|
1
|
Yang H, Chen L, Liu Y. Association of leukocyte telomere length with the risk of digestive diseases: A large-scale cohort study. Chin Med J (Engl) 2025; 138:60-67. [PMID: 39647990 PMCID: PMC11717523 DOI: 10.1097/cm9.0000000000002994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Indexed: 12/10/2024] Open
Abstract
BACKGROUND Leukocyte telomere length (LTL) shortening, a biomarker of telomere attrition, has been linked to multiple diseases. However, the relationship between LTL and digestive diseases remains uncertain. This study aimed to investigate the association between LTL and the risk of digestive diseases. METHODS A cohort analysis of over 500,000 participants from the UK Biobank (UKB) between 2006 and 2021 was conducted to estimate the associations of LTL with more than 90 common digestive diseases. LTL was quantified using multiplex quantitative polymerase chain reaction, and cases of each disease were determined according to inpatient and primary care data. Multivariable Cox proportional hazards regression analysis was used to evaluate the associations of LTL with the risk of digestive diseases. Furthermore, such associations were also evaluated after stratification by sex and ethnicity. RESULTS After a mean follow-up time of 11.8 years, over 20 International Classification of Diseases, 10th Revision ( ICD-10 ) codes were showed to be associated with telomere attrition. LTL shortening is associated with an increased risk of several digestive diseases, including gastroesophageal reflux disease (K21: hazard ratio [HR] = 1.30, 95% confidence interval [95% CI]: 1.19-1.42), esophageal ulcer (K221: HR = 1.81, 95% CI: 1.22-2.71), Barrett's esophagus (K227: HR = 1.58, 95% CI: 1.14-2.17), gastritis (K29: HR = 1.39, 95% CI: 1.26-1.52), duodenal ulcer (K26: HR = 1.55, 95% CI: 1.14-2.12), functional dyspepsia (K30X: HR = 1.36, 95% CI: 1.06-1.69), non-alcoholic fatty liver disease (NAFLD) (K760: HR = 1.39, 95% CI: 1.09-1.78), liver cirrhosis (K74: HR = 4.73, 95% CI: 3.27-6.85), cholangitis (K830: HR = 2.55, 95% CI: 1.30-5.00), and hernia (K43: HR = 1.50, 95% CI: 1.17-1.94; K44: HR = 1.29, 95% CI: 1.17-1.42). The risk of rectal polyps (K621: HR = 0.77, 95% CI: 0.63-0.92) decreased per unit shortening of LTL. CONCLUSIONS This study suggests that LTL shortening is associated with an increased risk of most digestive diseases except for rectal polyps. These findings may provide some clues for understanding the pathogenesis of digestive diseases.
Collapse
Affiliation(s)
- Hongqun Yang
- The Secondary Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Lanlan Chen
- The First Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yahui Liu
- The Secondary Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin 130021, China
| |
Collapse
|
|
2
|
Czaja AJ. Cellular senescence and its pathogenic and therapeutic implications in autoimmune hepatitis. Expert Rev Gastroenterol Hepatol 2024; 18:725-743. [PMID: 39575891 DOI: 10.1080/17474124.2024.2432480] [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: 09/25/2024] [Accepted: 11/18/2024] [Indexed: 12/28/2024]
Abstract
INTRODUCTION Senescent cells are characterized by replicative arrest and phenotypes that produce diverse pro-inflammatory and pro-oxidant mediators. The senescence of diverse hepatic cell types could constitute an unrecognized pathogenic mechanism and prognostic determinant in autoimmune hepatitis. The impact of cellular senescence in autoimmune hepatitis is unknown, and it may suggest adjunctive management strategies. AREAS COVERED This review describes the molecular mechanisms of cellular senescence, indicates its diagnostic features, suggests its consequences, presents possible therapeutic interventions, and encourages investigations of its pathogenic role and management in autoimmune hepatitis. Treatment prospects include elimination or reversal of senescent cells, generation of ectopic telomerase, reactivation of dormant telomerase, neutralization of specific pro-inflammatory secretory products, and mitigation of the effects of mitochondrial dysfunction. EXPERT OPINION The occurrence, nature, and consequences of cellular senescence in autoimmune hepatitis must be determined. The senescence of diverse hepatic cell types could affect the outcome of autoimmune hepatitis by impairing hepatic regeneration, intensifying liver inflammation, and worsening hepatic fibrosis. Cellular senescence could contribute to suboptimal responses during conventional glucocorticoid-based therapy. Interventions that target specific pro-inflammatory products of the senescent phenotype or selectively promote apoptosis of senescent cells may be preferred adjunctive treatments for autoimmune hepatitis depending on the cancer risk.
Collapse
Affiliation(s)
- Albert J Czaja
- Mayo Clinic, Department of Medicine, Division of Gastroenterology and Hepatology, Rochester, MN, USA
| |
Collapse
|
|
3
|
Wang W, Qian J, Shang M, Qiao Y, Huang J, Gao X, Ye Z, Tong X, Xu K, Li X, Liu Z, Zhou L, Zheng S. Integrative analysis of the transcriptome and metabolome reveals the importance of hepatokine FGF21 in liver aging. Genes Dis 2024; 11:101161. [PMID: 39022127 PMCID: PMC11252782 DOI: 10.1016/j.gendis.2023.101161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 10/03/2023] [Accepted: 10/16/2023] [Indexed: 07/20/2024] Open
Abstract
Aging is a contributor to liver disease. Hence, the concept of liver aging has become prominent and has attracted considerable interest, but its underlying mechanism remains poorly understood. In our study, the internal mechanism of liver aging was explored via multi-omics analysis and molecular experiments to support future targeted therapy. An aged rat liver model was established with d-galactose, and two other senescent hepatocyte models were established by treating HepG2 cells with d-galactose and H2O2. We then performed transcriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte models. In livers, genes related to peroxisomes, fatty acid elongation, and fatty acid degradation exhibited down-regulated expression with aging, and the hepatokine Fgf21 expression was positively correlated with the down-regulation of these genes. In senescent hepatocytes, similar to the results found in aged livers, FGF21 expression was also decreased. Moreover, the expressions of cell cycle-related genes were significantly down-regulated, and the down-regulated gene E2F8 was the key cell cycle-regulating transcription factor. We then validated that FGF21 overexpression can protect against liver aging and that FGF21 can attenuate the declines in the antioxidant and regenerative capacities in the aging liver. We successfully validated the results from cellular and animal experiments using human liver and blood samples. Our study indicated that FGF21 is an important target for inhibiting liver aging and suggested that pharmacological prevention of the reduction in FGF21 expression due to aging may be used to treat liver aging-related diseases.
Collapse
Affiliation(s)
- Wenchao Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
| | - Junjie Qian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
| | - Mingge Shang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
| | - Yiting Qiao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
| | - Jiacheng Huang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
| | - Xinxin Gao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
| | - Zhou Ye
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
| | - Xinyu Tong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
| | - Kangdi Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
| | - Xiang Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
| | - Zhengtao Liu
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, Zhejiang 310015, China
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310000, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310000, China
| |
Collapse
|
|
4
|
Nicholson T, Dhaliwal A, Quinlan JI, Allen SL, Williams FR, Hazeldine J, McGee KC, Sullivan J, Breen L, Elsharkawy AM, Armstrong MJ, Jones SW, Greig CA, Lord JM. Accelerated aging of skeletal muscle and the immune system in patients with chronic liver disease. Exp Mol Med 2024; 56:1667-1681. [PMID: 39026032 PMCID: PMC11297261 DOI: 10.1038/s12276-024-01287-y] [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: 10/09/2023] [Revised: 04/10/2024] [Accepted: 04/30/2024] [Indexed: 07/20/2024] Open
Abstract
Patients with chronic liver disease (CLD) often present with significant frailty, sarcopenia, and impaired immune function. However, the mechanisms driving the development of these age-related phenotypes are not fully understood. To determine whether accelerated biological aging may play a role in CLD, epigenetic, transcriptomic, and phenotypic assessments were performed on the skeletal muscle tissue and immune cells of CLD patients and age-matched healthy controls. Accelerated biological aging of the skeletal muscle tissue of CLD patients was detected, as evidenced by an increase in epigenetic age compared with chronological age (mean +2.2 ± 4.8 years compared with healthy controls at -3.0 ± 3.2 years, p = 0.0001). Considering disease etiology, age acceleration was significantly greater in both the alcohol-related (ArLD) (p = 0.01) and nonalcoholic fatty liver disease (NAFLD) (p = 0.0026) subgroups than in the healthy control subgroup, with no age acceleration observed in the immune-mediated subgroup or healthy control subgroup (p = 0.3). The skeletal muscle transcriptome was also enriched for genes associated with cellular senescence. Similarly, blood cell epigenetic age was significantly greater than that in control individuals, as calculated using the PhenoAge (p < 0.0001), DunedinPACE (p < 0.0001), or Hannum (p = 0.01) epigenetic clocks, with no difference using the Horvath clock. Analysis of the IMM-Age score indicated a prematurely aged immune phenotype in CLD patients that was 2-fold greater than that observed in age-matched healthy controls (p < 0.0001). These findings suggested that accelerated cellular aging may contribute to a phenotype associated with advanced age in CLD patients. Therefore, therapeutic interventions to reduce biological aging in CLD patients may improve health outcomes.
Collapse
Affiliation(s)
- Thomas Nicholson
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Birmingham, UK
| | - Amritpal Dhaliwal
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Jonathan I Quinlan
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
- School of Sport, Exercise and Rehabilitation Science, University of Birmingham, Birmingham, UK
| | - Sophie L Allen
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
- School of Sport, Exercise and Rehabilitation Science, University of Birmingham, Birmingham, UK
| | - Felicity R Williams
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
- School of Sport, Exercise and Rehabilitation Science, University of Birmingham, Birmingham, UK
| | - Jon Hazeldine
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Birmingham, UK
| | - Kirsty C McGee
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Birmingham, UK
| | - Jack Sullivan
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Birmingham, UK
| | - Leigh Breen
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Birmingham, UK
- School of Sport, Exercise and Rehabilitation Science, University of Birmingham, Birmingham, UK
| | - Ahmed M Elsharkawy
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
- Liver Transplantation Unit, Queen Elizabeth Hospital, Birmingham, UK
| | - Matthew J Armstrong
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
- Liver Transplantation Unit, Queen Elizabeth Hospital, Birmingham, UK
| | - Simon W Jones
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Birmingham, UK
| | - Carolyn A Greig
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Birmingham, UK
- School of Sport, Exercise and Rehabilitation Science, University of Birmingham, Birmingham, UK
| | - Janet M Lord
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK.
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Birmingham, UK.
| |
Collapse
|
|
5
|
Tornesello ML, Tornesello AL, Starita N, Cerasuolo A, Izzo F, Buonaguro L, Buonaguro FM. Telomerase: a good target in hepatocellular carcinoma? An overview of relevant preclinical data. Expert Opin Ther Targets 2022; 26:767-780. [PMID: 36369706 DOI: 10.1080/14728222.2022.2147062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 11/09/2022] [Indexed: 11/15/2022]
Abstract
INTRODUCTION The expression of telomerase reverse transcriptase (TERT) in liver is restricted to rare cells, that are able to replace senescent hepatocytes and regenerate tissue in response to hepatic damage, while becoming extinguished in differentiated progeny cells. TERT gene is permanently activated in liver neoplasms from the very early stage of the hepatocarcinogenesis mainly through the accumulation of genetic alterations, virus-related insertional mutagenesis and somatic mutations in the TERT promoter region. Several lines of evidence suggest that telomerase, beyond the canonical function of telomeres elongation, has multiple oncogenic activities in cancer cells and may represent a promising therapeutic target in hepatocellular carcinoma (HCC). AREAS COVERED We review the mechanisms of activation of telomerase in HCC, the canonical and non-canonical functions of TERT as well as experimental strategies to directly target telomerase or to inhibit pathways associated with telomerase activity. EXPERT OPINION TERT holoenzyme and telomerase components represent promising therapeutic targets in the treatment of liver malignancies. Several chemical agents and natural products known to alter telomerase activity are under evaluation for their potency to inhibit telomeres attrition in cirrhosis and TERT function in liver cancer. Therefore, this review outlines the current strategies pursued to suppress the multiple mechanisms of the major telomerase components in liver cancer.
Collapse
Affiliation(s)
- Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, Italy
| | - Anna Lucia Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, Italy
| | - Noemy Starita
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, Italy
| | - Andrea Cerasuolo
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, Italy
| | - Francesco Izzo
- Hepatobiliary Surgical Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Luigi Buonaguro
- Innovative Immunological Models Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, Italy
| | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, Italy
| |
Collapse
|
|
6
|
Huda N, Kusumanchi P, Perez K, Jiang Y, Skill NJ, Sun Z, Ma J, Yang Z, Liangpunsakul S. Telomere length in patients with alcohol-associated liver disease: a brief report. J Investig Med 2022; 70:1438-1441. [PMID: 35246468 PMCID: PMC9378353 DOI: 10.1136/jim-2021-002213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2022] [Indexed: 01/17/2023]
Abstract
The intact telomere structure is essential for the prevention of the chromosome end-to-end fusions and maintaining genomic integrity. The maintenance of telomere length is critical for cellular homeostasis. The shortening of telomeres has been reported in patients with chronic liver diseases. The telomere length has not been systemically studied in patients with alcohol-associated liver disease (ALD) at different stages, such as alcoholic hepatitis and alcoholic cirrhosis. In this brief report, we observed evidence of telomere shortening without changes in the telomerase activity in the liver of patients with alcoholic hepatitis and alcoholic cirrhosis when compared with controls. The alterations in the genes associated with telomere binding proteins were only observed in patients with alcoholic cirrhosis. Future studies are required to determine the mechanism of how alcohol affects the length of the telomere and if the shortening impacts the disease progression in ALD.
Collapse
Affiliation(s)
- Nazmul Huda
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Praveen Kusumanchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kristina Perez
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Yanchao Jiang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Nicholas J Skill
- Department of Surgery, Louisiana State University Health Science Center, New Orleans, LA, USA
| | - Zhaoli Sun
- Department of Surgery, Johns Hopkins University School of Medicine, Baltiore, MD, USA
| | - Jing Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
| |
Collapse
|
|
7
|
Bárcena B, Salamanca A, Pintado C, Mazuecos L, Villar M, Moltó E, Bonzón-Kulichenko E, Vázquez J, Andrés A, Gallardo N. Aging Induces Hepatic Oxidative Stress and Nuclear Proteomic Remodeling in Liver from Wistar Rats. Antioxidants (Basel) 2021; 10:antiox10101535. [PMID: 34679670 PMCID: PMC8533122 DOI: 10.3390/antiox10101535] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 12/13/2022] Open
Abstract
Aging is a continuous, universal, and irreversible process that determines progressive loss of adaptability. The liver is a critical organ that supports digestion, metabolism, immunity, detoxification, vitamin storage, and hormone signaling. Nevertheless, the relationship between aging and the development of liver diseases remains elusive. In fact, although prolonged fasting in adult rodents and humans delays the onset of the disease and increases longevity, whether prolonged fasting could exert adverse effects in old organisms remains incompletely understood. In this work, we aimed to characterize the oxidative stress and nuclear proteome in the liver of 3-month- and 24-month-old male Wistar rats upon 36 h of fasting and its adaptation in response to 30 min of refeeding. To this end, we analyzed the hepatic lipid peroxidation levels (TBARS) and the expression levels of genes associated with fat metabolism and oxidative stress during aging. In addition, to gain a better insight into the molecular and cellular processes that characterize the liver of old rats, the hepatic nuclear proteome was also evaluated by isobaric tag quantitation (iTRAQ) mass spectrometry-based proteomics. In old rats, aging combined with prolonged fasting had great impact on lipid peroxidation in the liver that was associated with a marked downregulation of antioxidant genes (Sod2, Fmo3, and Cyp2C11) compared to young rats. Besides, our proteomic study revealed that RNA splicing is the hepatic nuclear biological process markedly affected by aging and this modification persists upon refeeding. Our results suggest that aged-induced changes in the nuclear proteome could affect processes associated with the adaptative response to refeeding after prolonged fasting, such as those involved in the defense against oxidative stress.
Collapse
Affiliation(s)
- Brenda Bárcena
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Sciences and Chemical Technologies, University of Castilla-La Mancha, Avda. Camilo Jose Cela 10, 13071 Ciudad Real, Spain; (B.B.); (A.S.); (L.M.); (A.A.)
| | - Aurora Salamanca
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Sciences and Chemical Technologies, University of Castilla-La Mancha, Avda. Camilo Jose Cela 10, 13071 Ciudad Real, Spain; (B.B.); (A.S.); (L.M.); (A.A.)
| | - Cristina Pintado
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Environmental Sciences and Biochemistry, University of Castilla-La Mancha, Avda. Carlos III s/n, 45071 Toledo, Spain; (C.P.); (E.M.)
| | - Lorena Mazuecos
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Sciences and Chemical Technologies, University of Castilla-La Mancha, Avda. Camilo Jose Cela 10, 13071 Ciudad Real, Spain; (B.B.); (A.S.); (L.M.); (A.A.)
| | - Margarita Villar
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Sciences and Chemical Technologies, University of Castilla-La Mancha, Avda. Camilo Jose Cela 10, 13071 Ciudad Real, Spain; (B.B.); (A.S.); (L.M.); (A.A.)
- SaBio, Instituto de Investigación en Recursos Cinegéticos IREC-CSIC-UCLM-JCCM, Ronda de Toledo s/n, 13005 Ciudad Real, Spain
- Correspondence: (M.V.); (N.G.)
| | - Eduardo Moltó
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Environmental Sciences and Biochemistry, University of Castilla-La Mancha, Avda. Carlos III s/n, 45071 Toledo, Spain; (C.P.); (E.M.)
| | - Elena Bonzón-Kulichenko
- Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III and CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.B.-K.); (J.V.)
| | - Jesús Vázquez
- Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III and CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.B.-K.); (J.V.)
| | - Antonio Andrés
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Sciences and Chemical Technologies, University of Castilla-La Mancha, Avda. Camilo Jose Cela 10, 13071 Ciudad Real, Spain; (B.B.); (A.S.); (L.M.); (A.A.)
| | - Nilda Gallardo
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Sciences and Chemical Technologies, University of Castilla-La Mancha, Avda. Camilo Jose Cela 10, 13071 Ciudad Real, Spain; (B.B.); (A.S.); (L.M.); (A.A.)
- Correspondence: (M.V.); (N.G.)
| |
Collapse
|
|
8
|
Yuan P, Qi X, Song A, Ma M, Zhang X, Lu C, Bian M, Lian N, He J, Zheng S, Jin H. LncRNA MAYA promotes iron overload and hepatocyte senescence through inhibition of YAP in non-alcoholic fatty liver disease. J Cell Mol Med 2021; 25:7354-7366. [PMID: 34190396 PMCID: PMC8335668 DOI: 10.1111/jcmm.16764] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/02/2021] [Accepted: 06/15/2021] [Indexed: 12/13/2022] Open
Abstract
Although recent evidence has shown that hepatocyte senescence plays a crucial role in the pathogenesis and development of non‐alcoholic fatty liver disease (NAFLD), the mechanism is still not clear. The purpose of this study was to investigate the signal transduction pathways involved in the senescence of hepatocyte, in order to provide a potential strategy for blocking the process of NAFLD. The results confirmed that hepatocyte senescence occurred in HFD‐fed Golden hamsters and PA‐treated LO2 cells as manifested by increased levels of senescence marker SA‐β‐gal, p16 and p21, heterochromatin marker H3K9me3, DNA damage marker γ‐H2AX and decreased activity of telomerase. Further studies demonstrated that iron overload could promote the senescence of hepatocyte, whereas the overexpression of Yes‐associated protein (YAP) could blunt iron overload and alleviate the senescence of hepatocyte. Of importance, depression of lncRNA MAYA (MAYA) reduced iron overload and cellular senescence via promotion of YAP in PA‐treated hepatocytes. These effects were further supported by in vivo experiments. In conclusion, these data suggested that inhibition of MAYA could up‐regulate YAP, which might repress hepatocyte senescence through modulating iron overload. In addition, these findings provided a promising option for heading off the development of NAFLD by abrogating hepatocyte senescence.
Collapse
Affiliation(s)
- Ping Yuan
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Xiaoyu Qi
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Anping Song
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Mingyue Ma
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Xinbei Zhang
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Chunfeng Lu
- School of Pharmacy, Nantong University, Nantong, China
| | - Mianli Bian
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Naqi Lian
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Jianling He
- Ministry of Natural Resources, Third Institute of Oceanography, Xiamen, China
| | - Shuguo Zheng
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Huanhuan Jin
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu, China
| |
Collapse
|
|
9
|
Puttabyatappa M, Ciarelli JN, Chatoff AG, Padmanabhan V. Developmental programming: Metabolic tissue-specific changes in endoplasmic reticulum stress, mitochondrial oxidative and telomere length status induced by prenatal testosterone excess in the female sheep. Mol Cell Endocrinol 2021; 526:111207. [PMID: 33607270 PMCID: PMC8005473 DOI: 10.1016/j.mce.2021.111207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 02/07/2023]
Abstract
Prenatal testosterone (T) excess-induced metabolic dysfunctions involve tissue specific changes in insulin sensitivity with insulin resistant, oxidative and lipotoxic state in liver/muscle and insulin sensitive but inflammatory and oxidative state in visceral adipose tissues (VAT). We hypothesized that mitochondrial dysfunction, endoplasmic reticulum (ER) stress and premature cellular senescence are contributors to the tissue-specific changes in insulin sensitivity. Markers of mitochondrial number, function, and oxidative phosphorylation (OxPhos), ER stress and cellular senescence (telomere length) were assessed in liver, muscle and 4 adipose (VAT, subcutaneous [SAT], epicardiac [ECAT] and perirenal [PRAT]) depots collected from control and prenatal T-treated female sheep at 21 months of age. Prenatal T treatment led to: (a) reduction in mitochondrial number and OxPhos complexes and increase in ER stress markers in muscle; (b) increase in fibrosis with trend towards increase in short telomere fragments in liver (c) depot-specific mitochondrial changes with OxPhos complexes namely increase in SAT and reduction in PRAT and increase in mitochondrial number in ECAT; (d) depot-specific ER stress marker changes with increase in VAT, reduction in SAT, contrasting changes in ECAT and no changes in PRAT; and (d) reduced shorter telomere fragments in SAT, ECAT and PRAT. These changes indicate insulin resistance may be driven by mitochondrial and ER dysfunction in muscle, fibrosis and premature senescence in liver, and depot-specific changes in mitochondrial function and ER stress without involving cellular senescence in adipose tissue. These findings provide mechanistic insights into pathophysiology of metabolic dysfunction among female offspring from hyperandrogenic pregnancies.
Collapse
Affiliation(s)
| | - Joseph N Ciarelli
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
| | - Adam G Chatoff
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
| | | |
Collapse
|
|
10
|
Moustakas II, Katsarou A, Legaki AI, Pyrina I, Ntostoglou K, Papatheodoridi AM, Gercken B, Pateras IS, Gorgoulis VG, Koutsilieris M, Chavakis T, Chatzigeorgiou A. Hepatic Senescence Accompanies the Development of NAFLD in Non-Aged Mice Independently of Obesity. Int J Mol Sci 2021; 22:3446. [PMID: 33810566 PMCID: PMC8037476 DOI: 10.3390/ijms22073446] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 03/21/2021] [Accepted: 03/23/2021] [Indexed: 01/21/2023] Open
Abstract
Senescence is considered to be a cardinal player in several chronic inflammatory and metabolic pathologies. The two dominant mechanisms of senescence include replicative senescence, predominantly depending on age-induced telomere shortening, and stress-induced senescence, triggered by external or intracellular harmful stimuli. Recent data indicate that hepatocyte senescence is involved in the development of nonalcoholic fatty liver disease (NAFLD). However, previous studies have mainly focused on age-related senescence during NAFLD, in the presence or absence of obesity, while information about whether the phenomenon is characterized by replicative or stress-induced senescence, especially in non-aged organisms, is scarce. Herein, we subjected young mice to two different diet-induced NAFLD models which differed in the presence of obesity. In both models, liver fat accumulation and increased hepatic mRNA expression of steatosis-related genes were accompanied by hepatic senescence, indicated by the increased expression of senescence-associated genes and the presence of a robust hybrid histo-/immunochemical senescence-specific staining in the liver. Surprisingly, telomere length and global DNA methylation did not differ between the steatotic and the control livers, while malondialdehyde, a marker of oxidative stress, was upregulated in the mouse NAFLD livers. These findings suggest that senescence accompanies NAFLD emergence, even in non-aged organisms, and highlight the role of stress-induced senescence during steatosis development independently of obesity.
Collapse
Affiliation(s)
- Ioannis I. Moustakas
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.I.M.); (A.K.); (A.-I.L.); (A.-M.P.); (M.K.)
| | - Angeliki Katsarou
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.I.M.); (A.K.); (A.-I.L.); (A.-M.P.); (M.K.)
| | - Aigli-Ioanna Legaki
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.I.M.); (A.K.); (A.-I.L.); (A.-M.P.); (M.K.)
| | - Iryna Pyrina
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (I.P.); (B.G.); (T.C.)
| | - Konstantinos Ntostoglou
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (I.S.P.); (V.G.G.)
| | - Alkistis-Maria Papatheodoridi
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.I.M.); (A.K.); (A.-I.L.); (A.-M.P.); (M.K.)
| | - Bettina Gercken
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (I.P.); (B.G.); (T.C.)
| | - Ioannis S. Pateras
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (I.S.P.); (V.G.G.)
| | - Vassilis G. Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (I.S.P.); (V.G.G.)
- Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece
- Molecular and Clinical Cancer Sciences, Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M20 4GJ, UK
- Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michael Koutsilieris
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.I.M.); (A.K.); (A.-I.L.); (A.-M.P.); (M.K.)
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (I.P.); (B.G.); (T.C.)
| | - Antonios Chatzigeorgiou
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.I.M.); (A.K.); (A.-I.L.); (A.-M.P.); (M.K.)
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (I.P.); (B.G.); (T.C.)
| |
Collapse
|
|
11
|
Nutrients, Genetic Factors, and Their Interaction in Non-Alcoholic Fatty Liver Disease and Cardiovascular Disease. Int J Mol Sci 2020; 21:ijms21228761. [PMID: 33228237 PMCID: PMC7699550 DOI: 10.3390/ijms21228761] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/15/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and expose patients to increased risk of hepatic and cardiovascular (CV) morbidity and mortality. Both environmental factors and genetic predisposition contribute to the risk. An inappropriate diet, rich in refined carbohydrates, especially fructose, and saturated fats, and poor in fibers, polyunsaturated fats, and vitamins is one of the main key factors, as well as the polymorphism of patatin-like phospholipase domain containing 3 (PNPLA3 gene) for NAFLD and the apolipoproteins and the peroxisome proliferator-activated receptor (PPAR) family for the cardiovascular damage. Beyond genetic influence, also epigenetics modifications are responsible for various clinical manifestations of both hepatic and CV disease. Interestingly, data are accumulating on the interplay between diet and genetic and epigenetic modifications, modulating pathogenetic pathways in NAFLD and CV disease. We report the main evidence from literature on the influence of both macro and micronutrients in NAFLD and CV damage and the role of genetics either alone or combined with diet in increasing the risk of developing both diseases. Understanding the interaction between metabolic alterations, genetics and diet are essential to treat the diseases and tailoring nutritional therapy to control NAFLD and CV risk.
Collapse
|
|
12
|
Meroni M, Longo M, Rustichelli A, Dongiovanni P. Nutrition and Genetics in NAFLD: The Perfect Binomium. Int J Mol Sci 2020; 21:ijms21082986. [PMID: 32340286 PMCID: PMC7215858 DOI: 10.3390/ijms21082986] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/19/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents a global healthcare burden since it is epidemiologically related to obesity, type 2 diabetes (T2D) and Metabolic Syndrome (MetS). It embraces a wide spectrum of hepatic injuries, which include simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The susceptibility to develop NAFLD is highly variable and it is influenced by several cues including environmental (i.e., dietary habits and physical activity) and inherited (i.e., genetic/epigenetic) risk factors. Nonetheless, even intestinal microbiota and its by-products play a crucial role in NAFLD pathophysiology. The interaction of dietary exposure with the genome is referred to as 'nutritional genomics,' which encompasses both 'nutrigenetics' and 'nutriepigenomics.' It is focused on revealing the biological mechanisms that entail both the acute and persistent genome-nutrient interactions that influence health and it may represent a promising field of study to improve both clinical and health nutrition practices. Thus, the premise of this review is to discuss the relevance of personalized nutritional advices as a novel therapeutic approach in NAFLD tailored management.
Collapse
Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (A.R.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (A.R.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milano, Italy
| | - Alice Rustichelli
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (A.R.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (A.R.)
- Correspondence: ; Tel.: +39-02-5503-3467; Fax: +39-02-5503-4229
| |
Collapse
|
|
13
|
Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullak-Ublick GA, Watkins PB, Devarbhavi H, Merz M, Lucena MI, Kaplowitz N, Aithal GP. Drug-induced liver injury. Nat Rev Dis Primers 2019; 5:58. [PMID: 31439850 DOI: 10.1038/s41572-019-0105-0] [Citation(s) in RCA: 443] [Impact Index Per Article: 73.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/04/2019] [Indexed: 02/06/2023]
Abstract
Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when an individual is exposed to toxic doses of some compounds or as an unpredictable event with many drugs in common use. Drugs can be harmful to the liver in susceptible individuals owing to genetic and environmental risk factors. These risk factors modify hepatic metabolism and excretion of the DILI-causative agent leading to cellular stress, cell death, activation of an adaptive immune response and a failure to adapt, with progression to overt liver injury. Idiosyncratic DILI is a relative rare hepatic disorder but can be severe and, in some cases, fatal, presenting with a variety of phenotypes, which mimic other hepatic diseases. The diagnosis of DILI relies on the exclusion of other aetiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune-checkpoint inhibitors in patients with cancer.
Collapse
Affiliation(s)
- Raul J Andrade
- Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Malaga, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
| | - Naga Chalasani
- Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Einar S Björnsson
- Department of Gastroenterology, Landspitali University Hospital Reykjavik, University of Iceland, Reykjavík, Iceland.,Faculty of Medicine, University of Iceland, Reykjavík, Iceland
| | - Ayako Suzuki
- Gastroenterology, Duke University, Durham, NC, USA.,Gastroenterology, Durham VA Medical Centre, Durham, NC, USA
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland
| | - Paul B Watkins
- UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.,University of North Carolina Institute for Drug Safety Sciences, Research Triangle Park, Chapel Hill, NC, USA
| | - Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India
| | - Michael Merz
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Patient Safety, AstraZeneca, Gaithersburg, MD, USA
| | - M Isabel Lucena
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain. .,Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, UICEC SCReN, Universidad de Málaga, Málaga, Spain.
| | - Neil Kaplowitz
- Division of Gastroenterology and Liver Diseases, Department of Medicine, Keck School of Medicine, Los Angeles, CA, USA
| | - Guruprasad P Aithal
- National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Centre, Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, UK
| |
Collapse
|
|
14
|
Abstract
Previous studies have established a correlation between increasing chronological age and risk of cirrhosis. This pattern raised interest in the role of telomeres and the telomerase complex in the pathogenesis of liver fibrosis and cirrhosis. This review aims to summarize and analyze the current understanding of telomere regulation in hepatocytes and lymphocytes and how this ultimately relates to the development of liver fibrosis. Notably, in chronic viral hepatitis, telomere shortening in hepatocytes and lymphocytes occurs in such a way that may promote further viral replication while also leading to liver damage. However, while telomere shortening occurs in both hepatocytes and lymphocytes and ultimately results in cellular death, the mechanisms of telomere loss appear to be initiated by independent processes. The understanding of telomere maintenance on a hepatic and immune system level in both viral and non-viral etiologies of cirrhosis may open doors to novel therapeutic strategies.
Collapse
Affiliation(s)
- Abbey Barnard
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Ashley Moch
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
| | - Sammy Saab
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.,Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
| |
Collapse
|
|
15
|
Jin X, Zimmers TA, Zhang Z, Koniaris LG. Resveratrol Improves Recovery and Survival of Diet-Induced Obese Mice Undergoing Extended Major (80%) Hepatectomy. Dig Dis Sci 2019; 64:93-101. [PMID: 30284135 DOI: 10.1007/s10620-018-5312-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 09/28/2018] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Loss of hepatic epidermal growth factor receptor (EGFR) expression is a cause for the increased perioperative risk for complications and death in patients with obesity and fatty liver undergoing liver resection. Herein, we set out to identify agents that might increase EGFR expression and improve recovery for patients with fatty liver undergoing resection. Using the diet-induced obese (DIO) mouse model of fatty liver, we examined resveratrol as a therapy to induce EGFR expression and improve outcomes following 80% partial hepatectomy (PH) in a murine model. METHODS DIO mice were fed resveratrol or carrier control by gavage. EGFR expression and the response to major (80%) PH were examined. RESULTS Based on an Illumina analysis, resveratrol was identified as increasing EGFR gene expression in A549 cells. Resveratrol was observed to also increase EGFR protein expression in A549 cells. DIO mice fed resveratrol by gavage (75 mg/kg) demonstrated an increased EGFR expression without the identified hepatic toxicity. Resveratrol and control mice subjected to 80% PH, a model of high mortality hepatectomy in DIO mice, demonstrated macroscopically decreased fatty liver and fewer liver hemorrhagic petechiae. Resveratrol pretreatment ameliorated liver injury and accelerated regeneration of the hepatic remnant after 80% PH including decreasing serum ALT and bilirubin, while increasing hepatic PCNA expression. Resveratrol increased induction of p-STAT3 and p-AKT after 80% hepatectomy. Resveratrol pretreatment significantly improved survival rates in DIO mice undergoing extended 80% PH. CONCLUSIONS Oral resveratrol restores EGFR expression in fatty liver. Resveratrol may be a promising protective agent in instances where extensive hepatic resection of fatty liver is required.
Collapse
Affiliation(s)
- Xiaoling Jin
- Department of Surgery, Thomas Jefferson University School of Medicine, Philadelphia, PA, USA
| | - Teresa A Zimmers
- Department of Surgery, Indiana University School of Medicine, EH 511 SGEN, Indianapolis, IN, 46202, USA
| | - Zongxiu Zhang
- Department of Surgery, Thomas Jefferson University School of Medicine, Philadelphia, PA, USA
| | - Leonidas G Koniaris
- Department of Surgery, Indiana University School of Medicine, EH 511 SGEN, Indianapolis, IN, 46202, USA.
| |
Collapse
|
|
16
|
Taketani H, Nishikawa T, Nakajima H, Kodo K, Sugimoto S, Aoi W, Horike SI, Meguro-Horike M, Ishiba H, Seko Y, Umemura A, Yamaguchi K, Moriguchi M, Yasui K, Itoh Y. Aging-associated impairment in metabolic compensation by subcutaneous adipose tissue promotes diet-induced fatty liver disease in mice. Diabetes Metab Syndr Obes 2019; 12:1473-1492. [PMID: 31692556 PMCID: PMC6711723 DOI: 10.2147/dmso.s214093] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 07/16/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, and its progression is associated with aging-associated impairment in metabolic homeostasis. Recently, energy metabolism in adipose tissue has been the subject of renewed interest, because significant energy expenditure can be induced in cells derived from white adipose tissue progenitors, in addition to brown adipose tissue (BAT). Here we evaluated whether aging-associated change in various adipose tissue depots affects the progression of NAFLD. METHODS Six-week-old male C57BL/6NCrSlc mice were fed control chow (C) or high-fat diet (60% fat; HF) for 12 or 24 weeks (12w/C, 12w/HF, 24w/C and 24w/HF groups, respectively) or switched from C to HF diet at 18 weeks of age (24w/C/HF group) and fed for a further 24 weeks. Some 24w/HF mice received a subcutaneous transplantation of adipose progenitors (106 cells/mouse) from young donor mice. Basal energy expenditure, glucose tolerance, and liver and adipose tissue histology were then evaluated. In addition, features of senescence and the capacity of adipose progenitors to "brown" were compared in mice of various ages. RESULTS 12w/HF mice demonstrated compensation in the forms of hypertrophy of interscapular classical BAT and the appearance of subcutaneous beige adipocytes, consistent with improved metabolic homeostasis. In contrast, 24w/HF and 24w/C/HF mice developed obesity, glucose intolerance, and severe NAFLD, with accelerated senescence and loss of adipose progenitors in subcutaneous fat tissues. Recruitment of adipose progenitors ameliorated these findings in 24w/HF mice. CONCLUSION Impaired metabolic compensation in adipose tissue resulted in the progression of NAFLD, which was associated with aging-related deterioration in adipose progenitors. A new approach targeting adipose tissue progenitors might represent a potential strategy for the prevention of NAFLD.
Collapse
Affiliation(s)
- Hiroyoshi Taketani
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Taichiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Correspondence: Taichiro NishikawaKyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachidouri Hirokouji Agaru, Kamigyo-ku, Kyoto602-8566, JapanTel +81 75 251 5519Fax +81 75 251 1017Email
| | - Hisakazu Nakajima
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuki Kodo
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Satoru Sugimoto
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Wataru Aoi
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan
| | - Shin-ichi Horike
- Advanced Science Research Center, Kanazawa University, Kanazawa, Japan
| | | | - Hiroshi Ishiba
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuya Seko
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Atsushi Umemura
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kanji Yamaguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Michihisa Moriguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kohichiroh Yasui
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| |
Collapse
|
|
17
|
Lonardo A, Lugari S, Nascimbeni F. Telomere shortening: An innocent bystander at the crossroad of NASH with ageing and cardiometabolic risk? Liver Int 2018; 38:1730-1732. [PMID: 30256511 DOI: 10.1111/liv.13935] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
See Article on Page 1839
Collapse
Affiliation(s)
- Amedeo Lonardo
- Ospedale Civile di Baggiovara, Azienda Ospedaliero-Universitaria Modena, Modena, Italy
| | - Simonetta Lugari
- Ospedale Civile di Baggiovara, Azienda Ospedaliero-Universitaria Modena, Modena, Italy
- Università degli Studi di Modena and Reggio Emilia, Modena, Italy
| | - Fabio Nascimbeni
- Ospedale Civile di Baggiovara, Azienda Ospedaliero-Universitaria Modena, Modena, Italy
- Università degli Studi di Modena and Reggio Emilia, Modena, Italy
| |
Collapse
|
|
18
|
Kim MY. [The Progression of Liver Fibrosis in Non-alcoholic Fatty Liver Disease]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2018. [PMID: 28637102 DOI: 10.4166/kjg.2017.69.6.341] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Understanding the pathogenesis of non-alcoholic steatohepatitis (NASH) and its fibrosis progression is still evolving. Nonetheless, current evidence suggests that mechanisms involved are very complex parallel processes with multiple metabolic factors. Lipotoxicity related with excess saturated free fatty acids, obesity, and insulin resistance acts as the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence are also contribute to the activation of inflammasome via various intra- and inter-cellular signaling mechanisms that lead to fibrosis. Current evidence suggests that periportal components, including ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the T-helper 17 cell response may mediate disease progression. This review aims to provide a brief overview of the pathogenesis of NASH and fibrosis progression from inflammation to fibrosis.
Collapse
Affiliation(s)
- Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| |
Collapse
|
|
19
|
Jin X, Zimmers TA, Jiang Y, Milgrom DP, Zhang Z, Koniaris LG. Meloxicam increases epidermal growth factor receptor expression improving survival after hepatic resection in diet-induced obese mice. Surgery 2018; 163:1264-1271. [PMID: 29361369 DOI: 10.1016/j.surg.2017.11.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 11/08/2017] [Accepted: 11/28/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Patients with fatty liver have delayed regenerative responses, increased hepatocellular injury, and increased risk for perioperative mortality. Currently, no clinical therapy exists to prevent liver failure or improve regeneration in patients with fatty liver. Previously we demonstrated that obese mice have markedly reduced levels of epidermal growth factor receptor in liver. We sought to identify pharmacologic agents to increase epidermal growth factor receptor expression to improve hepatic regeneration in the setting of fatty liver resection. METHODS Lean (20% calories from fat) and diet-induced obese mice (60% calories from fat) were subjected to 70% or 80% hepatectomy. RESULTS Using the BaseSpace Correlation Engine of deposited gene arrays we identified agents that increased hepatic epidermal growth factor receptor. Meloxicam was identified as inducing epidermal growth factor receptor expression across species. Meloxicam improved hepatic steatosis in diet-induced obese mice both grossly and histologically. Immunohistochemistry and Western blot analysis demonstrated that meloxicam pretreatment of diet-induced obese mice dramatically increased epidermal growth factor receptor protein expression in hepatocytes. After 70% hepatectomy, meloxicam pretreatment ameliorated liver injury and significantly accelerated mitotic rates of hepatocytes in obese mice. Recovery of liver mass was accelerated in obese mice pretreated with meloxicam (by 26% at 24 hours and 38% at 48 hours, respectively). After 80% hepatectomy, survival was dramatically increased with meloxicam treatment. CONCLUSION Low epidermal growth factor receptor expression is a common feature of fatty liver disease. Meloxicam restores epidermal growth factor receptor expression in steatotic hepatocytes. Meloxicam pretreatment may be applied to improve outcome after fatty liver resection or transplantation with steatotic graft.
Collapse
Affiliation(s)
- Xiaoling Jin
- Department of Surgery, Thomas Jefferson University School of Medicine, Philadelphia, PA, USA
| | - Teresa A Zimmers
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Yanlin Jiang
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Daniel P Milgrom
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Zongxiu Zhang
- Department of Surgery, Thomas Jefferson University School of Medicine, Philadelphia, PA, USA
| | - Leonidas G Koniaris
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
| |
Collapse
|
|
20
|
Jin H, Lian N, Bian M, Zhang C, Chen X, Shao J, Wu L, Chen A, Guo Q, Zhang F, Zheng S. Oroxylin A inhibits ethanol-induced hepatocyte senescence via YAP pathway. Cell Prolif 2018; 51:e12431. [PMID: 29318697 DOI: 10.1111/cpr.12431] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 12/02/2017] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVES Oroxylin A, a natural flavonoid isolated from Scutellaria baicalensis, has been reported to have anti-hepatic injury effects. However, the effects of oroxylin A on alcoholic liver disease (ALD) remains unclear. The aim of this study was to elucidate the effects of oroxylin A on ALD and the potential mechanisms. MATERIALS AND METHODS Male ICR mice and human hepatocyte cell line LO2 were used. Yes-associated protein (YAP) overexpression and knockdown were achieved using plasmid and siRNA technique. Cellular senescence was assessed by analyses of the senescence-associated β-galactosidase (SA-β-gal), senescence marker p16, p21, Hmga1, cell cycle and telomerase activity. RESULTS Oroxylin A alleviated ethanol-induced hepatocyte damage by suppressing activities of supernatant marker enzymes. We found that oroxylin A inhibited ethanol-induced hepatocyte senescence by decreasing the number of SA-β-gal-positive LO2 cells and reducing the expression of senescence markers p16, p21 and Hmga1 in vitro. Moreover, oroxylin A affected the cell cycle and telomerase activity. Of importance, we revealed that YAP pharmacological inhibitor verteporfin or YAP siRNA eliminated the effect of oroxylin A on ethanol-induced hepatocyte senescence in vitro, and this was further supported by the evidence in vivo experiments. CONCLUSION Therefore, these aggregated data suggested that oroxylin A relieved alcoholic liver injury possibly by inhibiting the senescence of hepatocyte, which was dependent on its activation of YAP in hepatocytes.
Collapse
Affiliation(s)
- Huanhuan Jin
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Naqi Lian
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mianli Bian
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chenxi Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xingran Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiangjuan Shao
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Li Wu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Anping Chen
- Department of Pathology, School of Medicine, Saint Louis University, St Louis, MO, USA
| | - Qinglong Guo
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, China
| |
Collapse
|
|
21
|
Affiliation(s)
- Aloysious D Aravinthan
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.,National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Graeme J Alexander
- UCL Institute for Liver and Digestive Health, The Royal Free Trust, London, UK
| |
Collapse
|
|
22
|
Guo M. Cellular senescence and liver disease: Mechanisms and therapeutic strategies. Biomed Pharmacother 2017; 96:1527-1537. [PMID: 29174037 DOI: 10.1016/j.biopha.2017.11.075] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/13/2017] [Accepted: 11/13/2017] [Indexed: 12/12/2022] Open
Abstract
Cellular senescence is a fundamental cell fate caused by several cellular injuries which results in irreversible cell cycle arrest yet remaining metabolically active across all species. Cellular senescence not only can prevent tumor occurrence by inhibiting the proliferation of injured cells, but also can affect the surrounding cells through the senescence-associated secretory phenotype (SASP). Attractively, accumulating evidence shows that cellular senescence is closely related to various liver diseases. Therapeutic opportunities based on targeting senescent cells and the SASP are considered to be potential strategy for liver diseases. However, although research on cell senescence has attracted widespread attention, the overview on detailed mechanism and biological function of cell senescence in liver disease is still largely unknown. The present review summarizes the specific role of cell senescence in various liver diseases, and updates the molecular mechanisms underlying cell senescence. Moreover, the review also explores new strategies for prevention and treatment of liver disease through promoting senescence or counteracting excessive pathological senescence.
Collapse
Affiliation(s)
- Mei Guo
- Department of Pathogenic Biology and Immunology of Medical School, Southeast University, Nanjing, Jiangsu, 210009, China.
| |
Collapse
|
|
23
|
Aravinthan AD, Alexander GJM. Senescence in chronic liver disease: Is the future in aging? J Hepatol 2016; 65:825-834. [PMID: 27245432 DOI: 10.1016/j.jhep.2016.05.030] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 04/04/2016] [Accepted: 05/23/2016] [Indexed: 12/25/2022]
Abstract
Cellular senescence is a fundamental, complex mechanism with an important protective role present from embryogenesis to late life across all species. It limits the proliferative potential of damaged cells thus protecting against malignant change, but at the expense of substantial alterations to the microenvironment and tissue homeostasis, driving inflammation, fibrosis and paradoxically, malignant disease if the process is sustained. Cellular senescence has attracted considerable recent interest with recognition of pathways linking aging, malignancy and insulin resistance and the current focus on therapeutic interventions to extend health-span. There are major implications for hepatology in the field of fibrosis and cancer, where cellular senescence of hepatocytes, cholangiocytes, stellate cells and immune cells has been implicated in chronic liver disease progression. This review focuses on cellular senescence in chronic liver disease and explores therapeutic opportunities.
Collapse
Affiliation(s)
- Aloysious D Aravinthan
- Department of Medicine, University of Toronto, Toronto, Canada; National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Graeme J M Alexander
- UCL Institute for Liver and Digestive Health, The Royal Free Trust, London, UK; Department of Medicine, University of Cambridge, Cambridge, UK.
| |
Collapse
|
|
24
|
Laish I, Mannasse-Green B, Hadary R, Konikoff FM, Amiel A, Kitay-Cohen Y. Aneuploidy and asynchronous replication in non-alcholic fatty liver disease and cryptogenic cirrhosis. Gene 2016; 593:162-166. [PMID: 27520584 DOI: 10.1016/j.gene.2016.08.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 07/24/2016] [Accepted: 08/08/2016] [Indexed: 12/25/2022]
Abstract
BACKGROUND/AIMS Non-alcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis (CC), which is largely a late sequela of NAFLD, are considered pre-neoplastic conditions that might progress to hepatocellular carcinoma. Aneuploidy, telomere aggregates and synchronization of replication were evaluated as markers of genetic instability in these patients. METHODOLOGY Peripheral blood lymphocytes from 22 patients with NAFLD, 20 patients with CC and 20 age-matched healthy controls were analyzed. To determine random aneuploidy, we used the fluorescence in situ hybridization (FISH) with probes for chromosomes 9 and 18. The rate of aneuploidy was inferred from the fraction of cells revealing one, three or more hybridization signals per cell. Aggregate size was divided into three fusion groups of 2-5, 6-10 and 11-15 telomeres, relative to the size of a single telomere. The replication pattern was determined by FISH in two pairs of alleles, 15qter and 13qter. Asynchrony was determined by the presence of one single and one set of double dots in the same cell. RESULTS Significantly higher random aneuploidy rate was found in the CC patients than in the control group, and to a lesser degree in NAFLD patients. Telomere aggregates were insignificantly higher in both groups. Only patients with CC showed significantly higher rate of asynchronous replication with proportionately more cells with two single dots among the normal cells (p<0.001). CONCLUSIONS These results likely reflect changes in gene replication and cell cycle progression in these conditions, possibly correlating with their malignant potential.
Collapse
Affiliation(s)
- Ido Laish
- Gastroenterology and Hepatology Institute, Meir Medical Center, Kfar Saba, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | | | - Ruth Hadary
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Liver Unit, Meir Medical Center, Kfar Saba, Israel
| | - Fred M Konikoff
- Gastroenterology and Hepatology Institute, Meir Medical Center, Kfar Saba, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Aliza Amiel
- Genetic Institute, Meir Medical Center, Kfar Saba, Israel; Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel
| | - Yona Kitay-Cohen
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Liver Unit, Meir Medical Center, Kfar Saba, Israel
| |
Collapse
|
|
25
|
Irvine KM, Skoien R, Bokil NJ, Melino M, Thomas GP, Loo D, Gabrielli B, Hill MM, Sweet MJ, Clouston AD, Powell EE. Senescent human hepatocytes express a unique secretory phenotype and promote macrophage migration. World J Gastroenterol 2014; 20:17851-17862. [PMID: 25548483 PMCID: PMC4273135 DOI: 10.3748/wjg.v20.i47.17851] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 06/13/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a model of stress-induced senescence to study the hepatocyte senescence associated secretory phenotype (SASP).
METHODS: Hydrogen peroxide treatment was used to induce senescence in the human HepG2 hepatocyte cell line. Senescence was confirmed by cytochemical staining for a panel of markers including Ki67, p21, heterochromatin protein 1β, and senescence-associated-β-galactosidase activity. Senescent hepatocytes were characterised by gene expression arrays and quantitative polymerase chain reaction (qPCR), and conditioned media was used in proteomic analyses, a human chemokine protein array, and cell migration assays to characterise the composition and function of the hepatocyte SASP.
RESULTS: Senescent hepatocytes induced classical markers of senescence (p21, heterochromatin protein 1β, and senescence-associated-β-galactosidase activity); and downregulated the proliferation marker, Ki67. Hepatocyte senescence induced a 4.6-fold increase in total secreted protein (P = 0.06) without major alterations in the protein profile. Senescence-induced genes were identified by microarray (Benjamini Hochberg-corrected P < 0.05); and, consistent with the increase in secreted protein, gene ontology analysis revealed a significant enrichment of secreted proteins among inducible genes. The hepatocyte SASP included characteristic factors such as interleukin (IL)-8 and IL-6, as well as novel components such as SAA4, IL-32 and Fibrinogen, which were validated by qPCR and/or chemokine protein array. Senescent hepatocyte-conditioned medium elicited migration of inflammatory (granulocyte-macrophage colony stimulating factor, GM-CSF-derived), but not non-inflammatory (CSF-1-derived) human macrophages (P = 0.022), which could contribute to a pro-inflammatory microenvironment in vivo, or facilitate the clearance of senescent cells.
CONCLUSION: Our novel model of hepatocyte senescence provides insights into mechanisms by which senescent hepatocytes may promote chronic liver disease pathogenesis.
Collapse
|
|
26
|
The senescent hepatocyte gene signature in chronic liver disease. Exp Gerontol 2014; 60:37-45. [DOI: 10.1016/j.exger.2014.09.011] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/10/2014] [Accepted: 09/16/2014] [Indexed: 12/25/2022]
|
|
27
|
Aravinthan A, Challis B, Shannon N, Hoare M, Heaney J, Alexander GJM. Selective insulin resistance in hepatocyte senescence. Exp Cell Res 2014; 331:38-45. [PMID: 25263463 DOI: 10.1016/j.yexcr.2014.09.025] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 09/14/2014] [Accepted: 09/18/2014] [Indexed: 12/22/2022]
Abstract
Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence.
Collapse
Affiliation(s)
- Aloysious Aravinthan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Benjamin Challis
- Institute of Metabolic Sciences, University of Cambridge, Cambridge, UK
| | | | - Matthew Hoare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Institute, Cambridge, UK
| | - Judith Heaney
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK; Foundation for Liver Research, Institute of Hepatology, London, UK
| | - Graeme J M Alexander
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK.
| |
Collapse
|
|
28
|
Accelerated telomere reduction and hepatocyte senescence in tolerated human liver allografts. Transpl Immunol 2014; 31:55-9. [DOI: 10.1016/j.trim.2014.06.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2014] [Revised: 06/21/2014] [Accepted: 06/23/2014] [Indexed: 01/03/2023]
|
|
29
|
Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci 2014; 15:8591-638. [PMID: 24830559 PMCID: PMC4057750 DOI: 10.3390/ijms15058591] [Citation(s) in RCA: 289] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Revised: 03/20/2014] [Accepted: 04/17/2014] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an inflammatory cascade and ensuing fibrosis. The mechanisms underlying these changes and the complex inter-cellular interactions that mediate fibrogenesis are yet to be fully elucidated. Lipotoxicity, in the setting of excess free fatty acids, obesity, and insulin resistance, appears to be the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence contribute to activation of the inflammasome via a variety of intra- and inter-cellular signalling mechanisms leading to fibrosis. Current evidence suggests that periportal components, including the ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the Th17 response may mediate disease progression. This review aims to provide an overview of the pathogenesis of NASH and summarises the evidence pertaining to key mechanisms implicated in the transition from steatosis and inflammation to fibrosis. Currently there are limited treatments for NASH although an increasing understanding of its pathogenesis will likely improve the development and use of interventions in the future.
Collapse
Affiliation(s)
- William Peverill
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.
| | - Lawrie W Powell
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.
| | - Richard Skoien
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.
| |
Collapse
|
|
30
|
Kawano Y, Ishikawa N, Aida J, Sanada Y, Izumiyama-Shimomura N, Nakamura KI, Poon SSS, Matsumoto K, Mizuta K, Uchida E, Tajiri T, Kawarasaki H, Takubo K. Q-FISH measurement of hepatocyte telomere lengths in donor liver and graft after pediatric living-donor liver transplantation: donor age affects telomere length sustainability. PLoS One 2014; 9:e93749. [PMID: 24727734 PMCID: PMC3984102 DOI: 10.1371/journal.pone.0093749] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 03/07/2014] [Indexed: 12/22/2022] Open
Abstract
Along with the increasing need for living-donor liver transplantation (LDLT), the issue of organ shortage has become a serious problem. Therefore, the use of organs from elderly donors has been increasing. While the short-term results of LDLT have greatly improved, problems affecting the long-term outcome of transplant patients remain unsolved. Furthermore, since contradictory data have been reported with regard to the relationship between donor age and LT/LDLT outcome, the question of whether the use of elderly donors influences the long-term outcome of a graft after LT/LDLT remains unsettled. To address whether hepatocyte telomere length reflects the outcome of LDLT, we analyzed the telomere lengths of hepatocytes in informative biopsy samples from 12 paired donors and recipients (grafts) of pediatric LDLT more than 5 years after adult-to-child LDLT because of primary biliary atresia, using quantitative fluorescence in situ hybridization (Q-FISH). The telomere lengths in the paired samples showed a robust relationship between the donor and grafted hepatocytes (r = 0.765, p = 0.0038), demonstrating the feasibility of our Q-FISH method for cell-specific evaluation. While 8 pairs showed no significant difference between the telomere lengths for the donor and the recipient, the other 4 pairs showed significantly shorter telomeres in the recipient than in the donor. Multiple regression analysis revealed that the donors in the latter group were older than those in the former (p = 0.001). Despite the small number of subjects, this pilot study indicates that donor age is a crucial factor affecting telomere length sustainability in hepatocytes after pediatric LDLT, and that the telomeres in grafted livers may be elongated somewhat longer when the grafts are immunologically well controlled.
Collapse
Affiliation(s)
- Youichi Kawano
- Department of Surgery, Nippon Medical School, Tokyo, Japan
- Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
- * E-mail: (YK); (NI)
| | - Naoshi Ishikawa
- Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
- * E-mail: (YK); (NI)
| | - Junko Aida
- Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Yukihiro Sanada
- Department of Transplant Surgery, Jichi Medical University, Tochigi, Japan
| | | | - Ken-ichi Nakamura
- Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Steven S. S. Poon
- Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada
| | - Koshi Matsumoto
- Department of Clinical Pathology, Ebina General Hospital, Kanagawa, Japan
| | - Koichi Mizuta
- Department of Transplant Surgery, Jichi Medical University, Tochigi, Japan
| | - Eiji Uchida
- Department of Surgery, Nippon Medical School, Tokyo, Japan
| | - Takashi Tajiri
- Department of Surgery, Nippon Medical School, Tokyo, Japan
| | - Hideo Kawarasaki
- Department of Transplant Surgery, Jichi Medical University, Tochigi, Japan
| | - Kaiyo Takubo
- Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| |
Collapse
|
|
31
|
Aravinthan A, Mells G, Allison M, Leathart J, Kotronen A, Yki-Jarvinen H, Daly AK, Day CP, Anstee QM, Alexander G. Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease. Cell Cycle 2014; 13:1489-94. [PMID: 24626178 PMCID: PMC4050146 DOI: 10.4161/cc.28471] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 02/16/2014] [Accepted: 03/07/2014] [Indexed: 02/08/2023] Open
Abstract
Non-alcohol-related fatty liver disease (NAFLD) encompasses a wide spectrum, ranging from steatosis alone to steatohepatitis and fibrosis. Presence of steatohepatitis and fibrosis are key hallmarks of disease progression. Previous studies have demonstrated an association between hepatocyte p21 expression and fibrosis stage in NAFLD. The aim of this study is to investigate the association between the variants of CDKN1A, which encodes p21, and disease progression in NAFLD. To this end, the relation between CDKN1A polymorphism and liver fibrosis was studied in 2 cohorts of biopsy-proven NAFLD patients from UK (n = 323) and Finland (n = 123). Genotyping was performed using DNA isolated from lymphocytes collected at the time of liver biopsy. The findings of the UK cohort were tested in the Finnish cohort. Both the UK and Finnish cohorts were significantly different from each other in basic demographics. In the UK cohort, rs762623, of the 6 SNPs across CDKN1A tested, was significantly associated with disease progression in NAFLD. This association was confirmed in the Finnish cohort. Despite the influence on fibrosis development, SNPs across CDKN1A did not affect the progression of liver fibrosis. In conclusion, CDKN1A variant rs762623 is associated with the development but not the propagation of progressive liver disease in NAFLD.
Collapse
Affiliation(s)
| | - George Mells
- Department of Medicine; University of Cambridge; Cambridge, UK
| | - Michael Allison
- Department of Medicine; University of Cambridge; Cambridge, UK
| | - Julian Leathart
- Institute of Cellular Medicine; Newcastle University; Newcastle upon Tyne, UK
| | - Anna Kotronen
- Department of Medicine; University of Helsinki; Helsinki, Finland
| | | | - Ann K Daly
- Institute of Cellular Medicine; Newcastle University; Newcastle upon Tyne, UK
| | - Christopher P Day
- Institute of Cellular Medicine; Newcastle University; Newcastle upon Tyne, UK
| | - Quentin M Anstee
- Institute of Cellular Medicine; Newcastle University; Newcastle upon Tyne, UK
| | | |
Collapse
|
|
32
|
Focus. J Hepatol 2013; 58:407-8. [PMID: 23247068 DOI: 10.1016/j.jhep.2012.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 12/11/2012] [Indexed: 12/04/2022]
|
|
33
|
Aravinthan A, Scarpini C, Tachtatzis P, Verma S, Penrhyn-Lowe S, Harvey R, Davies SE, Allison M, Coleman N, Alexander G. Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. J Hepatol 2013; 58:549-56. [PMID: 23142622 DOI: 10.1016/j.jhep.2012.10.031] [Citation(s) in RCA: 228] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 10/30/2012] [Accepted: 10/31/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Models of non-alcohol-related fatty liver disease (NAFLD) reveal features of accelerated ageing, such as impaired regeneration, and an increased risk of hepatocellular carcinoma. The relation between accelerated ageing, disease progression and clinical outcome has not been previously investigated and is the subject of the current study. METHODS Liver sections from 70 patients with NAFLD (105 biopsies) and 60 controls were studied for telomere length, nuclear area, DNA damage and cell cycle phase markers, using quantitative fluorescent in situ hybridization and immunohistochemistry. RESULTS Hepatocyte telomeres were shorter in NAFLD than controls (p <0.0001). Hepatocytes in NAFLD demonstrated lack of cell cycle progression beyond G1/S phase and high-level expression of p21, the universal cell cycle inhibitor (p=0.001). γ-H(2)AX expression increased with steatosis (p=0.01), indicating DNA damage, and was associated with shorter hepatocyte telomeres (p <0.0001). Hepatocyte p21 expression correlated with fibrosis stage and diabetes mellitus, independently (p <0.001 and p=0.002, respectively). Further analysis revealed that an adverse liver-related outcome was strongly associated with higher hepatocyte p21 expression and greater hepatocyte nuclear area (p=0.02 and p=0.006), but not with telomere length. In paired biopsies, changes in hepatocyte p21 expression and nuclear area mirrored changes in fibrosis stage (p=0.01 and p=0.006, respectively). CONCLUSIONS These findings are consistent with hepatocyte senescence and permanent cell cycle arrest in NAFLD. Hepatocyte senescence correlated closely with fibrosis stage, diabetes mellitus, and clinical outcome. Hepatocyte p21 expression could be used as a prognostic marker and for stratification in clinical studies.
Collapse
Affiliation(s)
- Aloysious Aravinthan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Martins IJ, Lim WLF, Wilson AC, Laws SM, Martins RN. The acceleration of aging and Alzheimer’s disease through the biological mechanisms behind obesity and type II diabetes. Health (London) 2013. [DOI: 10.4236/health.2013.55121] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|
|
35
|
You NCY, Chen BH, Song Y, Lu X, Chen Y, Manson JE, Kang M, Howard BV, Margolis KL, Curb JD, Phillips LS, Stefanick ML, Tinker LF, Liu S. A prospective study of leukocyte telomere length and risk of type 2 diabetes in postmenopausal women. Diabetes 2012; 61:2998-3004. [PMID: 22829448 PMCID: PMC3478524 DOI: 10.2337/db12-0241] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Telomere length (TL) has been implicated in the pathogenesis of age-related disorders. However, there are no prospective studies directly investigating the role of TL and relevant genes in diabetes development. In the multiethnic Women's Health Initiative, we identified 1,675 incident diabetes case participants in 6 years of follow-up and 2,382 control participants matched by age, ethnicity, clinical center, time of blood draw, and follow-up duration. Leukocyte TL at baseline was measured using quantitative PCR, and Mendelian randomization analysis was conducted to test whether TL is causally associated with diabetes risk. After adjustment for matching and known diabetes risk factors, odds ratios per 1-kilobase increment were 1.00 (95% CI 0.90-1.11) in whites, 0.95 (0.85-1.06) in blacks, 0.96 (0.79-1.17) in Hispanics, and 0.88 (0.70-1.10) in Asians. Of the 80 single nucleotide polymorphisms (SNPs) in nine genes involved in telomere regulation, 14 SNPs were predictive of TL, but none were significantly associated with diabetes risk. Using ethnicity-specific SNPs as randomization instruments, we observed no statistically significant association between TL and diabetes risk (P = 0.52). Although leukocyte TL was weakly associated with diabetes risk, this association was not independent of known risk factors. These prospective findings indicate limited clinical utility of TL in diabetes risk stratification among postmenopausal women.
Collapse
Affiliation(s)
- Nai-chieh Y. You
- Program on Genomics and Nutrition, Department of Epidemiology, Fielding School of Public Health, and Departments of Medicine and Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, California
- Center for Metabolic Disease Prevention, UCLA, Los Angeles, California
| | - Brian H. Chen
- Program on Genomics and Nutrition, Department of Epidemiology, Fielding School of Public Health, and Departments of Medicine and Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, California
- Center for Metabolic Disease Prevention, UCLA, Los Angeles, California
| | - Yiqing Song
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - XuYang Lu
- Program on Genomics and Nutrition, Department of Epidemiology, Fielding School of Public Health, and Departments of Medicine and Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, California
- Center for Metabolic Disease Prevention, UCLA, Los Angeles, California
- Department of Biostatistics, UCLA, Los Angeles, California
| | - Yilin Chen
- Program on Genomics and Nutrition, Department of Epidemiology, Fielding School of Public Health, and Departments of Medicine and Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, California
- Center for Metabolic Disease Prevention, UCLA, Los Angeles, California
| | - JoAnn E. Manson
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Mo Kang
- Center for Metabolic Disease Prevention, UCLA, Los Angeles, California
- Division of Associated Clinical Sciences, School of Dentistry, UCLA, Los Angeles, California
| | - Barbara V. Howard
- MedStar Research Institute, Hyattsville, Maryland
- Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC
| | | | - J. David Curb
- John A. Burns School of Medicine, University of Hawaii, and Pacific Health Research Institute, Honolulu, Hawaii
| | - Lawrence S. Phillips
- Atlanta VA Medical Center, Decatur, Georgia
- Emory University School of Medicine, Atlanta, Georgia
| | - Marcia L. Stefanick
- Stanford Prevention Research Center, School of Medicine, Stanford University, Stanford, California
| | | | - Simin Liu
- Program on Genomics and Nutrition, Department of Epidemiology, Fielding School of Public Health, and Departments of Medicine and Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, California
- Center for Metabolic Disease Prevention, UCLA, Los Angeles, California
- Johnson Comprehensive Cancer Center, UCLA, Los Angeles, California
- Corresponding author: Simin Liu,
| |
Collapse
|
|
36
|
Verma S, Tachtatzis P, Penrhyn-Lowe S, Scarpini C, Jurk D, Von Zglinicki T, Coleman N, Alexander GJM. Sustained telomere length in hepatocytes and cholangiocytes with increasing age in normal liver. Hepatology 2012; 56:1510-20. [PMID: 22504828 DOI: 10.1002/hep.25787] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Accepted: 04/08/2012] [Indexed: 12/17/2022]
Abstract
UNLABELLED Telomeres, a validated biomarker of aging, comprise multiple nucleotide repeats capping chromosomes that shorten with each cell cycle until a critical length is achieved, precipitating cell senescence. Only two previous studies focused on the effect of aging in "normal" liver tissue, but these studies were compromised by small sample size, limited age range, tissue derived from individuals with an increased risk of senescence, and the use of liver homogenates. We developed a robust large-volume, four-color quantitative fluorescent in situ hybridization technique to measure telomere length in large numbers of hepatocytes, Kupffer cells, hepatic stellate cells, CD4-positive and CD8-positive lymphocytes, and cholangiocytes. Following validation against the gold standard (Southern blotting), the technique was applied to normal archived paraffin-embedded liver tissue obtained following reperfusion of implanted donor liver. We studied 73 highly selected donors aged 5-79 years with a short medical illness preceding death and no history of liver disease, reperfusion injury, or steatosis and normal graft function 1-year posttransplantation. Cholangiocytes had significantly longer telomeres compared with all other intrahepatic lineages over a wide age range (P < 0.05). Age-related telomere attrition was restricted to sinusoidal cells (i.e., Kupffer cells [P = 0.0054] and stellate cells [P = 0.0001]). Cholangiocytes and hepatocytes showed no age-related telomere shortening. CONCLUSION In normal liver and over a broad age range, cholangiocytes have longer telomeres than all other intrahepatic lineages. Age-related telomere length decline is restricted to Kupffer cells and stellate cells.
Collapse
Affiliation(s)
- Suman Verma
- Division of Gastroenterology & Hepatology, University Department of Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | | | | | | | | | | | | | | |
Collapse
|
|
37
|
|
|
38
|
Aini W, Miyagawa-Hayashino A, Tsuruyama T, Hashimoto S, Sumiyoshi S, Ozeki M, Tamaki K, Uemoto S, Haga H. Telomere shortening and karyotypic alterations in hepatocytes in long-term transplanted human liver allografts. Transpl Int 2012; 25:956-66. [PMID: 22775391 DOI: 10.1111/j.1432-2277.2012.01523.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The long-term fate of aged liver allografts in young recipients who received grafts from older donors is unknown. We evaluated graft aging by analyzing hepatocytic telomere length and karyotypic changes. Seventeen pediatric individuals who underwent living-donor liver transplantation for congenital biliary diseases were selected. At a median of 10.4 years post-transplant, ten had tolerated grafts with weaned off immunosuppressants, and seven had idiopathic post-transplantation hepatitis. Fluorescence in situ hybridization was used to evaluate the telomere signal intensity (TI) and karyotypic changes. First, we measured predictive age-dependent TI decline with regression analysis of donor livers. The mean TI at the earliest (within a year) and latest biopsies was significantly lower than the predicted TI of the studied allografts. With univariate analysis, a higher abnormal karyotype ratio in the donor liver was correlated with development of idiopathic post-transplantation hepatitis. With multivariate analysis that included clinical parameters, a greater TI decline at the earliest biopsy was correlated with the development of idiopathic post-transplantation hepatitis. In conclusion, graft aging as measured by TI decline and donor abnormal karyotype ratio was associated with idiopathic post-transplantation hepatitis of long-term transplanted liver allografts.
Collapse
Affiliation(s)
- Wulamujiang Aini
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Tzanetakou IP, Katsilambros NL, Benetos A, Mikhailidis DP, Perrea DN. "Is obesity linked to aging?": adipose tissue and the role of telomeres. Ageing Res Rev 2012; 11:220-9. [PMID: 22186032 DOI: 10.1016/j.arr.2011.12.003] [Citation(s) in RCA: 136] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2011] [Revised: 11/22/2011] [Accepted: 12/06/2011] [Indexed: 12/28/2022]
Abstract
Obesity is a condition in which excess or abnormal fat accumulation may present with adverse effects on health and decreased life expectancy. Increased body weight and adipose tissue accumulation amplifies the risk of developing various age-related diseases, such as cardiovascular disease, type 2 diabetes mellitus, musculoskeletal disorders, respiratory diseases and certain types of cancer. This imbalance in body composition and body weight is now recognized as a state of increased oxidative stress and inflammation for the organism. Increasing oxidative stress and inflammation affect telomeres. Telomeres are specialized DNA-protein structures found at the ends of eukaryotic chromosomes and serve as markers of biological aging rate. They also play a critical role in maintaining genomic integrity and are involved in age-related metabolic dysfunction. Erosion of telomeres is hazardous to healthy cells, as it is a known mechanism of premature cellular senescence and loss of longevity. The association of telomeres and oxidative stress is evident in cultured somatic cells in vitro, where oxidative stress enhances the process of erosion with each cycle of replication. Shorter telomeres have been associated with increasing body mass index, increased adiposity, and more recently with increasing waist to hip ratio and visceral excess fat accumulation. Furthermore, many of the metabolic imbalances of obesity (e.g. glycemic, lipidemic, etc.) give rise to organ dysfunction in a way that resembles the accelerated aging process. This article is a non-systematic review of the evidence linking obesity and accelerated aging processes as they are regulated by telomeres.
Collapse
Affiliation(s)
- Irene P Tzanetakou
- Laboratory for Experimental Surgery and Surgical Research "N. S. Christeas", University of Athens Medical School, Greece.
| | | | | | | | | |
Collapse
|
|
40
|
Nakajima T, Nakashima T, Yamaoka J, Shibuya A, Konishi E, Okada Y, Jo M, Nishikawa T, Itoh Y, Yoshikawa T. Greater age and hepatocellular aging are independent risk factors for hepatocellular carcinoma arising from non-B non-C non-alcoholic chronic liver disease. Pathol Int 2012; 61:572-6. [PMID: 21951665 DOI: 10.1111/j.1440-1827.2011.02743.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We previously reported that hepatocellular aging can be assessed by measuring the nuclear size of hepatocytes. We attempted to elucidate whether this method is useful to identify the high risk group of hepatocellular carcinoma (HCC) in the patients with non-B non-C non-alcoholic liver injury. Fourteen patients with HCC and 78 without HCC, both of whom presented with non-B non-C non-alcoholic chronic liver injury and underwent liver biopsy, were selected. Twelve histologically normal liver tissues were selected as controls. The relative nuclear size (RNS) was calculated as the average nuclear size of the hepatocytes divided by that of lymphocytes. Multiple clinicopathological parameters were studied. The RNS values of normal livers ranged from 1.32 to 2.10, showing a gradual increase in an age-dependent manner. The RNS values of the injured livers without HCC increased after middle age. Univariate analysis identified greater age, existence of diabetes and RNS, as significantly positive contributors and ALT value and the degree of steatosis as negative contributors for the occurrence of HCC. Only age and RNS retained significance in multivariate analysis. All of the HCC patients were older than 50 and showed RNS values higher than 2.00. Therefore, such patients are classified as a high risk group of HCC.
Collapse
Affiliation(s)
- Tomoki Nakajima
- Departments of Medicine Clinical Pathology, Saiseikai Kyoto Hospital, Nagaoka-kyo Molecular Gastroenterology and Hepatology, Kyoto, Japan.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Abstract
Oxidatively damaged DNA is implicated in various diseases, including neurodegenerative disorders, cancer, diabetes, cardiovascular and inflammatory diseases as well as aging. Several methods have been developed to detect oxidatively damaged DNA. They include chromatographic techniques, the Comet assay, (32)P-postlabelling and immunochemical methods that use antibodies to detect oxidized lesions. In this review, we discuss the detection of 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxodG), the most abundant oxidized nucleoside. This lesion is frequently used as a marker of exposure to oxidants, including environmental pollutants, as well as a potential marker of disease progression. We concentrate on studies published between the years 2000 and 2011 that used enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry to detect 8-oxodG in humans, laboratory animals and in cell lines. Oxidative damage observed in these organisms resulted from disease, exposure to environmental pollutants or from in vitro treatment with various chemical and physical factors.
Collapse
Affiliation(s)
- Pavel Rossner
- Laboratory of Genetic Ecotoxicology, Institute of Experimental Medicine AS CR, Videnska 1083, 142 20 Prague, Czech Republic.
| | | |
Collapse
|
|
42
|
van Steenbeek FG, van den Bossche L, Leegwater PAJ, Rothuizen J. Inherited liver shunts in dogs elucidate pathways regulating embryonic development and clinical disorders of the portal vein. Mamm Genome 2011; 23:76-84. [PMID: 22052005 PMCID: PMC3275728 DOI: 10.1007/s00335-011-9364-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Accepted: 10/13/2011] [Indexed: 12/14/2022]
Abstract
Congenital disorders of the hepatic portal vasculature are rare in man but occur frequently in certain dog breeds. In dogs, there are two main subtypes: intrahepatic portosystemic shunts, which are considered to stem from defective closure of the embryonic ductus venosus, and extrahepatic shunts, which connect the splanchnic vascular system with the vena cava or vena azygos. Both subtypes result in nearly complete bypass of the liver by the portal blood flow. In both subtypes the development of the smaller branches of the portal vein tree in the liver is impaired and terminal branches delivering portal blood to the liver lobules are often lacking. The clinical signs are due to poor liver growth, development, and function. Patency of the ductus venosus seems to be a digenic trait in Irish wolfhounds, whereas Cairn terriers with extrahepatic portosystemic shunts display a more complex inheritance. The genes involved in these disorders cannot be identified with the sporadic human cases, but in dogs, the genome-wide study of the extrahepatic form is at an advanced stage. The canine disease may lead to the identification of novel genes and pathways cooperating in growth and development of the hepatic portal vein tree. The same pathways likely regulate the development of the vascular system of regenerating livers during liver diseases such as hepatitis and cirrhosis. Therefore, the identification of these molecular pathways may provide a basis for future proregenerative intervention.
Collapse
Affiliation(s)
- Frank G van Steenbeek
- Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, PO Box 80154, 3508 TD Utrecht, The Netherlands.
| | | | | | | |
Collapse
|
|
43
|
Oxidative stress is closely associated with tumor angiogenesis of hepatocellular carcinoma. J Gastroenterol 2011; 46:809-21. [PMID: 21452000 DOI: 10.1007/s00535-011-0392-z] [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] [Received: 12/22/2009] [Accepted: 02/09/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND Oxidative stress (OS) plays an important role in the progression of chronic liver disease and hepatocarcinogenesis. However, the role of OS in the progression of hepatocellular carcinoma (HCC) is unclear. The aim of this study was to assess whether OS promotes angiogenesis in HCC. METHODS The expressions of vascular endothelial growth factor (VEGF), VEGF receptor2 (VEGFR2), and phosphorylated Akt were assessed, and microvessel density (MVD) and the cancer-associated fibroblast (CAF) population were examined by immunohistological staining in 55 HCC samples. The OS level in these tissues was assessed using 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) immunostaining, and an 8-OHdG enzyme-linked immunosorbent assay (ELISA). The expression and activation of angiogenic factors and the effect of growth stimulation of human umbilical vein endothelial cells (HUVECs) were also assessed in vitro, using HLE hepatoma-derived cells and conditioned medium with or without treatment with hydrogen peroxide (H₂O₂); a phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin; and an anti-oxidative agent, N-acetyl-L-cysteine (NAC). RESULTS A higher OS grade was significantly associated with higher MVD, VEGF expression, Akt activity, and OS grade of CAFs, but not with the percentage of the CAF population in HCC tissues. Additionally, cancer cells constituted a major population of OS marker-positive cells in HCC tissues. In vitro, H₂O₂ treatment induced up-regulation of VEGF at both the mRNA and protein levels, activated Akt, and resulted in the proliferation of HUVECs; the addition of wortmannin and NAC counteracted the effects of OS. CONCLUSIONS OS enhances the malignant potential of HCC through the stimulation of angiogenesis by activation of the Akt-VEGF pathway.
Collapse
|
|
44
|
Nakajima T, Nakashima T, Okada Y, Jo M, Nishikawa T, Mitsumoto Y, Katagishi T, Kimura H, Itoh Y, Kagawa K, Yoshikawa T. Nuclear size measurement is a simple method for the assessment of hepatocellular aging in non-alcoholic fatty liver disease: Comparison with telomere-specific quantitative FISH and p21 immunohistochemistry. Pathol Int 2010; 60:175-83. [PMID: 20403043 DOI: 10.1111/j.1440-1827.2009.02504.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Telomere-specific quantitative fluorescent in situ hybridization (Q-FISH) accurately evaluates hepatocellular aging on histological sections, but it requires appropriate tissue processing. To establish a more simple method for the assessment of hepatocellular aging, the usefulness of nuclear size measurement was clarified using biopsy liver samples from 64 patients with non-alcoholic fatty liver disease (NAFLD), a model for oxidative stress-associated hepatocellular aging, and 11 control individuals. Relative telomere intensity (RTI) was measured on Q-FISH, and the relative nuclear size (RNS) was calculated as the average nuclear size of the hepatocytes divided by that of lymphocytes. In normal individuals and NAFLD patients, the RTI and RNS were negatively correlated. The degree of nuclear enlargement in NAFLD patients was larger than that in normal individuals with the same telomere length, possibly reflecting telomere-independent senescence. In NAFLD patients with RNS >2.0, the regenerative responses, indicated by the ratio of Ki-67-positive index to serum alanine aminotransferase level, were significantly reduced. The RNS positively correlated with the p21 expression, another marker of senescence. This all indicates that nuclear enlargement progresses in parallel with reduced regenerative responses, telomere shortening, and p21 upregulation. Nuclear size measurement is an effective method for estimation of hepatocellular aging.
Collapse
Affiliation(s)
- Tomoki Nakajima
- Department of Medicine, Saiseikai Kyoto Hospital, Nagaoka-kyo City, Japan.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Sasaki M, Ikeda H, Yamaguchi J, Miyakoshi M, Sato Y, Nakanuma Y. Bile ductular cells undergoing cellular senescence increase in chronic liver diseases along with fibrous progression. Am J Clin Pathol 2010; 133:212-23. [PMID: 20093230 DOI: 10.1309/ajcpwmx47treywzg] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
We investigated the pathologic significance of ductular reactions in chronic liver diseases with respect to cellular senescence. The expression of senescence-associated markers (p16(INK4a) and p21(WAF1/Cip1)), cell proliferation, cell cycle markers (cyclin D and cyclin A), and neural cell adhesion molecule (NCAM) was examined immunohistochemically in primary biliary cirrhosis (PBC, n = 37), chronic viral hepatitis (n = 39), nonalcoholic steatohepatitis (n = 25), and control normal livers (n = 12). The expression of p16(INK4a) and p21(WAF1/Cip1) was frequently found in ductular cells in the advanced stage of chronic liver diseases, especially in PBC (P < .05). Double immunostaining disclosed that most senescent cells expressed cyclin D (G(1)-phase marker). NCAM was frequently coexpressed in ductular cells showing senescence-associated markers. Some ductular cells in ductular reactions in chronic liver diseases were at G(1) arrest and undergoing cellular senescence. Such senescent cells may be involved in the progression of fibrosis of these diseases, particularly in PBC.
Collapse
|
|
46
|
Aida J, Izumo T, Shimomura N, Nakamura KI, Ishikawa N, Matsuura M, Poon SS, Fujiwara M, Sawabe M, Arai T, Takubo K. Telomere lengths in the oral epithelia with and without carcinoma. Eur J Cancer 2009; 46:430-8. [PMID: 19910186 DOI: 10.1016/j.ejca.2009.10.018] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2009] [Revised: 10/09/2009] [Accepted: 10/15/2009] [Indexed: 10/20/2022]
Abstract
Aging appears to be intrinsically related to carcinogenesis. Genomic instability due to telomere shortening plays an important role in carcinoma development. In order to clarify telomere dysfunction in carcinoma development, we examined the uninvolved epithelium adjacent to carcinoma in situ (CIS), i.e. background of CIS, and CIS itself, compared to control without carcinoma, using an improved quantitative fluorescence in situ hybridization (Q-FISH) method. We also estimated anaphase bridge (AB), which is inferred to be related to chromosomal instability. In all cell types (basal, parabasal, and suprabasal), mean telomere lengths were significantly shorter in the background than in the control. We also demonstrated increased incidences of AB, not only in CIS, but also in the background and control epithelia with excessively shortened telomeres. Thus we have conclusively demonstrated that CIS arises from epithelium with short telomeres.
Collapse
Affiliation(s)
- Junko Aida
- Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Nishikawa T, Nakajima T, Katagishi T, Okada Y, Jo M, Kagawa K, Okanoue T, Itoh Y, Yoshikawa T. Oxidative stress may enhance the malignant potential of human hepatocellular carcinoma by telomerase activation. Liver Int 2009; 29:846-56. [PMID: 19141026 DOI: 10.1111/j.1478-3231.2008.01963.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIMS Continuous oxidative stress (OS) plays an important role in the progression of chronic liver diseases and hepatocarcinogenesis through telomere shortening in hepatocytes. However, it has not been established how the OS influences the progression of human hepatocellular carcinomas (HCCs). We examined the correlations of OS with telomere length of cancer cells, telomerase activity and other clinicopathological factors in 68 HCCs. METHODS The level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a marker of OS was examined immunohistochemically and OS was scored in four grades (0-3). The telomere length of cancer cells was measured by quantitative fluorescence in situ hybridization. Telomerase activity was measured by (i) immunodetection of human telomerase reverse transcriptase (hTERT) and (ii) telomere repeat amplification protocol (TRAP) assay. Telomerase related proteins, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Akt, and other clinicopathological factors were also evaluated. RESULTS As the OS grade increased, the average telomere length became significantly shorter in HCCs, especially in the hTERT-negative group. In the state of high-grade OS, hTERT-positive HCC cells showed more proliferative and less apoptotic features compared with hTERT-negative HCC cells. Telomerase activity, as measured by the TRAP assay, was strongly correlated with OS grade in HCCs. Furthermore, a high OS grade was correlated with the downexpression of PTEN and the activation of Akt. CONCLUSIONS Oxidative stress enhanced the malignant potential of HCCs through the activation of telomerase, which raises the possibility of using OS as a marker for assessing the clinical state of HCCs.
Collapse
Affiliation(s)
- Taichiro Nishikawa
- Kyoto Prefectural University of Medicine Graduate School of Medical Science, Molecular Gastroenterology and Hepatology, Kyoto, Japan.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Muller M. Cellular senescence: molecular mechanisms, in vivo significance, and redox considerations. Antioxid Redox Signal 2009; 11:59-98. [PMID: 18976161 DOI: 10.1089/ars.2008.2104] [Citation(s) in RCA: 179] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Cellular senescence is recognized as a critical cellular response to prolonged rounds of replication and environmental stresses. Its defining characteristics are arrested cell-cycle progression and the development of aberrant gene expression with proinflammatory behavior. Whereas the mechanistic events associated with senescence are generally well understood at the molecular level, the impact of senescence in vivo remains to be fully determined. In addition to the role of senescence as an antitumor mechanism, this review examines cellular senescence as a factor in organismal aging and age-related diseases, with particular emphasis on aberrant gene expression and abnormal paracrine signaling. Senescence as an emerging factor in tissue remodeling, wound repair, and infection is considered. In addition, the role of oxidative stress as a major mediator of senescence and the role of NAD(P)H oxidases and changes to intracellular GSH/GSSG status are reviewed. Recent findings indicate that senescence and the behavior of senescent cells are amenable to therapeutic intervention. As the in vivo significance of senescence becomes clearer, the challenge will be to modulate the adverse effects of senescence without increasing the risks of other diseases, such as cancer. The uncoupled relation between cell-cycle arrest and the senescent phenotype suggests that this is an achievable outcome.
Collapse
Affiliation(s)
- Michael Muller
- Centre for Education and Research on Ageing, ANZAC Research Institute, University of Sydney, Concord RG Hospital, Concord, Sydney, Australia.
| |
Collapse
|
|
49
|
Aida J, Izumiyama-Shimomura N, Nakamura KI, Ishikawa N, S.S. Poon S, Kammori M, Sawabe M, Arai T, Matsuura M, Fujiwara M, Kishimoto H, Takubo K. Basal cells have longest telomeres measured by tissue Q-FISH method in lingual epithelium. Exp Gerontol 2008; 43:833-9. [DOI: 10.1016/j.exger.2008.06.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2008] [Revised: 05/25/2008] [Accepted: 06/03/2008] [Indexed: 10/22/2022]
|
|
50
|
Sasaki M, Ikeda H, Yamaguchi J, Nakada S, Nakanuma Y. Telomere shortening in the damaged small bile ducts in primary biliary cirrhosis reflects ongoing cellular senescence. Hepatology 2008; 48:186-95. [PMID: 18536059 DOI: 10.1002/hep.22348] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
UNLABELLED Telomere shortening is a trigger of cellular senescence. Biliary epithelial cells in damaged small bile ducts in primary biliary cirrhosis (PBC) show senescent features such as the expression of senescence-associated beta-galactosidase and the increased expression of p16(INK4a) and p21(WAF1/Cip1). We investigated whether the telomere shortening is involved in the pathogenesis of biliary cellular senescence in PBC. We analyzed the telomere length of biliary epithelial cells using quantitative fluorescence in situ hybridization in livers taken from the patients with PBC (n = 13) and control livers (n = 13). We also assessed immunohistochemically the prevalence of DNA damage and the expression of p16(INK4a) and p21(WAF1/Cip1). The study showed a significant decrease in telomere length in biliary epithelial cells in the damaged small bile ducts and bile ductules in PBC compared with normal-looking bile ducts and bile ductules in PBC, chronic viral hepatitis, and normal livers (P < 0.01). gammaH2AX-DNA-damage-foci were detected in biliary epithelial cells in damaged small bile ducts and bile ductules in PBC but were absent in biliary epithelial cells in chronic viral hepatitis and normal livers. The expression of p16(INK4a) and p21(WAF1/Cip1) was increased corresponding to telomere shortening and gammaH2AX-DNA-damage-foci in the damaged small bile ducts in PBC. CONCLUSION Telomere shortening and an accumulation of DNA damage coincide with increased expression of p16(INK4a) and p21(WAF1/Cip1) in the damaged bile ducts, characterize biliary cellular senescence, and may play a role in the following progressive bile duct loss in PBC.
Collapse
Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | | | | | | | | |
Collapse
|