovery from it. Furthermore, inactive rhomboid proteins (iRhom) are involved in the trafficking and maturation of ADAM17 and have been linked to liver damage. Taken together, ADAM17 can contribute in a complex way to liver damage and injury.
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Affiliation(s)
- Mazin Al-Salihi
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
- School of Medicine, University of Central Lancashire, Preston, PR1 2HE, UK
| | - Anna Bornikoel
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Yuan Zhuang
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Pawel Stachura
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Jürgen Scheller
- Department of Biochemistry and Molecular Biology II, Medical Faculty, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Karl S Lang
- Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, D-45147 Essen, Germany
| | - Philipp A Lang
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany
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Wang Z, Li K, Maskey AR, Huang W, Toutov AA, Yang N, Srivastava K, Geliebter J, Tiwari R, Miao M, Li X. A small molecule compound berberine as an orally active therapeutic candidate against COVID-19 and SARS: A computational and mechanistic study. FASEB J 2021; 35:e21360. [PMID: 33749932 PMCID: PMC8250068 DOI: 10.1096/fj.202001792r] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 12/09/2020] [Accepted: 12/28/2020] [Indexed: 12/14/2022]
Abstract
The novel coronavirus disease, COVID-19, has grown into a global pandemic and a major public health threat since its breakout in December 2019. To date, no specific therapeutic drug or vaccine for treating COVID-19 and SARS has been FDA approved. Previous studies suggest that berberine, an isoquinoline alkaloid, has shown various biological activities that may help against COVID-19 and SARS, including antiviral, anti-allergy and inflammation, hepatoprotection against drug- and infection-induced liver injury, as well as reducing oxidative stress. In particular, berberine has a wide range of antiviral activities such as anti-influenza, anti-hepatitis C, anti-cytomegalovirus, and anti-alphavirus. As an ingredient recommended in guidelines issued by the China National Health Commission for COVID-19 to be combined with other therapy, berberine is a promising orally administered therapeutic candidate against SARS-CoV and SARS-CoV-2. The current study comprehensively evaluates the potential therapeutic mechanisms of berberine in preventing and treating COVID-19 and SARS using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analysis, and in silico molecular docking. An orally available immunotherapeutic-berberine nanomedicine, named NIT-X, has been developed by our group and has shown significantly increased oral bioavailability of berberine, increased IFN-γ production by CD8+ T cells, and inhibition of mast cell histamine release in vivo, suggesting a protective immune response. We further validated the inhibition of replication of SARS-CoV-2 in lung epithelial cells line in vitro (Calu3 cells) by berberine. Moreover, the expression of targets including ACE2, TMPRSS2, IL-1α, IL-8, IL-6, and CCL-2 in SARS-CoV-2 infected Calu3 cells were significantly suppressed by NIT-X. By supporting protective immunity while inhibiting pro-inflammatory cytokines; inhibiting viral infection and replication; inducing apoptosis; and protecting against tissue damage, berberine is a promising candidate in preventing and treating COVID-19 and SARS. Given the high oral bioavailability and safety of berberine nanomedicine, the current study may lead to the development of berberine as an orally, active therapeutic against COVID-19 and SARS.
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Affiliation(s)
- Zhen‐Zhen Wang
- Academy of Chinese Medical ScienceHenan University of Chinese MedicineZhengzhouChina
- Department of Microbiology & ImmunologyNew York Medical CollegeValhallaNYUSA
| | - Kun Li
- Department of PediatricsUniversity of IowaIowa CityIAUSA
| | - Anish R. Maskey
- Department of Microbiology & ImmunologyNew York Medical CollegeValhallaNYUSA
| | - Weihua Huang
- Department of PathologyNew York Medical CollegeValhallaNYUSA
| | | | - Nan Yang
- Department of Microbiology & ImmunologyNew York Medical CollegeValhallaNYUSA
- General Nutraceutical TechnologyElmsfordNYUSA
| | - Kamal Srivastava
- Department of Microbiology & ImmunologyNew York Medical CollegeValhallaNYUSA
- General Nutraceutical TechnologyElmsfordNYUSA
| | - Jan Geliebter
- Department of Microbiology & ImmunologyNew York Medical CollegeValhallaNYUSA
- Department of OtolaryngologySchool of MedicineNew York Medical CollegeValhallaNYUSA
| | - Raj Tiwari
- Department of Microbiology & ImmunologyNew York Medical CollegeValhallaNYUSA
- Department of OtolaryngologySchool of MedicineNew York Medical CollegeValhallaNYUSA
| | - Mingsan Miao
- Academy of Chinese Medical ScienceHenan University of Chinese MedicineZhengzhouChina
| | - Xiu‐Min Li
- Department of Microbiology & ImmunologyNew York Medical CollegeValhallaNYUSA
- Department of OtolaryngologySchool of MedicineNew York Medical CollegeValhallaNYUSA
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Combination of hepatocyte fraction and diffusion-weighted imaging as a predictor in quantitative hepatic fibrosis evaluation. Abdom Radiol (NY) 2020; 45:3681-3689. [PMID: 32266505 DOI: 10.1007/s00261-020-02520-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To investigate the performance of the combined hepatocyte fraction (HepF) and apparent diffusion coefficient (ADC) values to stage hepatic fibrosis (HF) in patients with hepatitis B/C. MATERIALS AND METHODS A total of 281 patients with hepatitis B/C prospectively underwent gadoxetate disodium-based T1 mapping and diffusion-weighted imaging. HepF was determined from pre and postcontrast T1 mapping with pharmacokinetics. The independent predictors of the HF stage (S0-4) were identified from HepF, ADC, conventional T1-based parameters, and age using a logistic regression analysis. The performances of independent and combined predictors in diagnosing various HF stages were compared by analyzing receiver operating characteristic curves. The intraclass correlation coefficient (ICC) was used to assess the interobserver reproducibility of each predictor. RESULTS In total, 167 patients with various stages of HF were included. All measurements had excellent interobserver agreement (ICC ≥ 0.75). The hepatic relative enhancement, HepF ,and ADC values were significantly different among various HF stages (p < 0.05). The HepF and ADC were independent predictors of > S0, > S1, > S2 , and > S3 disease (p < 0.05). T1Liver, T1Spleen, and T1Liver/Spleen were independent predictors of S > 2 disease (p < 0.05). The performance of HepF combined with the ADC (area under the curve (AUC) = 0.84-0.95) was higher than HepF (AUC = 0.79-0.92) or ADC (AUC = 0.82-0.89) alone in diagnosing > S0, > S1, > S2 , and > S3 disease. CONCLUSION The combined predictor of HepF and ADC shows acceptable performance for staging HF.
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Sabitha R, Nishi K, Gunasekaran VP, Agilan B, David E, Annamalai G, Vinothkumar R, Perumal M, Subbiah L, Ganeshan M. p-Coumaric acid attenuates alcohol exposed hepatic injury through MAPKs, apoptosis and Nrf2 signaling in experimental models. Chem Biol Interact 2020; 321:109044. [PMID: 32151596 DOI: 10.1016/j.cbi.2020.109044] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 02/26/2020] [Accepted: 03/06/2020] [Indexed: 02/07/2023]
Abstract
Overconsumption of alcohol could lead to severe liver injury that connects with oxidative stress, apoptosis, and inflammatory response. Previously, we proved that p-coumaric acid prevents ethanol induced reproductive toxicity; however, p-coumaric acid (PCA) on ethanol mediated hepatotoxicity has not been examined yet. In our work, we sought to study the potential of PCA in contradiction of ethanol induced hepatoxicity which linking with MAPKs, apoptosis, oxidative stress, and Nrf2 signaling. Foremost, we found that PCA could protect ethanol induced both L-02 and HepG2 hepatic cells by inhibiting cytotoxicity, ROS production, mitochondrial depolarization, and nuclear fragmentation. Also, in vivo experiments showed that the ethanol increasing the lipid markers (TBARS, CD) and depletes the antioxidants thereby increased phosphorylation of JNK, ERK, and p38 in rat liver tissues. Interestingly, PCA treatments inhibit ethanol exposed lipid markers and depletion of antioxidants, which directs the inhibition of MAPKs activation in rat liver tissues. We also noticed that the PCA protected ethanol induced apoptosis and liver markers by inhibiting the expression of Bax, caspases; AST, ALT, ALS, and LDH in liver tissue. Overall, the ameliorative consequence of PCA on ethanol induced oxidative stress and apoptosis was achieved by suppressing the expression of CYP2E1 and overexpressing Nrf2 and its target protein HO-1 in rat liver tissue. As a result, PCA was marked to be an effective antioxidant with notable hepatoprotection by inhibiting MAPKs and apoptosis signaling via enhancing Nrf2 signaling.
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Affiliation(s)
- Ramakrishnan Sabitha
- Department of Biomedical Science, Bharathidasan University, Tiruchirappalli, 620024, Tamil Nadu, India
| | - Kumari Nishi
- Department of Biomedical Science, Bharathidasan University, Tiruchirappalli, 620024, Tamil Nadu, India
| | | | - Balupillai Agilan
- Department of Biotechnology, Thiruvalluvar University, Serkadu, 632115, Vellore, Tamil Nadu, India; Department of Biochemistry and Biotechnology, Annnamalai University, Annamalainagar, 608 002, Tamil Nadu, India
| | - Ernest David
- Department of Biotechnology, Thiruvalluvar University, Serkadu, 632115, Vellore, Tamil Nadu, India
| | - Govindhan Annamalai
- Department of Biochemistry and Biotechnology, Annnamalai University, Annamalainagar, 608 002, Tamil Nadu, India
| | - Rajamanickam Vinothkumar
- Key Laboratory of Imaging Diagnosis and Minimally Invasive and Intervention Research, Lishui Hospital, Zhejiang University School of Medicine, Lishui, Zhejiang, China
| | - Malliga Perumal
- Department of Marine Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620 024, India
| | - Latha Subbiah
- Department of Pharmaceutical Technology, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli, 620 024, Tamil Nadu, India
| | - Mathan Ganeshan
- Department of Biomedical Science, Bharathidasan University, Tiruchirappalli, 620024, Tamil Nadu, India.
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Integration of VEGF and α-SMA Expression Improves the Prediction Accuracy of Fibrosis in Chronic Hepatitis C Liver Biopsy. Appl Immunohistochem Mol Morphol 2019; 25:261-270. [PMID: 26990742 DOI: 10.1097/pai.0000000000000299] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The progression of fibrosis in chronic hepatitis C (CHC) is a multifactorial process. The high adverse effects and the cost of standard health care increase the demand to discover new predictors for the progression of fibrosis in CHC patients. Our study aims to establish the relation between the angiogenic marker [vascular endothelial growth factor (VEGF)] and activated hepatic stellate cells (HSCs) represented by the expression of α-smooth muscle actin (α-SMA) and whether these 2 markers can be used as predictors for the progression of fibrosis in patients with CHC. MATERIALS AND METHODS Histopathologic and immunohistochemical analyses were used for examining the morphology and the expression of VEGF and α-SMA in 60 CHC biopsies procured from CHC patients. Multivariate analysis was used to correlate the protein expression with staging and grading of liver fibrosis. Cutoff values of α-SMA and VEGF were determined by the receiver operating characteristics curve. RESULTS There was a positive correlation between VEGF and HSCs expressing α-SMA (ρ=0.287, P=0.026) and both factors were correlated with the stage of fibrosis (P<0.001). Using the receiver operating characteristics curve, both VEGF (area under the curve=0.71, P<0.006) and α-SMA (area under the curve=0.82, P<0.001) were positive predictors for moderate and severe fibrosis. CONCLUSIONS This study demonstrates the relation between VEGF expression and the activated HSCs denoted by the expression of α-SMA in CHC biopsies and together can be used as a predictor for the progression of fibrosis.
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Parafati M, Kirby RJ, Khorasanizadeh S, Rastinejad F, Malany S. A nonalcoholic fatty liver disease model in human induced pluripotent stem cell-derived hepatocytes, created by endoplasmic reticulum stress-induced steatosis. Dis Model Mech 2018; 11:11/9/dmm033530. [PMID: 30254132 PMCID: PMC6176998 DOI: 10.1242/dmm.033530] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 08/08/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatic steatosis, a reversible state of metabolic dysregulation, can promote the onset of nonalcoholic steatohepatitis (NASH), and its transition is thought to be critical in disease evolution. The association between endoplasmic reticulum (ER) stress response and hepatocyte metabolism disorders prompted us to characterize ER stress-induced hepatic metabolic dysfunction in human induced pluripotent stem cell-derived hepatocytes (hiPSC-Hep), to explore regulatory pathways and validate a phenotypic in vitro model for progression of liver steatosis. We treated hiPSC-Hep with a ratio of unsaturated and saturated fatty acids in the presence of an inducer of ER stress to synergistically promote triglyceride accumulation and dysregulate lipid metabolism. We monitored lipid accumulation by high-content imaging and measured gene regulation by RNA sequencing and reverse transcription quantitative PCR analyses. Our results show that ER stress potentiated intracellular lipid accumulation by 5-fold in hiPSC-Hep in the absence of apoptosis. Transcriptome pathway analysis identified ER stress pathways as the most significantly dysregulated of all pathways affected. Obeticholic acid dose dependently inhibited lipid accumulation and modulated gene expression downstream of the farnesoid X receptor. We were able to identify modulation of hepatic markers and gene pathways known to be involved in steatosis and nonalcoholic fatty liver disease (NAFLD), in support of a hiPSC-Hep disease model that is relevant to clinical data for human NASH. Our results show that the model can serve as a translational discovery platform for the understanding of molecular pathways involved in NAFLD, and can facilitate the identification of novel therapeutic molecules based on high-throughput screening strategies. Summary: Our study demonstrates expanded use of human induced pluripotent stem cell-derived hepatocytes for molecular studies and drug screening, to evaluate new therapeutics with an antisteatotic mechanism of action for nonalcoholic fatty liver disease.
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Affiliation(s)
- Maddalena Parafati
- Translational Biology, Conrad Prebys Center for Chemical Genomics, Orlando, FL 32827, USA
| | - R Jason Kirby
- Translational Biology, Conrad Prebys Center for Chemical Genomics, Orlando, FL 32827, USA
| | - Sepideh Khorasanizadeh
- Center for Metabolic Origins of Disease, Sanford Burham Prebys Medical Discovery Institute, 6400 Sanger Rd, Orlando, FL 32827, USA
| | - Fraydoon Rastinejad
- Center for Metabolic Origins of Disease, Sanford Burham Prebys Medical Discovery Institute, 6400 Sanger Rd, Orlando, FL 32827, USA
| | - Siobhan Malany
- Translational Biology, Conrad Prebys Center for Chemical Genomics, Orlando, FL 32827, USA
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11
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Tardelli LP, Breda L, Marques LF, Gomes Carvalho Lima NC, Furtado de Camargo T, Scherer BR, Moreira NF, Dias JF, Dalia RA, Thomazini BF, Corezolla do Amaral ME, Alves AA. High lipid and low carbohydrate content diet, immediately after weaning, causes hepatic injury, systemic oxidative stress and diminishment of lipids in white adipose tissue. JOURNAL OF NUTRITION & INTERMEDIARY METABOLISM 2018. [DOI: 10.1016/j.jnim.2018.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
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12
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Moghoofei M, Mostafaei S, Ashraf-Ganjouei A, Kavosi H, Mahmoudi M. HBV reactivation in rheumatic diseases patients under therapy: A meta-analysis. Microb Pathog 2018; 114:436-443. [PMID: 29223453 DOI: 10.1016/j.micpath.2017.12.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 12/04/2017] [Accepted: 12/05/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND Hepatitis B is one of the most common infectious diseases worldwide. In patients undergoing immunosuppressive therapy such as rheumatic diseases, reactivation of hepatitis B virus (HBV) is considered clinically important. This systematic review and meta-analysis were performed to determine the prevalence rate of HBV reactivation in rheumatic patients from different parts of the world. METHODS The authors performed a systematic literature review from several reliable databases including Scopus, ISI Web of Science and PubMed. Furthermore, the keywords of this research were "Hepatitis B virus", "Rheumatic diseases", "HBV reactivation", "Anti-TNF", "DMARDs" and "Biologic agents". RESULTS The authors selected 30 studies out of 983 for the present review. The overall estimation of the prevalence of HBV reactivation was 1.4 (95% confidence interval (CI): 1.3-1.6). Also, the heterogeneity in estimating the pooled prevalence among the studies was shown; Cochran Q test, P < 0.001, I2 = 99.9%. It should be noted that max and min reactivation rate of HBV were in Italy and France respectively. CONCLUSIONS Rheumatic disease patients with resolved hepatitis B should be tightly monitored for possible HBV reactivation by elevation of liver enzymes and HBV DNA levels.
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Affiliation(s)
- Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shayan Mostafaei
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ashraf-Ganjouei
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hoda Kavosi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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13
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Masalova OV, Lesnova EI, Solyev PN, Zakirova NF, Prassolov VS, Kochetkov SN, Ivanov AV, Kushch AA. Modulation of Cell Death Pathways by Hepatitis C Virus Proteins in Huh7.5 Hepatoma Cells. Int J Mol Sci 2017; 18:2346. [PMID: 29113144 PMCID: PMC5713315 DOI: 10.3390/ijms18112346] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 10/27/2017] [Accepted: 11/03/2017] [Indexed: 12/20/2022] Open
Abstract
The hepatitis C virus (HCV) causes chronic liver disease leading to fibrosis, cirrhosis, and hepatocellular carcinoma. HCV infection triggers various types of cell death which contribute to hepatitis C pathogenesis. However, much is still unknown about the impact of viral proteins on them. Here we present the results of simultaneous immunocytochemical analysis of markers of apoptosis, autophagy, and necrosis in Huh7.5 cells expressing individual HCV proteins or their combinations, or harboring the virus replicon. Stable replication of the full-length HCV genome or transient expression of its core, Е1/Е2, NS3 and NS5B led to the death of 20-47% cells, 72 h posttransfection, whereas the expression of the NS4A/B, NS5A or NS3-NS5B polyprotein did not affect cell viability. HCV proteins caused different impacts on the activation of caspases-3, -8 and -9 and on DNA fragmentation. The structural core and E1/E2 proteins promoted apoptosis, whereas non-structural NS4A/B, NS5A, NS5B suppressed apoptosis by blocking various members of the caspase cascade. The majority of HCV proteins also enhanced autophagy, while NS5A also induced necrosis. As a result, the death of Huh7.5 cells expressing the HCV core was induced via apoptosis, the cells expressing NS3 and NS5B via autophagy-associated death, and the cells expressing E1/E2 glycoproteins or harboring HCV the replicon via both apoptosis and autophagy.
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Affiliation(s)
- Olga V Masalova
- Ivanovsky Institute of Virology, Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia.
| | - Ekaterina I Lesnova
- Ivanovsky Institute of Virology, Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia.
| | - Pavel N Solyev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
| | - Natalia F Zakirova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
| | - Vladimir S Prassolov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
| | - Sergey N Kochetkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
| | - Alexander V Ivanov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
| | - Alla A Kushch
- Ivanovsky Institute of Virology, Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia.
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Takaki H, Akazawa Y, Kido Y, Morishita M, Honda T, Shibata H, Miuma S, Miyaaki H, Taura N, Kondo H, Nakao K. Hepatitis C Virus Infection Increases c-Jun N-Terminal Kinase (JNK) Phosphorylation and Accentuates Hepatocyte Lipoapoptosis. Med Sci Monit 2017; 23:4526-4532. [PMID: 28931802 PMCID: PMC5621789 DOI: 10.12659/msm.903210] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background Hepatitis C virus (HCV) infection and metabolic diseases including nonalcoholic steatohepatitis (NASH) exhibit a complex interplay. Although free fatty acid-mediated apoptosis is a prominent feature of NASH, the impact of HCV infection on hepatocyte lipotoxicity has remained largely unexplored. The study aimed at identifying whether infection by HCV affected the apoptotic pathway in hepatocytes during fatty acid assault. Material/Methods OR6 cells, which are derived from human hepatocellular carcinoma Huh-7 cells and harbor a full-length HCV RNA genome replication system, were treated with palmitate. Apoptosis was examined by 4′,6-diamidino-2-phenylindole staining. Activation and expression of JNK, Bim, cIAP-1, and Mcl-1 were examined by immunoblotting. mRNA expression of CHOP, a major player in endoplasmic reticulum stress-mediated apoptosis, was assessed by real-time PCR. Results Palmitate-induced hepatocyte apoptosis was significantly enhanced in OR6 cells compared to cured cells, in which the HCV genome had been eradicated by treatment with interferon-α. Although basal expression of CHOP mRNA was enhanced in OR6 cells compared to cured cells, it was similarly upregulated in both cell lines following palmitate treatment. Notably, palmitate-induced JNK phosphorylation was accentuated in OR6 cells compared to cured cells. Inhibition of JNK with SP600125 attenuated palmitate-induced apoptosis. Palmitate-mediated upregulation of BH3-only protein Bim, which acts downstream of JNK, was also enhanced in OR6 cells compared to cured cells. In contrast, Mcl-1 and cIAP-1 were equally reduced in OR6 cells and cured cells following palmitate treatment. Conclusions These findings suggest that during lipoapoptosis, HCV infection may enhance hepatocyte toxicity by increasing JNK phosphorylation.
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Affiliation(s)
- Hiroko Takaki
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki City, Nagasaki, Japan
| | - Yuko Akazawa
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki City, Nagasaki, Japan.,Department of Pathology, Nagasaki University Hospital, Nagasaki City, Nagasaki, Japan
| | - Youko Kido
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki City, Nagasaki, Japan
| | - Mami Morishita
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki City, Nagasaki, Japan
| | - Takuya Honda
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki City, Nagasaki, Japan
| | - Hidetaka Shibata
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki City, Nagasaki, Japan
| | - Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki City, Nagasaki, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki City, Nagasaki, Japan
| | - Naota Taura
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki City, Nagasaki, Japan
| | - Hisayoshi Kondo
- Biostatistics Section, Division of Scientific Data Registry, Department of Radioisotope Medicine, Atomic Bomb Disease Institute, Nagasaki City, Nagasaki, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki City, Nagasaki, Japan
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Zhang Y, Zhao J, Zhou SF, Yu ZL, Wang XY, Zhu PL, Chu ZS, Pan SY, Xie M, Ko KM. Biochemical mechanism underlying hypertriglyceridemia and hepatic steatosis/hepatomegaly induced by acute schisandrin B treatment in mice. Lipids Health Dis 2017; 16:8. [PMID: 28086886 PMCID: PMC5237187 DOI: 10.1186/s12944-017-0406-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 01/02/2017] [Indexed: 12/15/2022] Open
Abstract
Background It has been demonstrated that acute oral administration of schisandrin B (Sch B), an active dibenzocyclooctadiene isolated from Schisandrae Fructus (a commonly used traditional Chinese herb), increased serum and hepatic triglyceride (TG) levels and hepatic mass in mice. The present study aimed to investigate the biochemical mechanism underlying the Sch B-induced hypertriglyceridemia, hepatic steatosis and hepatomegaly. Methods Male ICR mice were given a single oral dose of Sch B (0.25–2 g/kg). Sch B-induced changes in serum levels of biomarkers, such as TG, total cholesterol (TC), apolipoprotein B48 (ApoB 48), very-low-density lipoprotein (VLDL), non-esterified fatty acid (NEFA) and hepatic growth factor (HGF), as well as hepatic lipids and mass, epididymal adipose tissue (EAT) and adipocyte size, and histological changes of the liver and EAT were examined over a period of 12–120 h after Sch B treatment. Results Serum and hepatic TG levels were increased by 1.0–4.3 fold and 40–158% at 12–72 h and 12–96 h, respectively, after Sch B administration. Sch B treatment elevated serum ApoB 48 level (up to 12%), a marker of exogenous TG, but not VLDL, as compared with the vehicle treatment. Treatment with Sch B caused a time-/dose-dependent reduction in EAT index (up to 39%) and adipocyte size (up to 67%) and elevation in serum NEFA level (up to 55%). Sch B treatment induced hepatic steatosis in a time-/dose-dependent manner, as indicated by increases in total vacuole area (up to 3.2 fold vs. the vehicle control) and lipid positive staining area (up to 17.5 × 103 μm2) in liver tissue. Hepatic index and serum HGF levels were increased by 18–60% and 42–71% at 12–120 h and 24–72 h post-Sch B dosing, respectively. In addition, ultrastructural changes, such as increase in size and disruption of cristae, in hepatic mitochondria were observed in Sch B-treated mice. Conclusion Our findings suggest that exogenous sources of TG and the breakdown of fat storage in the body contribute to Sch B-induced hypertriglyceridemia and hepatic steatosis in mice. Hepatomegaly (a probable hepatotoxic action) caused by Sch B may result from the fat accumulation and mitochondrial damage in liver tissue.
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Affiliation(s)
- Yi Zhang
- Department of Pharmacology, Beijing University of Chinese Medicine, Beijing, 100102, China
| | - Jing Zhao
- Institute of Integrated Bioinfomedicine & Translational Science, HKBU Shenzhen Research and Continuing Education, Shenzhen, 518057, China
| | - Shu-Feng Zhou
- Department of Bioengineering and Biotechnology, College of Chemical Engineering, Huaqiao University, Xiamen, Fujian, 361021, China
| | - Zhi-Ling Yu
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China
| | - Xiao-Yan Wang
- Department of Pharmacology, Beijing University of Chinese Medicine, Beijing, 100102, China
| | - Pei-Li Zhu
- Department of Pharmacology, Beijing University of Chinese Medicine, Beijing, 100102, China
| | - Zhu-Sheng Chu
- Department of Pharmacology, Beijing University of Chinese Medicine, Beijing, 100102, China
| | - Si-Yuan Pan
- Department of Pharmacology, Beijing University of Chinese Medicine, Beijing, 100102, China.
| | - Ming Xie
- Department of Formulaology, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Kam-Ming Ko
- Division of Life Science, Hong Kong University of Science & Technology, Hong Kong, SAR, China
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Zhang H, Xue L, Chen L, Jiang S, Xin Y, Xuan S. A Meta-Analysis of the Association Between the I148M Variant of Patatin-Like Phospholipase Domain Containing 3 Gene and the Presence of Chronic Hepatitis C. HEPATITIS MONTHLY 2015; 15:e31987. [PMID: 26834791 PMCID: PMC4717312 DOI: 10.5812/hepatmon.31987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Revised: 09/20/2015] [Accepted: 10/02/2015] [Indexed: 12/11/2022]
Abstract
CONTEXT The objective of the current study was to evaluate the association between the I148M variant of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and the presence of Chronic Hepatitis C (CHC) across different populations. EVIDENCE ACQUISITION This study was a meta-analysis of all relevant researches published in the literature from year 2000 to 2015. The odds ratios (ORs) of PNPLA3 allele distributions in CHC patients were analyzed and compared with healthy controls. The meta-analysis Revman 5.2 software was applied for investigating heterogeneity among individual studies and for summarizing all the studies. The meta-analysis was carried out according to the Cochrane Reviewers' Handbook recommendations. A total of 120 clinical trials or reports were retrieved, yet only five trials met the study selection criteria. RESULTS Five hospital-based case-control studies were included in the final analysis. The overall frequency of PNPLA3 gene polymorphisms was 20.4% (205/1005) in CHC and 10.23% (53/518) in controls. The summary odds ratio for the association of gene polymorphisms of PNPLA3 with the risk for CHC was determined as 2.20 (95% CI: 1.56 -3.11) and was statistically significant (P < 0.05). CONCLUSIONS The current meta-analysis showed an association between frequency of GG genotype of PNPLA3 and the risk of development of CHC in various populations throughout the world.
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Affiliation(s)
- Haiying Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Medical College, Qingdao University, Qingdao, China
- Department of Gastroenterology, Qingdao Central Hospital, Qingdao, China
- Corresponding Authors: Haiying Zhang, Department of Gastroenterology, The Second Affiliated Hospital of Medical College, Qingdao University, Qingdao, China. Tel: +86-53284963627, Fax: +86-53288905293, E-mail: ; Shiying Xuan, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China. Tel: +86-53288905289, Fax: +86-53288905293, E-mail:
| | - Li Xue
- Department of Gastroenterology, The Second Affiliated Hospital of Medical College, Qingdao University, Qingdao, China
- Department of Gastroenterology, Qingdao Central Hospital, Qingdao, China
| | - Lizhen Chen
- Medical College, Qingdao University, Qingdao, China
| | - Shunshun Jiang
- Department of Gastroenterology, The Second Affiliated Hospital of Medical College, Qingdao University, Qingdao, China
- Department of Gastroenterology, Qingdao Central Hospital, Qingdao, China
| | - Yongning Xin
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
| | - Shiying Xuan
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
- Corresponding Authors: Haiying Zhang, Department of Gastroenterology, The Second Affiliated Hospital of Medical College, Qingdao University, Qingdao, China. Tel: +86-53284963627, Fax: +86-53288905293, E-mail: ; Shiying Xuan, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China. Tel: +86-53288905289, Fax: +86-53288905293, E-mail:
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Kukla M, Piotrowski D, Waluga M, Hartleb M. Insulin resistance and its consequences in chronic hepatitis C. Clin Exp Hepatol 2015; 1:17-29. [PMID: 28856251 PMCID: PMC5421163 DOI: 10.5114/ceh.2015.51375] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 03/10/2015] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Hepatitis C virus (HCV) may contribute to a broad spectrum of metabolic disturbances - namely, steatosis, insulin resistance (IR), increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus (T2DM), lipid metabolism abnormalities and atherosclerosis. HCV can directly or indirectly cause both IR and steatosis, but it is still not resolved whether this viral impact bears the same prognostic value as the metabolic counterparts. As the population exposed to HCV ages, the morbidity due to this disease is increasing. The rising epidemic of obesity contributes to higher prevalence of IR and T2DM. Our understanding of the mutual association between both disease states continues to grow, but is still far from complete. This review briefly discusses the most probable mechanisms involved in IR development in the course of CHC. Molecular mechanisms for the direct and indirect influence of HCV on intracellular insulin signaling are described. Subsequently, the consequences of IR/T2DM for disease progression and management are summarized.
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Affiliation(s)
- Michał Kukla
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Damian Piotrowski
- Department of Infectious Diseases in Bytom, Medical University of Silesia in Katowice, Poland
| | - Marek Waluga
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Marek Hartleb
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
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Huang CF, Dai CY, Yeh ML, Huang CI, Tai CM, Hsieh MH, Liang PC, Lin YH, Hsieh MY, Yang HL, Huang JF, Lin ZY, Chen SC, Yu ML, Chuang WL. Association of diabetes and PNPLA3 genetic variants with disease severity of patients with chronic hepatitis C virus infection. J Hepatol 2015; 62:512-518. [PMID: 25457210 DOI: 10.1016/j.jhep.2014.10.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 10/06/2014] [Accepted: 10/08/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Genetic variants of patatin-like phospholipase domain-containing 3 (PNPLA3) and diabetes are associated with liver disease severity, in patients with chronic hepatitis C (CHC) infection. We aimed at exploring their interaction in determining hepatitis C virus (HCV)-related liver fibrosis. METHODS The PNPLA3 genetic polymorphism at rs738409 was verified in 1077 biopsy-proven CHC patients. Other clinical variables, including diabetes status, were analysed for factors associated with bridging fibrosis. RESULTS Patients with advanced liver fibrosis had higher proportions of the GG genotype (14.5% vs. 10.4%, p=0.06 in recessive model) and GG/GC genotype carriage (64.0% vs. 56.8%, p=0.03 in dominant model). Stepwise logistic regression analysis revealed that factors predictive of advanced liver fibrosis included age (odds ratio [OR]: 1.02, 95% confidence intervals [CI]: 1.008-1.037, p=0.002), diabetes (OR: 1.81, CI: 1.236-2.653, p=0.002), α-fetoprotein (OR: 1.006, CI: 1.001-1.01, p=0.01), platelet counts (OR: 1.009, CI: 1.006-1.012, p<0.001), and PNPLA3 rs738409 CG/GG genotype (OR: 1.34, CI: 1.006-1.785, p=0.046). When patients were grouped according to their diabetes status, the PNPLA3 genetic variants were associated with advanced liver fibrosis in diabetic patients only, but not in non-diabetic patients. The PNPLA3 gene was the most important predictive factor of bridging fibrosis in diabetic patients, using the recessive model (OR: 4.53, CI: 1.356-15.106, p=0.014) or the dominant model (OR: 2.20, CI: 1.026-4.734, p=0.04). Compared to non-diabetic patients, patients with the diabetes/GG genotype were more likely to have advanced liver fibrosis (OR: 8.79, CI: 2.889-26.719, p<0.001), followed by those with diabetes/non-GG genotype (OR: 1.55, CI: 1.048-2.286, p=0.03). CONCLUSIONS The effect of PNPLA3 genetic variants in HCV-related advanced liver fibrosis was enhanced in diabetic patients. The strong genetic-environmental interaction contributed to the high risk of advanced liver disease in CHC patients.
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Affiliation(s)
- Chung-Feng Huang
- Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-I Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chi-Ming Tai
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Meng-Hsuan Hsieh
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hua-Ling Yang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Boštjančič E, Bandelj E, Luzar B, Poljak M, Glavač D. Hepatic expression of miR-122, miR-126, miR-136 and miR-181a and their correlation to histopathological and clinical characteristics of patients with hepatitis C. J Viral Hepat 2015; 22:146-57. [PMID: 25065618 DOI: 10.1111/jvh.12266] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 04/03/2014] [Indexed: 12/13/2022]
Abstract
It has been shown for hepatitis C virus (HCV) infection that host miRNAs contribute to the replication of the viral RNA genome. However, the clinical impact of these and many other cellular miRNAs on HCV in humans is still largely unclear. We therefore analysed the expression of miR-122, miR-126, miR-181a and miR-136 in HCV-infected patients. The study included liver biopsies of 65 patients infected with HCV of different genotypes (gt 1, gt 1a, gt 1b, gt 3 and gt 4) and nine noninfected individuals. Expression analysis of miRNAs was performed by qPCR, and they were analysed for differences between patient gender and age, genotypes, stage of fibrosis, grade of inflammation, serum level of liver enzymes, serum viral load, the presence of steatosis and mode of transmission. Different target prediction algorithms were used to search for targets of analyzed miRNAs. Statistical analysis revealed significant up-regulation of miR-136 and down-regulation of miR-126 and miR-181a in patients infected with HCV of different genotypes compared with noninfected individuals. The same expression pattern was observed in different stages and grades of liver disease. miR-122 was up-regulated in women relative to men and associated to portal inflammation, miR-122 and miR-126 correlated with serum HCV load and miR-136 and miR-122 correlated with the presence of steatosis. miR-126 and miR-136 were differentially expressed between different modes of HCV transmission. There were approximately 2000 different targets predicted for all four miRNAs and each of the analyzed miRNAs could be involved in more than a 100 different biochemical pathways. miR-122, miR-126, miR-136 and miR-181a have been shown to be involved in HCV infection with different genotypes. Their expression has been associated with the gender, stage and grade of liver disease, mode of transmission, serum HCV load and the presence of steatosis. Numerous target genes and biochemical pathways are predicted for each of the analyzed miRNAs. All these results suggest their role in HCV-infected liver disease.
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Affiliation(s)
- E Boštjančič
- Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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Prakoso E, Tirnitz-Parker JEE, Clouston AD, Kayali Z, Lee A, Gan EK, Ramm GA, Kench JG, Bowen DG, Olynyk JK, McCaughan GW, Shackel NA. Analysis of the intrahepatic ductular reaction and progenitor cell responses in hepatitis C virus recurrence after liver transplantation. Liver Transpl 2014; 20:1508-19. [PMID: 25241637 DOI: 10.1002/lt.24007] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Revised: 08/30/2014] [Accepted: 09/14/2014] [Indexed: 02/07/2023]
Abstract
Fibrosis in livers with hepatitis C virus (HCV) recurrence after liver transplantation (LT) can be rapidly progressive, and the mechanisms underlying this process are poorly understood. In livers with HCV infections in the non-LT setting, there is a significant relationship between the development of structures known as the ductular reaction (DR), hepatic progenitor cells (HPCs), and fibrosis. This study characterizes the DR, HPCs, and fibrosis associated with HCV recurrence after LT. Immunohistochemistry and confocal microscopy were used to characterize the DR, HPC, and fibrosis in liver biopsy specimens. Key findings were confirmed in a separate, independent cohort. The initial characterization cohort had 194 biopsy samples from 105 individuals with HCV recurrence after LT. The immunophenotype, morphology, and location of the DR were consistent with an HPC origin. The DR correlated with intrahepatic fibrosis (rs = 0.529, P < 0.001) and the number of activated hepatic stellate cells (HSCs; rs = 0.446, P < 0.001). There was an early occurrence of hepatocyte replicative arrest as well as increased hepatocyte proliferation that correlated with the DR (rs = 0.295, P < 0.001). Replicative arrest preceded hepatocyte proliferation in early-stage injury. Hepatocyte proliferation decreased with advanced fibrosis; in contrast, the extent of the DR and the number of activated HSCs continued to increase. In the second cohort of 37 individuals, the DR and the number of HPCs similarly correlated with fibrosis and inflammation after LT. In conclusion, this is the first characterization of the DR in HCV-associated liver injury after LT. There was a significant correlation between the DR and the development of progressive fibrosis in HCV recurrence. These results suggest a pivotal role for both the DR and the HPC responses in the aggressive fibrosis seen with HCV recurrence after LT.
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Affiliation(s)
- Emilia Prakoso
- Centenary Institute of Cancer Medicine and Cell Biology, Sydney, Australia; A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia; University of Sydney, Sydney, Australia
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Valva P, Gismondi MI, Casciato PC, Galoppo M, Lezama C, Galdame O, Gadano A, Galoppo MC, Mullen E, De Matteo EN, Preciado MV. Distinctive intrahepatic characteristics of paediatric and adult pathogenesis of chronic hepatitis C infection. Clin Microbiol Infect 2014; 20:O998-1009. [PMID: 24942073 DOI: 10.1111/1469-0691.12728] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 05/23/2014] [Accepted: 06/15/2014] [Indexed: 12/17/2022]
Abstract
Mechanisms leading to liver damage in chronic hepatitis C (CHC) are being discussed, but both the immune system and the virus are involved. The aim of this study was to evaluate intrahepatic viral infection, apoptosis and portal and periportal/interface infiltrate in paediatric and adult patients to elucidate the pathogenesis of chronic hepatitis C. HCV-infected, activated caspase-3(+) and TUNEL(+) hepatocytes, as well as total, CD4(+), CD8(+), Foxp3(+) and CD20(+) lymphocytes infiltrating portal and periportal/interface tracts were evaluated in 27 paediatric and 32 adult liver samples by immunohistochemistry or immunofluorescence. The number of infected hepatocytes was higher in paediatric than in adult samples (p 0.0078). In children, they correlated with apoptotic hepatocytes (activated caspase-3(+) r = 0.74, p < 0.0001; TUNEL(+) r = 0.606, p 0.0017). Also, infected (p = 0.026) and apoptotic hepatocytes (p = 0.03) were associated with the severity of fibrosis. In adults, activated caspase-3(+) cell count was increased in severe hepatitis (p = 0.009). Total, CD4(+), CD8(+) and Foxp3(+) lymphocyte count was higher in adult samples (p < 0.05). Paediatric CD8(+) cells correlated with infected (r = 0.495, p 0.04) and TUNEL(+) hepatocytes (r = 0.474, p = 0.047), while adult ones correlated with activated caspase-3(+) hepatocytes (r = 0.387, p 0.04). In adults, CD8(+) was associated with hepatitis severity (p < 0.0001) and correlated with inflammatory activity (CD8(+) r = 0.639, p 0.0003). HCV, apoptosis and immune response proved to be involved in CHC pathogenesis of both paediatric and adult patients. However, liver injury in paediatric CHC would be largely associated with a viral cytopathic effect mediated by apoptosis, while in adults it would be mainly associated with an exacerbated immune response.
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Affiliation(s)
- P Valva
- Laboratory of Molecular Biology, Pathology Division, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
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22
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Quantification of portal-bridging fibrosis area more accurately reflects fibrosis stage and liver stiffness than whole fibrosis or perisinusoidal fibrosis areas in chronic hepatitis C. Mod Pathol 2014; 27:1035-45. [PMID: 24390214 DOI: 10.1038/modpathol.2013.225] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Accepted: 10/13/2013] [Indexed: 12/11/2022]
Abstract
Morphometry provides an objective evaluation of fibrosis in liver diseases. We developed an image analysis algorithm using automated thresholding and segmentation to separately quantify the areas and the fractal dimensions of portal-bridging fibrosis and perisinusoidal fibrosis in chronic hepatitis C liver biopsies. We studied 427 digitized liver biopsies and compared the automated measures of the different fibrosis compartments with (1) the Metavir F (fibrosis) and A (activity) histological scores, (2) the digitally assessed area of steatosis, and (3) the liver stiffness measured by elastography (Fibroscan). The perisinusoidal fibrosis area was higher than that of portal fibrosis in stages ≤F2; it reached its highest value in F2 stage and stabilized thereafter. The F3 stage was characterized by equal proportions of portal-bridging and perisinusoidal fibrosis, whereas portal-bridging area was predominant in cirrhosis. Measurement of portal-bridging fibrosis showed highly significantly different values between contiguous F stages; the ratio of portal-bridging fibrosis/perisinusoidal fibrosis displayed less overlap between Metavir stages than did the whole fibrosis area values. Fractal dimension showed that portal-bridging fibrosis tended to display a homogeneous surface-like spatial organization, whereas perisinusoidal fibrosis appeared more heterogeneous according to stage and curvilinear. The portal-bridging fibrosis area was low in cases with low Metavir activity and little steatosis, and became predominant with increasing activity and steatosis. Using stepwise multiple linear regression analysis, the liver stiffness was independently correlated to the portal-bridging fibrosis area (first step, P<0.001), the steatosis area (second step, P<0.001), and the Metavir A grade (third step, P=0.001), but not to the perisinusoidal fibrosis area. Automated quantification in a large cohort of chronic hepatitis C showed that perisinusoidal fibrosis progressively grew in early fibrosis stages but did not increase in septal or cirrhotic stages and that the portal-bridging fibrosis area appeared as a more accurate tool to assess fibrosis progression than the whole fibrosis area.
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Melatonin in the regulation of liver steatosis following prenatal glucocorticoid exposure. BIOMED RESEARCH INTERNATIONAL 2014; 2014:942172. [PMID: 24822223 PMCID: PMC4005100 DOI: 10.1155/2014/942172] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 03/25/2014] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease patients are characterized by hepatic steatosis. Prenatal glucocorticoid overexposure can result in steatosis. In this study, we aimed to determine the mechanism and cellular apoptosis of prenatal glucocorticoid overexposure in rats and whether melatonin can rescue the prenatal glucocorticoid-induced steatosis and apoptosis in neonatal rats. Pregnant Sprague-Dawley rats at gestational days 14 to 21 were administered dexamethasone. Acute effects of prenatal programming liver were assessed at postnatal day 7. The expression of proteins involved in the apoptotic and methylation pathways was analyzed by RT-PCR and Western blotting. Apoptosis and steatosis were examined by histology staining. The liver steatosis and apoptosis were increased in prenatal glucocorticoid group more than in control group and decreased in melatonin group. The expression of leptin decreased in prenatal glucocorticoid and increased in melatonin group by liver RT-PCR and Western blot study. Caspase 3, TNF-α proteins expression, and TUNEL stains increased in prenatal glucocorticoid compared with control and decreased in melatonin group. The liver histone deacetylase, DNA methyltransferase activity, and DNA methylation were increased in prenatal glucocorticoid and decreased in melatonin group. The present study showed that the prenatal glucocorticoid induced programming liver steatosis at day 7 after delivery, possibly via altered leptin expression. Melatonin can reverse the methylation of leptin and decreased liver steatosis.
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Zampino R, Marrone A, Restivo L, Guerrera B, Sellitto A, Rinaldi L, Romano C, Adinolfi LE. Chronic HCV infection and inflammation: Clinical impact on hepatic and extra-hepatic manifestations. World J Hepatol 2013; 5:528-540. [PMID: 24179612 PMCID: PMC3812455 DOI: 10.4254/wjh.v5.i10.528] [Citation(s) in RCA: 165] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Revised: 08/06/2013] [Accepted: 09/13/2013] [Indexed: 02/06/2023] Open
Abstract
The liver has a central role in regulating inflammation by its capacity to secrete a number of proteins that control both local and systemic inflammatory responses. Chronic inflammation or an exaggerated inflammatory response can produce detrimental effects on target organs. Chronic hepatitis C virus (HCV) infection causes liver inflammation by complex and not yet well-understood molecular pathways, including direct viral effects and indirect mechanisms involving cytokine pathways, oxidative stress and steatosis induction. An increasing body of evidence recognizes the inflammatory response in chronic hepatitis C as pathogenically linked to the development of both liver-limited injury (fibrosis, cirrhosis and hepatocellular carcinoma) and extrahepatic HCV-related diseases (lymphoproliferative disease, atherosclerosis, cardiovascular and brain disease). Defining the complex mechanisms of HCV-induced inflammation could be crucial to determine the global impact of infection, to estimate progression of the disease, and to explore novel therapeutic approaches to avert HCV-related diseases. This review focuses on HCV-related clinical conditions as a result of chronic liver and systemic inflammatory states.
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25
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Yang M, Li N, Li F, Zhu Q, Liu X, Han Q, Wang Y, Chen Y, Zeng X, Lv Y, Zhang P, Yang C, Liu Z. Xanthohumol, a main prenylated chalcone from hops, reduces liver damage and modulates oxidative reaction and apoptosis in hepatitis C virus infected Tupaia belangeri. Int Immunopharmacol 2013; 16:466-474. [PMID: 23669332 DOI: 10.1016/j.intimp.2013.04.029] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Revised: 03/30/2013] [Accepted: 04/23/2013] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection in Tupaia belangeri (Tupaia) represents an important model of HCV infection. Xanthohumol (XN), a major prenylated chalcone from hops, has various biological activities including hepatopreventive and anti-viral activities. In this study, Tupaias infected with HCV RNA positive serum were used to evaluate the effects of XN on liver damage, oxidative reaction, apoptosis and viral protein expression in liver tissues. The Tupaias inoculated with HCV positive serum had elevated serum aminotransferase levels and inflammation, especially hepatic steatosis, and HCV core protein expression in liver tissue. In the animals inoculated with HCV positive serum, XN significantly decreased aminotransferase levels, histological activity index, hepatic steatosis score and transforming growth factor β1 expression in liver tissue compared with the animals without XN intervention. XN reduced HCV core protein expression in liver tissue compared with those without XN intervention but the difference was not significant. XN significantly decreased malondialdehyde, potentiated superoxide dismutase and glutathione peroxidase, reduced Bax expression, promoted Bcl-xL and inhibited caspase 3 activity in liver tissues compared with the animals without XN intervention. These results indicate that XN may effectively improve hepatic inflammation, steatosis and fibrosis induced by HCV in Tupaias primarily through inhibition of oxidative reaction and regulation of apoptosis and possible suppression of hepatic stellate cell activation. The anti-HCV potential of XN needs further investigation.
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Affiliation(s)
- Mingbo Yang
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, People's Republic of China
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Macaluso FS, Maida M, Minissale MG, Li Vigni T, Attardo S, Orlando E, Petta S. Metabolic factors and chronic hepatitis C: a complex interplay. BIOMED RESEARCH INTERNATIONAL 2013; 2013:564645. [PMID: 23956991 PMCID: PMC3730187 DOI: 10.1155/2013/564645] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 06/29/2013] [Indexed: 12/15/2022]
Abstract
In the last years, several lines of evidence showed how metabolic factors may influence the natural history of patients with chronic hepatitis C. Chronic HCV infection is able to perturb the metabolic homeostasis of the host, in a context of complex interactions where pre-existent metabolic status and genetic background play an important role, allowing us to state that HCV infection is a systemic disease. In this review, we discuss the most recent lines of evidence on the main metabolic factors that are known to be associated with CHC, namely, insulin resistance/type 2 diabetes, steatosis, visceral obesity, atherosclerosis, vitamin D, menopause, fructose and coffee intake, lipoproteins, methylenetetrahydrofolate reductase status, and hyperuricaemia. In particular, we focus on the pathophysiological mechanisms underlying the correlation between HCV infection and metabolic disorders, the impact of metabolic factors on the progression of liver and non-liver-related diseases, and, on the contrary, the possible influence of chronic HCV infection on metabolic features. In this setting, the importance of a multifaceted evaluation of CHC patients and a prompt correction of modifiable metabolic risk factors should be emphasized.
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Affiliation(s)
- Fabio Salvatore Macaluso
- Section of Gastroenterology, DiBiMIS, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy.
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Wu D, Li H, Xiang G, Zhang L, Li L, Cao Y, Zhang J. Adiponectin and its receptors in chronic hepatitis B patients with steatosis in china. HEPATITIS MONTHLY 2013; 13:e6065. [PMID: 23914225 PMCID: PMC3725260 DOI: 10.5812/hepatmon.6065] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 08/03/2012] [Accepted: 01/31/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND HBV infection is a serious public health problem worldwide, which can contribute to the incidence of chronic hepatitis B (CHB), cirrhosis, and hepatocellular carcinoma (HCC). OBJECTIVES In the present report, we assessed the association between adiponectin, its receptors and hepatic steatosis, fibrosis, and inflammation with hepatitis B virus. PATIENTS AND METHODS Liver biopsies from 89 patients with untreated chronic hepatitis B (34 steatosis vs. 55 without steatosis) were analyzed; liver biopsies from 50 healthy adults were used as control. The liver biopsies were subjected to routine histological examination, and stained immunohistochemically for adiponectin and adiponectin receptor2 (adipoR2). RESULTS The two groups were found to be comparable with respect to demographic, biochemical, metabolic, histological, and viral characteristics. BMI, γ-GT, FPG, insulin, and insulin sensitivity estimated by the HOMA index were significantly higher in patients with steatosis. The viral load of HBV and HBeAg positivity was higher in patients with steatosis than those without steatosis. High serum adiponectin levels were significantly correlated with abnormal serum ALT level (vs. normal ALT, P = 0.000), and HBV genotype C (vs. genotype B, P = 0.018). In patients with chronic HBV, the insulin sensitizing adipokine adiponectin, and its receptor AdipoR2were associated with steatosis. While adiponectin may becorrelated with inflammation, adiponectin, and its receptors were not associated with viral factors. CONCLUSIONS Our results suggest that the role of adiponectin might be impaired in chronic hepatitis B with steatosis. Reduced hepatic expression of adiponectin and adipoR2 might be of pathophysiological relevance in CHB patients with steatosis. These findings indicated that reduced liver adiponectin expression may play an important role in the pathogenesis, and progression of CHB patients with steatosis. However, hepatic expression of adiponectin, and adipoR2 was not associated with various measures of HBV infection.
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Affiliation(s)
- Di Wu
- Department of Ultrasound, Air Force General Hospital of PLA, Beijing, China
| | - Hongqi Li
- Department of Radiation Oncology, Air Force General Hospital of PLA, Beijing, China
- Daping Hospital,Third Military Medical University, Chongqing, China
| | - Guoan Xiang
- Department of General Surgery, the Second People's Hospital of Guangdong Province, Guangzhou, China
| | - Liwei Zhang
- Department of Cardiology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China
| | - Lihong Li
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Yongmei Cao
- International Mongolian Hospital, Hohhot of Inner Mongolia, Hohhot, China
- Corresponding authors: Yongmei Cao, International Mongolian Hospital, Hohhot of Inner Mongolia, 010065, Hohhot, China. Tel.: +86-4715182063, Fax: +86-4715182063, E-mail: ; Jinqian Zhang, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China. Tel.: +86-10864322622, Fax: +86-1084322616, E-mail:
| | - Jinqian Zhang
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Corresponding authors: Yongmei Cao, International Mongolian Hospital, Hohhot of Inner Mongolia, 010065, Hohhot, China. Tel.: +86-4715182063, Fax: +86-4715182063, E-mail: ; Jinqian Zhang, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China. Tel.: +86-10864322622, Fax: +86-1084322616, E-mail:
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Hepatorenal index as an accurate, simple, and effective tool in screening for steatosis. AJR Am J Roentgenol 2013; 199:997-1002. [PMID: 23096171 DOI: 10.2214/ajr.11.6677] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The hepatorenal index has been reported to be a sensitive and noninvasive test to quantify steatosis, but it is cumbersome and time-consuming and requires specialized software. The aim of this study was to improve and simplify the hepatorenal index calculation and determine whether it is an effective tool for differentiating patients with steatosis from those without steatosis, thereby eliminating the need for biopsy in a large number of patients. MATERIALS AND METHODS One hundred one patients who had undergone ultrasound-guided percutaneous liver biopsy at our institution were selected from a patient database. Patients with renal disease, patients with liver masses, and patients whose liver and right kidney were not included on the same image were excluded. Images were acquired with high-resolution ultrasound, and the hepatorenal index was calculated using freeware based on comparison of hepatic and renal brightness. RESULTS Of the 101 patients, 63 had 5% or less steatosis and 38 had more than 5% steatosis. Using freeware available online from the National Institutes of Health, we calculated hepatorenal index values for all patients. Our data showed a strong correlation between the hepatorenal index and percentage of fat (r = 0.71, p < 0.0001). A hepatorenal index of 1.28 or greater had a 100% sensitivity for identifying more than 5% fat, 54% specificity, 0.57 positive predictive value, and 1.0 negative predictive value. If this method had been used prospectively to select patients for biopsy in our sample, 34% of biopsies could have been avoided. CONCLUSION The hepatorenal index is a simple, reliable, and cost-effective screening tool for identifying patients who should not undergo liver biopsy for evaluation of steatosis.
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Khattab MA, Eslam M, Aly MM, Shatat M, Hussen A, Moussa YI, Elsaghir G, Abdalhalim H, Aly A, Gaber S, Harrison SA. Association of serum adipocytokines with insulin resistance and liver injury in patients with chronic hepatitis C genotype 4. J Clin Gastroenterol 2012; 46:871-879. [PMID: 22664476 DOI: 10.1097/mcg.0b013e318256b68a] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection, especially genotypes 1 and 4, is associated with metabolic dysfunction. We investigated the potential role of adipocytokines in HCV-induced insulin resistance (IR) and modulating the progression of liver disease in patients with HCV-4. METHODS Serum adiponectin, high molecular weight adiponectin, leptin, tumor necrosis factor-α, interluekin-6, homeostasis model for the assessment of insulin resistance, and M30 protein were measured in 147 HCV patients and 89 controls. Liver biopsies were evaluated for steatosis/inflammation/fibrosis, adiponectin mRNA/protein, AdipoR1/-R2 mRNA, and phosphoenolpyruvate carboxykinase gene expression, and adiponectin and CD95 immunoreactivity. RESULTS CD95 immunoreactivity and adiponectin immunoreactivity were detected in all biopsies examined. Hepatic adiponectin immunostaining correlated positively with the intensity of hepatic CD95/Fas immunostaining (r=0.424; P=0.001). Hepatocyte CD95/Fas upregulation correlated with fibrosis, inflammation, and steatosis (r=0.52, P=0.0001; r=0.16, P=0.04; r=0.24, P=0.0001; respectively). Significant correlations of serum adiponectin, its receptors mRNA expression, hepatic adiponectin immunostaining, and mRNA transcription for phosphoenolpyruvate carboxykinase were identified with steatosis. A positive association between adiponectin and hepatic inflammation and fibrosis was identified. This correlation remained significant even after adjusting for age, sex, and body mass index. Among body mass index, age, and sex-matched HCV-negative controls, patients with HCV-4 have higher serum leptin, adiponectin, and high molecular weight adiponectin, and these changes are independently correlated with IR. CONCLUSIONS Our findings in patients with HCV-4 show that adiponectin correlates with IR and with the different stages of liver injury. Steatosis upregulates hepatocyte CD95/Fas and thus increases apoptosis, which facilitates inflammation and fibrosis. These findings may provide potential clues for novel therapeutic intervention.
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Gunduz F, Aboulnasr FM, Chandra PK, Hazari S, Poat B, Baker DP, Balart LA, Dash S. Free fatty acids induce ER stress and block antiviral activity of interferon alpha against hepatitis C virus in cell culture. Virol J 2012; 9:143. [PMID: 22863531 PMCID: PMC3490746 DOI: 10.1186/1743-422x-9-143] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Accepted: 07/27/2012] [Indexed: 12/12/2022] Open
Abstract
Background Hepatic steatosis is recognized as a major risk factor for liver disease progression and impaired response to interferon based therapy in chronic hepatitis C (CHC) patients. The mechanism of response to interferon-alpha (IFN-α) therapy under the condition of hepatic steatosis is unexplored. We investigated the effect of hepatocellular steatosis on hepatitis C virus (HCV) replication and IFN-α antiviral response in a cell culture model. Methods Sub-genomic replicon (S3-GFP) and HCV infected Huh-7.5 cells were cultured with a mixture of saturated (palmitate) and unsaturated (oleate) long-chain free fatty acids (FFA). Intracytoplasmic fat accumulation in these cells was visualized by Nile red staining and electron microscopy then quantified by microfluorometry. The effect of FFA treatment on HCV replication and IFN-α antiviral response was measured by flow cytometric analysis, Renilla luciferase activity, and real-time RT-PCR. Results FFA treatment induced dose dependent hepatocellular steatosis and lipid droplet accumulation in the HCV replicon cells was confirmed by Nile red staining, microfluorometry, and by electron microscopy. Intracellular fat accumulation supports replication more in the persistently HCV infected culture than in the sub-genomic replicon (S3-GFP) cell line. FFA treatment also partially blocked IFN-α response and viral clearance by reducing the phosphorylation of Stat1 and Stat2 dependent IFN-β promoter activation. We show that FFA treatment induces endoplasmic reticulum (ER) stress response and down regulates the IFNAR1 chain of the type I IFN receptor leading to defective Jak-Stat signaling and impaired antiviral response. Conclusion These results suggest that intracellular fat accumulation in HCV cell culture induces ER stress, defective Jak-Stat signaling, and attenuates the antiviral response, thus providing an explanation to the clinical observation regarding how hepatocellular steatosis influences IFN-α response in CHC.
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Affiliation(s)
- Feyza Gunduz
- Department of Medicine, Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
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Brenner T, Rosenhagen C, Brandt H, Schmitt FCF, Jung GE, Schemmer P, Schmidt J, Mieth M, Bruckner T, Lichtenstern C, Martin EO, Weigand MA, Hofer S. Cell death biomarkers as early predictors for hepatic dysfunction in patients after orthotopic liver transplantation. Transplantation 2012; 94:185-191. [PMID: 22743549 DOI: 10.1097/tp.0b013e318254397c] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Valid prognostic factors for early identification of a complicated course after orthotopic liver transplantation from deceased donors are rare. The aim of this study was to investigate the prognostic value of different cell death biomarkers and inflammatory markers in patients after orthotopic liver transplantation from deceased donors. METHODS In total, 100 patients were evaluated for short-term complications within 10 days after orthotopic liver transplantation from deceased donors. Blood samples were collected before surgery, immediately after the end of the surgical procedure, and 1 day and 3, 5, and 7 days later. Plasma levels of total keratin 18, keratin 18 fragments, interleukin 6, tumor necrosis factor α, and soluble intercellular adhesion molecule 1 were measured. RESULTS Total keratin 18 was demonstrated to be favorable in its prognostic value for early identification of a complicated course in comparison to routine markers of liver impairment (e.g., aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase). In contrast, inflammation markers (e.g., interleukin 6, tumor necrosis factor α and soluble intercellular adhesion molecule 1) were unsuitable for predicting early complications after liver transplantation from deceased donors. CONCLUSIONS For early identification of patients at high risk for complications, the implementation of total keratin 18 measurements in routine diagnostics after orthotopic liver transplantation from deceased donors should be taken into consideration.
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Affiliation(s)
- Thorsten Brenner
- Department of Anaesthesiology, University of Heidelberg, Heidelberg, Germany.
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Xiang X, Gui H, King NJC, Cole L, Wang H, Xie Q, Bao S. IL-22 and non-ELR-CXC chemokine expression in chronic hepatitis B virus-infected liver. Immunol Cell Biol 2012; 90:611-9. [PMID: 21946664 DOI: 10.1038/icb.2011.79] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis B virus infection is still a major global health problem, despite decades of research. Interleukin (IL)-22 induces acute phase reactants and chemokines, favors anti-microbial defence and protects tissues from damage. IL-22 is important in chronic skin inflammation, but its role in chronic hepatitis B (CHB) is unclear. This study explores the association between intra-hepatic IL-22 expression, its relevant associated cytokines and the severity of liver inflammation/fibrosis in CHB patients. IL-22, IL-17, IL-10, IL-6, non-ELR-CXC chemokines (CXCL-9, CXCL-10, CXCL-11), fibroblast growth factors and Kupffer cell (KC) numbers were measured in patients with CHB (n=65), acute hepatitis B (AHB; n=4), chronic hepatitis C (CHC; n=14) and non-viral hepatitis (n=23), using immunohistochemistry. Expression of IL-22, IL-17, IL-10, IL-6, non-ELR-CXC chemokines and number of KCs in liver tissues were substantially higher in AHB patients than others. In CHB patients, the expression of IL-22, IL-6, CXCL-9 and CXCL-10 were significantly higher with alanine aminotransferase (ALT) levels ≤ twice the upper limit of normal (ULN), compared with those with ALT levels >twice the ULN, whereas IL-10 and IL-17 showed a reverse pattern. IL-22 was inversely (P<0.01), but IL-17 was positively (P<0.05), correlated with the histological activity index) in these patients, and a significant negative correlation between the fibrosis stage and IL-22 or non-ELR-CXC chemokines was observed. Furthermore, immunofluorescent labeling demonstrated a close spatial association of IL-22, CXCL-9, -10 or -11 in the CHB liver. We speculate that IL-22 and non-ELR-CXC chemokines synergistically may provide protection in liver inflammation/fibrosis during CHB infection.
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Affiliation(s)
- Xiaogang Xiang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Jazwinski AB, Thompson AJ, Clark PJ, Naggie S, Tillmann HL, Patel K. Elevated serum CK18 levels in chronic hepatitis C patients are associated with advanced fibrosis but not steatosis. J Viral Hepat 2012; 19:278-82. [PMID: 22404726 PMCID: PMC4892381 DOI: 10.1111/j.1365-2893.2011.01546.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cytokeratin-18 (CK-18) is a major intermediate filament protein in liver cells. The M30 fragment of CK-18 has been identified as a useful marker of apoptosis associated with fibrosis and steatosis in nonalcoholic steatohepatitis (NASH). We sought to assess the relationship of this marker and steatosis in a cohort of adult patients with chronic hepatitis C. The study cohort included sera from 267 treatment-naïve chronic hepatitis C (CHC) patients and 100 healthy controls with normal alanine aminotransferase (ALT). Biopsies from CHC patients were assessed for METAVIR fibrosis stage, Histology Activity Index (HAI) inflammation score and steatosis grade by expert histopathologists. The M30 fragment of CK-18 was quantified by ELISA. Wilcoxon Rank Sum, Spearman Correlation and Linear Regression tests were performed for statistical analysis. Median CK-18 levels were higher in CHC patients compared to controls (411 vs 196 U/L, P < 0.0001). Fibrosis stage was associated with increasing serum CK-18 levels (P = 0.015) and CK-18 levels were higher for F2-F4 vs F0-F1 (500 vs 344 U/L; P = 0.001). There was no association between CK-18 and increasing steatosis grade 1, 2 or 3 (460.7 vs 416.8 vs 508.3 U/L; P = 0.35) and presence or absence of steatosis (445.3 vs 365.8 U/L; P = 0.075). Fibrosis stage was independently associated with serum M30 in a multivariable linear regression model (P = 0.03). CK-18 levels were higher in CHC compared to healthy controls and associated with hepatic fibrosis. There was no difference in CK-18 M30 levels between CHC patients with and without steatosis. Although apoptosis may still contribute to hepatitis C virus (HCV)-mediated steatosis, our results suggest that serum CK-18 will not be a clinically useful test for identifying significant steatosis in CHC.
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Affiliation(s)
- A B Jazwinski
- Division of Gastroenterology and Hepatology, Duke Clinical Research Institute and Duke University Medical Center, Durham, NC 27710, USA.
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Camel's milk alleviates alcohol-induced liver injury in rats. Food Chem Toxicol 2012; 50:1377-83. [PMID: 22281157 DOI: 10.1016/j.fct.2012.01.016] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Revised: 12/22/2011] [Accepted: 01/10/2012] [Indexed: 12/20/2022]
Abstract
Alcoholic liver disease (ALD) represents a spectrum of clinical illness and morphological changes that range from fatty liver, hepatic inflammation and necrosis to progressive fibrosis. For the etiology of ALD, oxidative stress, increased expression of proinflammatory cytokines and apoptosis have been described. The present study aimed to investigate the effectiveness of camel's milk (CM) in alleviating alcohol-induced hepatotoxicity as a model of clinical liver illness. Male rats were grouped into four groups from which one group received normal saline and served as control. Groups from 2 to 4 received a daily oral dose of 56% ethanol for 4 weeks. Group 2 served as untreated control while groups 3 and 4 were respectively treated with CM either in a prophylactic or a curative approach. Alanine transaminase, aspartate transaminase, alkaline phosphatase, triglycerides, as well as cholesterol levels were estimated in the serum. Malondialdehyde, total antioxidant capacity, and tumor necrosis factor-alpha levels along with caspase-3 activity were determined in liver tissue homogenate. A histopathological analysis of liver tissue was also achieved. Results showed amelioration of all tested parameters following administration of CM. Conclusively, treatment with camel's milk alleviates alcohol-associated hazards and protects hepatic tissue from alcohol-induced toxicity.
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Mechanisms and biomarkers of apoptosis in liver disease and fibrosis. Int J Hepatol 2012; 2012:648915. [PMID: 22567408 PMCID: PMC3332069 DOI: 10.1155/2012/648915] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Accepted: 01/24/2012] [Indexed: 02/07/2023] Open
Abstract
Liver fibrosis and cirrhosis are a major cause of morbidity and mortality worldwide. Development of the fibrotic scar is an outcome of chronic liver diseases of varying aetiologies including alcoholic liver disease (ALD) nonalcoholic liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH) viral hepatitis B and C (HBV, HCV). The critical step in the development of scar is activation of hepatic stellate cells (HSCs), which become the primary source of extracellular matrix. Aberrant apoptosis is a feature of chronic liver diseases and is associated with worsening stages of fibrosis. However, apoptosis is also the main mechanism promoting the resolution of fibrosis, and spontaneous or targeted apoptosis of HSC is associated with regression of fibrosis in animal models and patients with chronic liver disease. Given the importance of apoptosis in disease progression and resolution, there is much interest in precisely delineating the mechanisms involved and also developing biomarkers that accurately reflect the underlying pathogenesis. Here, we review the mechanisms driving apoptosis in development of liver disease and use of apoptosis -related biomarkers to aid in clinical diagnosis. Finally, we will also examine the recent literature regarding new insights into mechanisms involved in apoptosis of activated HSCs as possible method of fibrosis regression.
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Basaranoglu M, Basaranoglu G. Pathophysiology of insulin resistance and steatosis in patients with chronic viral hepatitis. World J Gastroenterol 2011; 17:4055-62. [PMID: 22039318 PMCID: PMC3203355 DOI: 10.3748/wjg.v17.i36.4055] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Revised: 05/16/2011] [Accepted: 05/23/2011] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis due to any cause leads to cirrhosis and end-stage liver disease. A growing body of literature has also shown that fatty liver due to overweight or obesity is a leading cause of cirrhosis. Due to the obesity epidemic, fatty liver is now a significant problem in clinical practice. Steatosis has an impact on the acceleration of liver damage in patients with chronic hepatitis due to other causes. An association between hepatitis C virus (HCV) infection, steatosis and the onset of insulin resistance has been reported. Insulin resistance is one of the leading factors for severe fibrosis in chronic HCV infections. Moreover, hyperinsulinemia has a deleterious effect on the management of chronic HCV. Response to therapy is increased by decreasing insulin resistance by weight loss or the use of thiazolidenediones or metformin. The underlying mechanisms of this complex interaction are not fully understood. A direct cytopathic effect of HCV has been suggested. The genomic structure of HCV (suggesting that some viral sequences are involved in the intracellular accumulation of triglycerides), lipid metabolism, the molecular links between the HCV core protein and lipid droplets (the core protein of HCV and its transcriptional regulatory function which induce a triglyceride accumulation in hepatocytes) and increased neolipogenesis and inhibited fatty acid degradation in mitochondria have been investigated.
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Kaddai V, Negro F. Current understanding of insulin resistance in hepatitis C. Expert Rev Gastroenterol Hepatol 2011; 5:503-16. [PMID: 21780897 DOI: 10.1586/egh.11.43] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Important breakthroughs have been made in recent years into understanding the close interaction between hepatitis C virus (HCV) infection and glucose homeostasis. Both cross-sectional and longitudinal studies have demonstrated that infection with HCV is associated with an increased risk of developing insulin resistance and Type 2 diabetes. A direct effect of HCV on hepatocyte insulin signaling has been shown in experimental models. Some preliminary observations seem to suggest that indirect mechanisms involving extrahepatic organs might also play a role. The interaction between HCV and glucose metabolism has significant clinical consequences. Insulin resistance and Type 2 diabetes not only accelerate the histological and clinical progression of chronic hepatitis C, but also reduce the virological response to IFN-α-based therapy. Thus, understanding the mechanisms underlying HCV-associated glucose metabolism derangements is of paramount interest in order to improve the clinical management of chronic hepatitis C. This article will focus on the studies that consistently argue in favor of an interrelation between HCV and insulin resistance and will highlight the latest discoveries in this field.
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Affiliation(s)
- Vincent Kaddai
- Department of Pathology and Immunology, Centre Médical Universitaire, Rue Michel-Servet 1, Geneva, Switzerland
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Abstract
Type 2 Diabetes mellitus (T2D) is the most common endocrine disorder associated to metabolic syndrome (MS) and occurs when insulin secretion can no compensate peripheral insulin resistance. Among peripheral tissues, the liver controls glucose homeostasis due to its ability to consume and produce glucose. The molecular mechanism underlying hepatic insulin resistance is not completely understood; however, it involves the impairment of the insulin signalling network. Among the critical nodes of hepatic insulin signalling, insulin receptor substrate 2 (IRS2) and protein tyrosine phosphatase 1B (PTP1B) modulate the phosphatidylinositol (PI) 3-kinase/Akt/Foxo1 pathway that controls the suppression of gluconeogenic genes. In this review, we will focus on recent findings regarding the molecular mechanism by which IRS2 and PTP1B elicit opposite effects on carbohydrate metabolism in the liver in response to insulin. Finally, we will discuss the involvement of the critical nodes of insulin signalling in non-alcoholic fatty liver disease (NAFLD) in humans.
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Affiliation(s)
- Angela M Valverde
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), C/Arturo Duperier 4, 28029 Madrid, Spain.
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Trépo E, Pradat P, Potthoff A, Momozawa Y, Quertinmont E, Gustot T, Lemmers A, Berthillon P, Amininejad L, Chevallier M, Schlué J, Kreipe H, Devière J, Manns M, Trépo C, Sninsky J, Wedemeyer H, Franchimont D, Moreno C. Impact of patatin-like phospholipase-3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. Hepatology 2011; 54:60-9. [PMID: 21488075 DOI: 10.1002/hep.24350] [Citation(s) in RCA: 152] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
UNLABELLED Only 20% of patients with chronic hepatitis C (CHC) will develop cirrhosis, and fibrosis progression remains highly unpredictable. A recent genome-wide association study identified a genetic variant in the patatin-like phospholipase-3 (PNPLA3) gene (rs738409 C>G) associated with steatosis that was further demonstrated to influence severity of fibrosis in nonalcoholic fatty liver disease. The aim of this study was to assess the impact of this polymorphism on histological liver damage and response to antiviral therapy in CHC. We recruited 537 Caucasian CHC patients from three European centers (Brussels, Belgium [n = 229]; Hannover, Germany [n = 171]; Lyon, France [n = 137]); these patients were centrally genotyped for the PNPLA3 (rs738409 C>G) polymorphism. We studied the influence of rs738409 and other variants in the PNPLA3 region on steatosis and fibrosis assessed both in a cross-sectional and longitudinal manner. Seven other variants previously associated with fibrosis progression were included. Finally, we explored the impact of rs738409 on response to standard antiviral therapy using the interferon lambda 3 (IL28B) [rs12979860 C>T] variant both as a comparator and as a positive control. After adjustment for age, sex, body mass index, alcohol consumption, and diabetes, rs738409 mutant G allele homozygote carriers remained at higher risk for steatosis (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.08-6.03, P = 0.034), fibrosis (OR 3.13, 95% CI 1.50-6.51, P = 0.002), and fibrosis progression (OR 2.64, 95% CI 1.22-5.67, P = 0.013). Conversely, rs738409 was not independently associated with treatment failure (OR 1.07, 95% CI 0.46-2.49, P = 0.875) and did not influence clinical or biological variables. CONCLUSION The PNPLA3 (rs738409 C>G) polymorphism favors steatosis and fibrosis progression in CHC. This polymorphism may represent a valuable genetic predictor and a potential therapeutic target in CHC liver damage.
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Affiliation(s)
- Eric Trépo
- Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, Erasme Hospital, Brussels, Belgium
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Serbetçi K, Uysal O, Erkasap N, Köken T, Baydemir C, Erkasap S. Anti-apoptotic and antioxidant effect of leptin on CCl₄-induced acute liver injury in rats. Mol Biol Rep 2011; 39:1173-80. [PMID: 21607623 DOI: 10.1007/s11033-011-0847-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Accepted: 05/12/2011] [Indexed: 01/30/2023]
Abstract
The aim of this study is to investigate the effect of leptin in rats on carbon tetrachloride (CCl(4)) induced acute liver damage using immunohistochemical methods for apoptosis and biochemical parameters. In this experimental study, 18 Spraque-Dawley rats were divided into three groups viz; control, CCl(4) and CCl(4)+leptin treatment. 0.8 ml/kg olive oil was administered intraperitoneally (i.p.) to the control group and 0.8 ml/kg CCl(4) (1:1 dissolved in olive oil) was administered i.p. to the CCl(4) and CCl(4)+leptin treatment groups, respectively. After 6 h of administrating CCl(4), CCl(4)+leptin treatment group was given i.p. leptin (10 μg/kg). Twenty-four hours after administrating CCl(4) all of the groups were euthanized. Biochemical assessments were performed using serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), plasma tumor necrosis factor alpha (TNF-α) levels and tissue malondialdehyde (MDA), and TNF-α levels. Histological assessments were then performed using Hematoxylin&Eosin (H&E) staining in light microscope and apoptosis assessment using Terminal Transferase dUTP Nick End Labeling (TUNEL)-staining. Serum AST, ALT, ALP and plasma TNF-α levels, tissue MDA and TNF-α levels had all increased in CCl(4) group, but were found to be significantly decreased in CCl(4)+leptin treatment group. Moreover, TUNEL-positive cell counts in liver had significantly increased in CCl(4) group, but decreased in CCl(4)+leptin treatment group (P < 0.05). The results of our study the biochemical, histological and TUNEL-staining showed that leptin has treatment effects on liver CCl(4) induced injury. It plays a role as a potent free radical scavenger, a powerful antioxidant and it also has anti-apoptotic effects.
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Affiliation(s)
- Kerim Serbetçi
- Department of General Surgery, Eskişehir Osmangazi University, Medical Faculty, Eskisehir, Turkey
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Yan J, Jie Z, Hou L, Wanderley JL, Soong L, Gupta S, Qiu S, Chan T, Sun J. Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice. Hepatology 2011; 53:1455-67. [PMID: 21360722 PMCID: PMC3082591 DOI: 10.1002/hep.24270] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
UNLABELLED The healthy adult human liver expresses low levels of major histocompatibility complex class II (MHC II) and undetectable levels of immune costimulatory molecules. However, high levels of MHC II, CD40, and B7 family molecules are expressed in the activated Kupffer cells and hepatocytes of patients with viral hepatitis. The precise role of these molecules in viral clearance and immune-mediated liver injury is not well understood. We hypothesized that parenchymal CD40 expression enhances T cell recruitment and effector functions, which may facilitate viral clearance and alleviate liver injury. To test this hypothesis, we generated novel liver-specific, conditional CD40 transgenic mice, and we challenged them intravenously with a recombinant replication-deficient adenovirus carrying Cre recombinase (AdCre). Wild-type mice infected with AdCre developed a relatively mild course of viral hepatitis and recovered spontaneously. CD40 expression in the livers of transgenic animals, however, resulted in CD80 and CD86 expression. The dysregulation of population dynamics and effector functions of intrahepatic lymphocytes (IHLs) resulted in severe lymphocytic infiltration, apoptosis, necroinflammation, and serum alanine aminotransferase elevations in a dose-dependent fashion. To our surprise, an early expansion and subsequent contraction of IHLs (especially CD8(+) and natural killer cells), accompanied by increased granzyme B and interferon-γ production, did not lead to faster viral clearance in CD40 transgenic mice. CONCLUSION Our results demonstrate that hepatic CD40 expression does not accelerate adenoviral clearance but rather exacerbates liver injury. This study unveils a previously unknown deleterious effect of hepatic CD40 on adenovirus-induced liver inflammation.
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Affiliation(s)
- Jiabin Yan
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1019, USA
| | - Zuliang Jie
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1019, USA
| | - Lifei Hou
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1019, USA
| | - Joao L. Wanderley
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1019, USA, Morphological Sciences Program, Federal University of Rio de Janeiro, RJ, Brazil
| | - Lynn Soong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1019, USA, Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-1019, USA
| | - Shalini Gupta
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1019, USA
| | - Suimin Qiu
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-1019, USA
| | - Tehsheng Chan
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1019, USA
| | - Jiaren Sun
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1019, USA, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas 77555-1019, USA
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Jang JY, Shao RX, Lin W, Weinberg E, Chung WJ, Tsai WL, Zhao H, Goto K, Zhang L, Mendez-Navarro J, Jilg N, Peng LF, Brockman MA, Chung RT. HIV infection increases HCV-induced hepatocyte apoptosis. J Hepatol 2011; 54:612-20. [PMID: 21146890 PMCID: PMC3060969 DOI: 10.1016/j.jhep.2010.07.042] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Revised: 07/12/2010] [Accepted: 07/16/2010] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS HCV related liver disease is one of the most important complications in persons with HIV, with accelerated fibrosis progression in coinfected persons compared to those with HCV alone. We hypothesized that HCV-HIV coinfection increases HCV related hepatocyte apoptosis and that HCV and HIV influence TRAIL signaling in hepatocytes. METHODS We analyzed the effect of HIV in JFH1-infected Huh7.5.1 cells. Apoptosis was measured by Caspase-Glo 3/7 assay and Western blotting for cleaved PARP. TRAIL, TRAIL receptor 1 (DR4), and 2 (DR5) mRNA and protein levels were assessed by real-time PCR and Western blot, respectively. We also investigated activation of caspase pathways using caspase inhibitors and assessed expression of Bid and cytochrome C. RESULTS We found increased caspase 3/7 activity and cleaved PARP in JFH1 HCV-infected Huh7.5.1 cells in the presence of heat-inactivated HIV, compared to Huh7.5.1 cells infected with JFH1 or exposed to heat-inactivated HIV alone. Both DR4 and DR5 mRNA and protein expression were increased in JFH1-infected cells in the presence of inactivated HIV compared to Huh7.5.1 cells infected with JFH1 or exposed to heat-inactivated HIV alone. Pancaspase, caspase-8, and caspase-9 inhibition blocked apoptosis induced by HCV, inactivated HIV, and HCV plus inactivated HIV. A caspase-9 inhibitor blocked apoptosis induced by HCV, HIV, and HCV-HIV comparably to pancaspase and caspase-8 inhibitors. HCV induced the activation of Bid cleavage and cytochrome C release. The addition of HIV substantially augmented this induction. CONCLUSIONS Our findings indicate that hepatocyte apoptosis is increased in the presence of HCV and HIV compared to HCV or HIV alone, and that this increase is mediated by DR4 and DR5 up-regulation. These results provide an additional mechanism for the accelerated liver disease progression observed in HCV-HIV co-infection.
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Affiliation(s)
- Jae Young Jang
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul, South Korea
| | - Run-Xuan Shao
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Wenyu Lin
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Ethan Weinberg
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Woo Jin Chung
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Wei Lun Tsai
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Hong Zhao
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Kaku Goto
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Leiliang Zhang
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Jorge Mendez-Navarro
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Nikolaus Jilg
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Lee F. Peng
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Mark A. Brockman
- Partners AIDS Research Center, Massachusetts General Hospital and Division of AIDS, Harvard Medical School
| | - Raymond T. Chung
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
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McPherson S, Powell EE, Barrie HD, Clouston AD, McGuckin M, Jonsson JR. No evidence of the unfolded protein response in patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol 2011; 26:319-27. [PMID: 21261722 DOI: 10.1111/j.1440-1746.2010.06368.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIM Hepatitis C virus (HCV) proteins activate the unfolded protein response (UPR) in experimental models. The role of the UPR in the pathogenesis of HCV-induced liver injury has not been determined. Our aim was to investigate the role of the UPR in the pathogenesis of chronic HCV. METHODS Liver biopsy samples from 124 patients with chronic HCV and 24 HCV/HBV-negative subjects with histologically normal liver (NDL) were assessed. The hepatic mRNA expression of components of the UPR was measured by semi-quantitative real-time polymerase chain reaction. Glucose regulated protein (GRP) 78 protein expression was assessed by immunohistochemistry. RESULTS The expression of GRP78 mRNA and growth arrest and damage inducible protein 34 (GADD34) mRNA was significantly lower in subjects with HCV than NDL (P = 0.007 and P < 0.001, respectively). There was no significant difference in the expression of GRP94 mRNA, spliced X box binding protein 1 (sXBP1) mRNA, C/EBP homologous protein mRNA (CHOP) and ER degradation enhancing α-mannosidase-like protein (EDEM) mRNA and GRP78 protein between patients with HCV and NDL. There were no relationships between elements of the UPR and inflammation or fibrosis in patients with HCV. CONCLUSION Downstream components of UPR were not activated in patients with chronic HCV. Therefore, the UPR may not play a prominent role in liver injury in patients with chronic HCV infection.
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Affiliation(s)
- Stuart McPherson
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
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44
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García-Monzón C, Lo Iacono O, Mayoral R, González-Rodríguez A, Miquilena-Colina ME, Lozano-Rodríguez T, García-Pozo L, Vargas-Castrillón J, Casado M, Boscá L, Valverde AM, Martín-Sanz P. Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C. J Hepatol 2011; 54:142-152. [PMID: 20888662 DOI: 10.1016/j.jhep.2010.06.021] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2010] [Revised: 05/06/2010] [Accepted: 06/08/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We aimed to elucidate whether hepatic insulin resistance may contribute to hepatocyte apoptosis and fibrogenesis in nonalcoholic fatty liver disease (NAFLD) and in chronic hepatitis C virus (HCV) infection. METHODS Twenty-seven nonalcoholic steatosis (NAST), 24 nonalcoholic steatohepatitis (NASH), 71 HCV, and 29 patients with histological normal liver (NL) were studied. Real-time PCR, the TUNEL assay, and Western blots were used to assess insulin-signaling molecules, hepatocyte apoptosis, antiapoptotic mediators, active caspase 3, and type I collagen in liver biopsies. HCV core-transfected human hepatocytes were used as an in vitro model. RESULTS In NAFLD patients, hepatic levels of insulin receptor substrate (IRS) 1, IRS2 2, the p85α subunit of phosphatidylinositol 3-kinase (p85α), phosphorylated protein kinase B (pAkt), phosphorylated forkhead box-containing protein O subfamily-1 (FoxO), and phosphorylated 5' adenosine monophosphate-activated protein kinase (pAMPK) as well as the antiapoptotic mediators B-cell lymphoma 2 protein (Bcl-2) and myeloid cell leukemia protein-1 (Mcl-1) were significantly lower in NASH than in NAST and NL. Furthermore, hepatocyte apoptosis and increased active caspase 3 were only present in NASH. In HCV patients, hepatic insulin signaling was markedly impaired, regardless of viral genotype and the presence of steatosis paralleled with enhanced apoptosis. In cultured human hepatocytes, HCV core protein decreased pAkt and increased phosphorylation of c-Jun N-terminal kinase (JNK). This effect was more pronounced in lipid-loaded hepatocytes. CONCLUSIONS Hepatic insulin signaling is impaired in NASH and HCV patients, and downregulation of insulin-sensitive targets is associated with increased apoptosis and fibrogenesis in both conditions. JNK might be a target for HCV-induced insulin resistance.
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Affiliation(s)
- Carmelo García-Monzón
- Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
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Abstract
Fibrosis is a common feature of chronic liver injury and is initiated by cell death inside the liver. Hepatocyte death results in apoptotic bodies and other cellular debris, which are phagocytosed by hepatic stellate cells (HSCs), resulting in their activation, proliferation, differentiation, and matrix deposition. This profibrotic effect of cellular death is balanced by an antifibrotic effect of HSC death. Many HSC survival signals are obtained from the extracellular matrix, and active proapoptotic signals are provided by immune cells, particularly natural killer (NK) cells. Quiescent HSCs are relatively resistant to apoptotic signals but become sensitive after activation. The important role of NK cells in inducing HSC apoptosis may explain the increased fibrosis associated with immune suppression (e.g., in the transplant recipient) and HIV infection. HSCs also undergo senescence, which limits their function and sensitizes them to apoptosis.
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Affiliation(s)
- Wajahat Mehal
- Section of Digestive Diseases, Yale University, New Haven, Connecticut
| | - Avlin Imaeda
- Section of Digestive Diseases, Yale University, New Haven, Connecticut
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Valva P, De Matteo E, Galoppo MC, Gismondi MI, Preciado MV. Apoptosis markers related to pathogenesis of pediatric chronic hepatitis C virus infection: M30 mirrors the severity of steatosis. J Med Virol 2010; 82:949-57. [DOI: 10.1002/jmv.21699] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Papatheodoridis GV, Hadziyannis E, Tsochatzis E, Georgiou A, Kafiri G, Tiniakos DG, Margariti K, Manolakopoulos S, Manesis EK, Archimandritis AJ. Serum apoptotic caspase activity in chronic hepatitis C and nonalcoholic Fatty liver disease. J Clin Gastroenterol 2010; 44:e87-e95. [PMID: 19881359 DOI: 10.1097/mcg.0b013e3181c0945a] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Apoptotic caspases are substantially activated in liver and serum caspase activity has been suggested as a marker of early liver injury. AIM To investigate whether serum levels of caspase-generated fragments of cytokeratin-18 are associated with the severity of histologic lesions in chronic hepatitis C virus (HCV) infection and nonalcoholic fatty liver disease (NAFLD). METHODS We included 134 patients with chronic HCV infection and 58 patients with NAFLD, who consecutively underwent liver biopsy, and 40 healthy controls. Caspase-generated cytokeratin-18 fragment levels were blindly measured in stored serum samples. RESULTS Median cytokeratin-18 fragment levels were lower in HCV-positive patients with minimal/mild than patients with moderate/severe histologic lesions (174 U/L vs. 223 U/L, P<0.001) offering moderate accuracy for differentiation between the 2 groups (c-statistic: 0.74). Cytokeratin-18 fragments levels were lower in healthy subjects (148 U/L) than patients with simple fatty liver (174 U/L, P=0.013) than patients with nonalcoholic steatohepatitis (355 U/L, P<0.001) offering excellent diagnostic accuracy for differentiation between the 2 latter groups (c-statistic: 0.87). CONCLUSIONS Serum apoptotic caspase activity is associated with the severity of liver histologic lesions in both chronic HCV infection and NAFLD, but it has excellent diagnostic accuracy in NAFLD and moderate accuracy in chronic HCV patients.
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Affiliation(s)
- George V Papatheodoridis
- Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, 114 Vas. Sophias Ave, 115 27 Athens, Greece.
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Abstract
The finding of lipid accumulation in the liver, so-called hepatic steatosis or non-alcoholic fatty liver disease, is a common condition frequently found in healthy subjects. Its prevalence, in fact, has been estimated by magnetic resonance studies to be about 35% in the general population and 75% in obese persons. Nevertheless, its presence generates liver damage only in a small percentage of subjects not affected by other liver diseases. It should be defined as a “co-factor” capable of affecting severity and progression, and also therapeutic perspectives, of liver diseases to which it is associated. Herein we will evaluate the impact of hepatic steatosis and obesity on the most common liver diseases: chronic viral hepatitis C and B, and alcoholic liver disease.
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Lee Y, Friedman SL. Fibrosis in the Liver. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2010; 97:151-200. [DOI: 10.1016/b978-0-12-385233-5.00006-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Cross TJS, Quaglia A, Hughes S, Joshi D, Harrison PM. The impact of hepatic steatosis on the natural history of chronic hepatitis C infection. J Viral Hepat 2009; 16:492-9. [PMID: 19200134 DOI: 10.1111/j.1365-2893.2009.01098.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Since patients with hepatitis C virus (HCV) often have hepatic steatosis, this retrospective analysis aimed to assess whether steatosis influences fibrosis progression. We studied 112 HCV RNA positive subjects (median age 44, IQR 39-51 years), who had two liver biopsies performed (median biopsy interval 50, 34-74 months). Fibrosis was staged using the Ishak method and steatosis by the Kleiner system (<5% steatosis = S0, 5-33% = S1, 33-66% = S2, and >66% = S3). The subjects were untreated because they had mild fibrosis (n = 59), declined therapy (n = 48), or had co-existing disease precluding treatment (n = 5). On first liver biopsy, 60 (54%) had S0, 34 (30%) had S1, 12 (11%) had S2, and 6 (5%) had S3. Steatosis was associated with genotype 3, odds ratio 4.8 (95% CI 1.3-16.7, P = 0.02). Twenty-three patients (21%) had disease progression on the second biopsy, defined as an increase in Ishak score by > or =1 stage. On univariate analysis, fibrosis progression was associated with older age (P = 0.004), higher AST (P = 0.04), and steatosis (P = 0.005) but on multivariate analysis, only baseline steatosis was significant, odds ratio 14.3 (2.1-111.1, P = 0.006). Kaplan-Meier analysis demonstrated that steatosis impacted on time to progression to both significant fibrosis (Ishak > or =F3) and cirrhosis (Ishak F5-6) (P = 0.001 and P = 0.049, respectively). The finding that steatosis was significantly associated with fibrosis progression indicates that, independent of baseline fibrosis stage, patients should be considered for anti-viral treatment if steatosis is present. Furthermore, strategies to reduce steatosis may have a beneficial effect on fibrosis progression and, therefore, patient outcome.
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Affiliation(s)
- T J S Cross
- Hepatology Department, Derriford Hospital, Plymouth, UK
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