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India-Aldana S, Midya V, Betanzos-Robledo L, Yao M, Alcalá C, Andra SS, Arora M, Calafat AM, Chu J, Deierlein A, Estrada-Gutierrez G, Jagani R, Just AC, Kloog I, Landero J, Oulhote Y, Walker RW, Yelamanchili S, Baccarelli AA, Wright RO, Téllez Rojo MM, Colicino E, Cantoral A, Valvi D. Impact of metabolism-disrupting chemicals and folic acid supplementation on liver injury and steatosis in mother-child pairs. J Hepatol 2025; 82:956-966. [PMID: 39674324 DOI: 10.1016/j.jhep.2024.11.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 11/20/2024] [Accepted: 11/26/2024] [Indexed: 12/16/2024]
Abstract
BACKGROUND & AIMS Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on steatotic liver disease limits opportunities for intervention. We evaluated pregnancy MDC-mixture associations with liver outcomes, and effect modification by folic acid (FA) supplementation in mother-child pairs. METHODS We studied ∼200 mother-child pairs from the Mexican PROGRESS cohort, with 43 MDCs measured during pregnancy (estimated air pollutants, blood/urine metals or metalloids, urine high- and low-molecular-weight phthalate [HMWPs, LMWPs] and organophosphate-pesticide metabolites), and serum liver enzymes (ALT, AST) at ∼9 years post-parturition. Outcomes included elevated liver enzymes in children and established clinical scores for steatosis and fibrosis in mothers (i.e. , AST ALT, FLI, HSI, FIB-4). Bayesian-weighted quantile sum regression assessed MDC-mixture associations with liver outcomes. We further examined chemical-chemical interactions and effect modification by self-reported FA supplementation. RESULTS In children, many MDC-mixtures were associated with liver injury. Per quartile HMWP-mixture increase, ALT increased by 10.1% (95% CI 1.67%, 19.4%) and AST by 5.27% (95% CI 0.80%, 10.1%). LMWP-mixtures and air pollutant-mixtures were associated with higher AST and ALT, respectively. Air pollutant and non-essential metal/element associations with liver enzymes were attenuated by maternal cobalt blood concentrations (p-interactions <0.05). In mothers, only the LMWP-mixture was associated with odds for steatosis (odds ratio = 1.53, 95% CI 1.01-2.28 for HSI >36, and odds ratio 1.62, 95% CI 1.05-2.49 for AST:ALT <1). In mothers and children, most associations were attenuated (null) at FA supplementation ≥600 μg/day (p-interactions <0.05). CONCLUSIONS Pregnancy MDC exposures may increase risk of liver injury and steatosis, particularly in children. Adequate FA supplementation and maternal cobalt levels may attenuate these associations. IMPACT AND IMPLICATIONS The effects of environmental chemical exposures on steatotic liver diseases are not well understood. In a parallel investigation of mothers and children, we found that pregnancy exposures to metabolism-disrupting chemicals may increase the risk of liver injury and steatosis, especially in the child, and that these associations could be attenuated by higher folic acid and/or cobalt levels. These findings can inform policies to decrease environmental chemical pollution and contribute to the design of clinical interventions addressing the metabolic dysfunction-associated steatotic liver disease epidemic.
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Affiliation(s)
- Sandra India-Aldana
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Vishal Midya
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Larissa Betanzos-Robledo
- Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico
| | - Meizhen Yao
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Cecilia Alcalá
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Syam S Andra
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Manish Arora
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Antonia M Calafat
- Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA
| | - Jaime Chu
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Andrea Deierlein
- New York University School of Global Public Health, New York, NY, USA
| | | | - Ravikumar Jagani
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Allan C Just
- Department of Epidemiology, School of Public Health, Brown University, Providence, RI, USA
| | - Itai Kloog
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Julio Landero
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Youssef Oulhote
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ryan W Walker
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shirisha Yelamanchili
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Robert O Wright
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Martha María Téllez Rojo
- Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico
| | - Elena Colicino
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Damaskini Valvi
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Mahmoudi SK, Abdolahi S, Saniee P, Zali MR, Hatami B, Baghaei K. Limosilactobacillus fermentum role in combination with human mesenchymal stem cell-derived secretome: A novel approach to alleviate inflammation in NASH pathogenesis. Int Immunopharmacol 2025; 156:114686. [PMID: 40250073 DOI: 10.1016/j.intimp.2025.114686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 04/01/2025] [Accepted: 04/14/2025] [Indexed: 04/20/2025]
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) is caused by the accumulation of excess fat in the liver, chronic inflammation, and cell death. The role of the secretome derived from Wharton's jelly and mesenchymal stem cells (WJ-MSC) in reducing inflammation and apoptosis has been investigated in several studies. Also, the strain Limosilactobacillus fermentum (L.fermentum) was identified as an antimicrobial and antioxidant probiotic. This study looked into the role of a combination of secretome and L.fermentum on cellular stress, apoptosis, and inflammation-related pathways in an NASH in-vitro model. METHODS Oil Red O staining confirmed the NASH model was induced using oleic acid and palmitic acid. Then, the 3 different groups were treated with two concentrations of WJ-MSCs-derived secretome, cell-free extract (CFE) of L.fermentum, and their combination. Oxidative stress was evaluated, and western blotting was used to identify the protein. Gene expression and protein quantity were assessed using real-time PCR and ELISA. RESULT The analysis revealed the secretome, L.fermentum, and their combination decreased oxidative stress. Additionally, the low levels of Caspase 3 and 9 led to a reduction in apoptosis. The combined treatment significantly impacted inflammation by increasing IL-10 and decreasing IL-6. The expression of STAT3 was also confirmed to be reduced using western blotting. Despite the significant modulation of TNF-alpha and STAT3 by L. fermentum at a high dose, the combined approach led to enhanced performance and restored the cell proliferation. CONCLUSION This enhancement has the potential to substantially influence the treatment of NASH disease by impacting inflammation, apoptosis, and oxidative stress, thereby revealing therapeutic potential for NASH disease.
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Affiliation(s)
- Seyedeh Kosar Mahmoudi
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Shahrokh Abdolahi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parastoo Saniee
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Ran S, Zhang J, Tian F, Qian ZM, Wei S, Wang Y, Chen G, Zhang J, Arnold LD, McMillin SE, Lin H. Association of metabolic signatures of air pollution with MASLD: Observational and Mendelian randomization study. J Hepatol 2025; 82:560-570. [PMID: 39349253 DOI: 10.1016/j.jhep.2024.09.033] [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: 01/11/2024] [Revised: 08/27/2024] [Accepted: 09/17/2024] [Indexed: 10/02/2024]
Abstract
BACKGROUND & AIMS Air pollution is a significant public health issue and an important risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), though the underlying mechanisms of this association are unknown. Herein, we aimed to identify metabolic signatures associated with exposure to ambient air pollution and to explore their associations with the risk of MASLD. METHODS We utilized data from the UK Biobank cohort. Annual mean concentrations of PM2.5, PM10, NO2 and NOx were assessed for each participant using bilinear interpolation. The elastic net regression model was used to identify metabolites associated with four air pollutants and to construct metabolic signatures. Associations between air pollutants, metabolic signatures and MASLD were analyzed using Cox models. Mendelian randomization (MR) analysis was used to examine potential causality. Mediation analysis was employed to examine the role of metabolic signatures in the association between air pollutants and MASLD. RESULTS A total of 244,842 participants from the UK Biobank were included in this analysis. We identified 87, 65, 76, and 71 metabolites as metabolic signatures of PM2.5, PM10, NO2, and NOx, respectively. Metabolic signatures were associated with risk of MASLD, with hazard ratios (HRs) and 95% CIs of 1.10 (1.06-1.14), 1.06 (1.02-1.10), 1.24 (1.20-1.29) and 1.14 (1.10-1.19), respectively. The four pollutants were associated with increased risk of MASLD, with HRs (95% CIs) of 1.03 (1.01-1.05), 1.02 (1.01-1.04), 1.01 (1.01-1.02) and 1.01 (1.00-1.01), respectively. MR analysis indicated an association between PM2.5, NO2 and NOx-related metabolic signatures and MASLD. Metabolic signatures mediated the association of PM2.5, PM10, NO2 and NOx with MASLD. CONCLUSION PM2.5, PM10, NO2 and NOx-related metabolic signatures appear to be associated with MASLD. These signatures mediated the increased risk of MASLD associated with PM2.5, PM10, NO2 and NOx. IMPACT AND IMPLICATIONS Air pollution is a significant public health issue and an important risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), however, the mechanism by which air pollution affects MASLD remains unclear. Our study used integrated serological metabolic data of 251 metabolites from a large-scale cohort study to demonstrate that metabolic signatures play a crucial role in the elevated risk of MASLD caused by air pollution. These results are relevant to patients and policymakers because they suggest that air pollution-related metabolic signatures are not only potentially associated with MASLD but also involved in mediating the process by which PM2.5, PM10, NO2, and NOx increase the risk of MASLD. Focusing on changes in air pollution-related metabolic signatures may offer a new perspective for preventing air pollution-induced MASLD and serve as protective measures to address this emerging public health challenge.
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Affiliation(s)
- Shanshan Ran
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Jingyi Zhang
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Fei Tian
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Zhengmin Min Qian
- Department of Epidemiology and Biostatistics College for Public Health & Social Justice, Saint Louis University, Saint Louis, MO, USA
| | - Shengtao Wei
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Yuhua Wang
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Ge Chen
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Junguo Zhang
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Lauren D Arnold
- Department of Epidemiology and Biostatistics College for Public Health & Social Justice, Saint Louis University, Saint Louis, MO, USA
| | | | - Hualiang Lin
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China.
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Termite F, Archilei S, D’Ambrosio F, Petrucci L, Viceconti N, Iaccarino R, Liguori A, Gasbarrini A, Miele L. Gut Microbiota at the Crossroad of Hepatic Oxidative Stress and MASLD. Antioxidants (Basel) 2025; 14:56. [PMID: 39857390 PMCID: PMC11759774 DOI: 10.3390/antiox14010056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 12/30/2024] [Accepted: 01/02/2025] [Indexed: 01/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition marked by excessive lipid accumulation in hepatic tissue. This disorder can lead to a range of pathological outcomes, including metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Despite extensive research, the molecular mechanisms driving MASLD initiation and progression remain incompletely understood. Oxidative stress and lipid peroxidation are pivotal in the "multiple parallel hit model", contributing to hepatic cell death and tissue damage. Gut microbiota plays a substantial role in modulating hepatic oxidative stress through multiple pathways: impairing the intestinal barrier, which results in bacterial translocation and chronic hepatic inflammation; modifying bile acid structure, which impacts signaling cascades involved in lipidic metabolism; influencing hepatocytes' ferroptosis, a form of programmed cell death; regulating trimethylamine N-oxide (TMAO) metabolism; and activating platelet function, both recently identified as pathogenetic factors in MASH progression. Moreover, various exogenous factors impact gut microbiota and its involvement in MASLD-related oxidative stress, such as air pollution, physical activity, cigarette smoke, alcohol, and dietary patterns. This manuscript aims to provide a state-of-the-art overview focused on the intricate interplay between gut microbiota, lipid peroxidation, and MASLD pathogenesis, offering insights into potential strategies to prevent disease progression and its associated complications.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Luca Miele
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy (S.A.)
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He X, Zhang S, Bai Q, Pan M, Jiang Y, Liu W, Li W, Gong Y, Li X. Air pollution exposure and prevalence of non-alcoholic fatty liver disease and related cirrhosis: A systematic review and meta-analysis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 289:117469. [PMID: 39657383 DOI: 10.1016/j.ecoenv.2024.117469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 12/12/2024]
Abstract
BACKGROUND AND OBJECTIVE A systematic review and meta-analysis were used to investigate the relationship between air pollution exposure and the prevalence of non-alcoholic fatty liver disease (NAFLD) and its related cirrhosis. Through this study, we hope to clarify the potential public health risks of air pollution as an environmental exposure factor. METHODS Through a comprehensive and systematic search of the EMBASE, PubMed, Web of Science, and Cochrane library databases, studies published up to March 30, 2024, that met the eligibility criteria were identified. The meta-analysis aimed to determine the association between air pollution exposure and NAFLD risk. Subgroup analyses were conducted based on regional economic development after adjusting for confounding factors. The combined odds ratio (OR) was calculated, publication bias was assessed using funnel plots, and consideration was given to heterogeneity among study-specific relative risks. RESULTS This review included 14 observational studies (including 7 cohort studies and 7 cross-sectional studies) involving 43,475,41 participants. The pooled analysis showed that PM2.5, NOx, PM10, PM2.5-10, passive smoking, PM1, and air pollution from solid fuels were positively associated with the incidence and prevalence of NAFLD and its related cirrhosis. The risk ratios for PM2.5, NOx, PM10, PM2.5-10, passive smoking, and air pollution from solid fuels for NAFLD and its related cirrhosis were 1.33 (95 % CI: 1.25, 1.42), 1.19 (95 % CI: 1.14, 1.23), 1.27 (95 % CI: 1.05, 1.55), 1.05 (95 % CI: 1.00, 1.11), 1.53 (95 % CI: 1.12, 2.09), 1.50 (95 % CI: 0.86, 2.63), and 1.18 (95 % CI: 0.85, 1.63), respectively. In contrast, the risk ratio for O3 was 0.75 (95 % CI: 0.69, 0.83), suggesting that O3 may lower the incidence and prevalence of NAFLD and its related cirrhosis. We also conducted subgroup analyses based on the level of national development to examine the impact of PM2.5 on NAFLD and its related cirrhosis. The results showed that the risk of NAFLD and its related cirrhosis associated with PM2.5 in developing countries was 1.41 (95 % CI: 1.29, 1.53), which was higher than 1.20 (95 % CI: 1.12, 1.29) in developed countries. CONCLUSION The study findings show that PM2.5, NOx, PM10, PM2.5-10, passive smoking, PM1, and air pollution from solid fuels can increase an individual's risk of developing NAFLD and its related cirrhosis; while O3 can reduce the risk. In developing countries, the risk level of NAFLD and its related cirrhosis due to PM2.5 is higher than that in developed countries.
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Affiliation(s)
- Xingyi He
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China
| | - Shipeng Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China
| | - Qinglin Bai
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China
| | - Moshen Pan
- School of Economics, Shanghai University of Finance and Economics, Shanghai 200433, PR China
| | - Yanjie Jiang
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, No.157 Daming Road, Nanjing 210022, PR China
| | - Weiwei Liu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Wei Li
- Department of Intensive Care Medicine, Sichuan Hospital of Integrated Traditional Chinese and Western Medicine, Chengdu 610041, PR China
| | - Yuanyuan Gong
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
| | - Xueping Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
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Ramanathan G, Zhao Y, Gupta R, Langmo S, Bhetraratana M, Yin F, Driscoll W, Ricks J, Louie A, Stewart JA, Gould TR, Larson TV, Kaufman J, Rosenfeld ME, Yang X, Araujo JA. Integrated hepatic transcriptomics and metabolomics identify Pck1 as a key factor in the broad dysregulation induced by vehicle pollutants. Part Fibre Toxicol 2024; 21:55. [PMID: 39734207 PMCID: PMC11684268 DOI: 10.1186/s12989-024-00605-6] [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: 01/22/2024] [Accepted: 10/07/2024] [Indexed: 12/31/2024] Open
Abstract
BACKGROUND Exposure to air pollution is associated with worldwide morbidity and mortality. Diesel exhaust (DE) emissions are important contributors which induce vascular inflammation and metabolic disturbances by unknown mechanisms. We aimed to determine molecular pathways activated by DE in the liver that could be responsible for its cardiometabolic toxicity. METHODS Apolipoprotein E knockout (ApoE KO) mice were exposed to DE or filtered air (FA) for two weeks, or DE for two weeks followed by FA for 1 week. Expression microarrays and global metabolomics assessment were performed in the liver. An integrated transcriptomic and metabolomic analytical strategy was employed to dissect critical pathways and identify candidate genes that could dissect DE-induced pathogenesis. HepG2 cells were treated with an organic extract of DE particles (DEP) vs. vehicle control to test candidate genes. RESULTS DE exposure for 2 weeks dysregulated 658 liver genes overrepresented in whole cell metabolic pathways, especially including lipid and carbohydrate metabolism, and the respiratory electron transport pathway. DE exposure significantly dysregulated 118 metabolites, resulting in increased levels of triglycerides and fatty acids due to mitochondrial dysfunction as well as increased levels of glucose and oligosaccharides. Consistently, DEP treatment of HepG2 cells led to increased gluconeogenesis and glycogenolysis indicating the ability of the in-vitro approach to model effects induced by DE in vivo. As an example, while gene network analysis of DE livers identified phosphoenolpyruvate carboxykinase 1 (Pck1) as a key driver gene of DE response, DEP treatment of HepG2 cells resulted in increased mRNA expression of Pck1 and glucose production, the latter replicated in mouse primary hepatocytes. Importantly, Pck1 inhibitor mercaptopicolinic acid suppressed DE-induced glucose production in HepG2 cells indicating that DE-induced elevation of hepatic glucose was due in part to upregulation of Pck1 and increased gluconeogenesis. CONCLUSIONS Short-term exposure to DE induced widespread alterations in metabolic pathways in the liver of ApoE KO mice, especially involving carbohydrate and lipid metabolism, together with mitochondrial dysfunction. Pck1 was identified as a key driver gene regulating increased glucose production by activation of the gluconeogenesis pathway.
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Affiliation(s)
- Gajalakshmi Ramanathan
- Division of Cardiology, David Geffen School of Medicine, University of California-Los Angeles, 10833 Le Conte Avenue, CHS 43-264, P.O. Box 951679, Los Angeles, CA, 90095, USA
| | - Yuqi Zhao
- Department of Integrative Biology and Physiology, University of California-Los Angeles, Los Angeles, CA, USA
| | - Rajat Gupta
- Division of Cardiology, David Geffen School of Medicine, University of California-Los Angeles, 10833 Le Conte Avenue, CHS 43-264, P.O. Box 951679, Los Angeles, CA, 90095, USA
- Environmental and Molecular Toxicology Interdepartmental Program, University of California-Los Angeles, Los Angeles, CA, USA
| | - Siri Langmo
- Division of Cardiology, David Geffen School of Medicine, University of California-Los Angeles, 10833 Le Conte Avenue, CHS 43-264, P.O. Box 951679, Los Angeles, CA, 90095, USA
- Environmental and Molecular Toxicology Interdepartmental Program, University of California-Los Angeles, Los Angeles, CA, USA
- Department of Environmental Health Sciences, Fielding School of Public Health, University of California-Los Angeles, Los Angeles, CA, USA
| | - May Bhetraratana
- Division of Cardiology, David Geffen School of Medicine, University of California-Los Angeles, 10833 Le Conte Avenue, CHS 43-264, P.O. Box 951679, Los Angeles, CA, 90095, USA
| | - Fen Yin
- Division of Cardiology, David Geffen School of Medicine, University of California-Los Angeles, 10833 Le Conte Avenue, CHS 43-264, P.O. Box 951679, Los Angeles, CA, 90095, USA
| | - Will Driscoll
- Department of Pathology, University of Washington, Seattle, WA, USA
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
| | - Jerry Ricks
- Department of Pathology, University of Washington, Seattle, WA, USA
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
| | - Allen Louie
- Division of Cardiology, David Geffen School of Medicine, University of California-Los Angeles, 10833 Le Conte Avenue, CHS 43-264, P.O. Box 951679, Los Angeles, CA, 90095, USA
- Environmental and Molecular Toxicology Interdepartmental Program, University of California-Los Angeles, Los Angeles, CA, USA
| | - James A Stewart
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
| | - Timothy R Gould
- Department of Civil and Environmental Engineering, University of Washington, Seattle, WA, USA
| | - Timothy V Larson
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
- Department of Civil and Environmental Engineering, University of Washington, Seattle, WA, USA
| | - Joel Kaufman
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
| | - Michael E Rosenfeld
- Department of Pathology, University of Washington, Seattle, WA, USA
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California-Los Angeles, Los Angeles, CA, USA
- Environmental and Molecular Toxicology Interdepartmental Program, University of California-Los Angeles, Los Angeles, CA, USA
- Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA, USA
| | - Jesus A Araujo
- Division of Cardiology, David Geffen School of Medicine, University of California-Los Angeles, 10833 Le Conte Avenue, CHS 43-264, P.O. Box 951679, Los Angeles, CA, 90095, USA.
- Environmental and Molecular Toxicology Interdepartmental Program, University of California-Los Angeles, Los Angeles, CA, USA.
- Department of Environmental Health Sciences, Fielding School of Public Health, University of California-Los Angeles, Los Angeles, CA, USA.
- Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA, USA.
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India-Aldana S, Midya V, Betanzos-Robledo L, Yao M, Alcalá C, Andra SS, Arora M, Calafat AM, Chu J, Deierlein A, Estrada-Gutierrez G, Jagani R, Just AC, Kloog I, Landero J, Oulhote Y, Walker RW, Yelamanchili S, Baccarelli AA, Wright RO, Téllez Rojo MM, Colicino E, Cantoral A, Valvi D. Metabolism-Disrupting Chemical Mixtures during Pregnancy, Folic Acid Supplementation, and Liver Injury in Mother-Child Pairs. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.06.13.24308903. [PMID: 38947077 PMCID: PMC11213105 DOI: 10.1101/2024.06.13.24308903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Background and Aims Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on liver injury limits opportunities for intervention. We evaluated pregnancy MDC-mixture associations with liver injury and effect modification by folic acid (FA) supplementation in mother-child pairs. Methods We studied ∼200 mother-child pairs from the Mexican PROGRESS cohort, with measured 43 MDCs during pregnancy (estimated air pollutants, blood/urine metals or metalloids, urine high- and low-molecular-weight phthalate [HMWPs, LMWPs] and organophosphate-pesticide [OP] metabolites), and serum liver enzymes (ALT, AST) at ∼9 years post-parturition. We defined liver injury as elevated liver enzymes in children, and using established clinical scores for steatosis and fibrosis in mothers (i.e., AST:ALT, FLI, HSI, FIB-4). Bayesian Weighted Quantile Sum regression assessed MDC-mixture associations with liver injury outcomes. We further examined chemical-chemical interactions and effect modification by self-reported FA supplementation. Results In children, many MDC-mixtures were associated with liver injury outcomes. Per quartile HMWP-mixture increase, ALT increased by 10.1% (95%CI: 1.67%, 19.4%) and AST by 5.27% (95% CI: 0.80%, 10.1%). LMWP-mixtures and air pollutant-mixtures were associated with higher AST and ALT, respectively. Air pollutant and non-essential metal/element associations with liver enzymes were attenuated by maternal cobalt blood concentrations ( p -interactions<0.05). In mothers, only the LMWP-mixture was associated with liver injury [OR=1.53 (95%CI: 1.01, 2.28) for HSI>36, and OR=1.62 (95%CI: 1.05, 2.49) for AST:ALT<1]. In mothers and children, most associations were attenuated (null) at FA supplementation≥600mcg/day ( p -interactions<0.05). Conclusions Pregnancy MDC exposures may increase liver injury risk, particularly in children. These associations may be attenuated by higher FA supplementation and maternal cobalt levels.
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Bo Y, Lin C, Guo C, Wong M, Huang B, Lau A, Huang Y, Lao XQ. Chronic exposure to ambient air pollution and the risk of non-alcoholic fatty liver disease: A cross-sectional study in Taiwan and Hong Kong. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 275:116245. [PMID: 38520807 DOI: 10.1016/j.ecoenv.2024.116245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 03/17/2024] [Accepted: 03/18/2024] [Indexed: 03/25/2024]
Abstract
BACKGROUND Information on the relation of air pollution with non-alcoholic fatty liver disease (NAFLD) is scarce. We thus conducted a large cross-sectional study in Asia to investigate the role of air pollution in NAFLD. METHODS We recruited 329,048 adults (mean age: 41.0 years) without other liver disease (hepatitis and cirrhosis) or excessive alcohol consumption in Taiwan and Hong Kong from 2001 to 2018. The concentrations of nitrogen dioxide (NO2) and ozone (O3) were estimated using a space-time regression model, and the concentrations of fine particulate matter (PM2.5) was evaluated using a satellite-based spatio-temporal model. NAFLD was determined using either the fatty liver index (FLI) or the hepatic steatosis index (HSI). The NAFLD-related advanced fibrosis was defined according to BARD score or the fibrosis-4 (FIB-4). A logistic regression model was adopted to explore the relationships of ambient air pollution with the odds of NAFLD and NAFLD-related advanced fibrosis. RESULTS We found positive relationships between PM2.5 and the odds of NAFLD and advanced fibrosis, with every standard deviation (SD, 7.5 µg/m3) increases in PM2.5 exposure being associated with a 10% (95% confidence interval [CI]: 9%-11%) increment in the prevalence of NAFLD and an 8% (95% CI: 7%-9%) increment in the prevalence of advanced fibrosis. Similarly, the prevalence of NAFLD and advanced fibrosis increased by 8% (95% CI: 7%-9%) and 7% (95% CI: 6%-8%) with per SD (18.9 µg/m3) increasement in NO2 concentration, respectively. Additionally, for every SD (9.9 µg/m3) increasement in O3 concentration, the prevalence of NAFLD and advanced fibrosis decreased by 12% (95% CI: 11%-13%) and 11% (95% CI: 9%-12%), respectively. CONCLUSION Higher ambient PM2.5 and NO2 are linked with higher odds of NAFLD and advanced fibrosis. Our findings indicate that reducing PM2.5 and NO2 concentrations may be an effective way for preventing NAFLD. Further studies on O3 are warranted.
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Affiliation(s)
- Yacong Bo
- School of Public Health, Zhengzhou University, China
| | - Changqing Lin
- Division of Environment and Sustainability, the Hong Kong University of Science and Technology, Hong Kong, China
| | - Cui Guo
- Jockey Club School of Public Health and Primary Care, the Chinese University of Hong Kong, Hong Kong, China
| | - Martin Wong
- Jockey Club School of Public Health and Primary Care, the Chinese University of Hong Kong, Hong Kong, China
| | - Bo Huang
- Department of Geography and Resource Management, the Chinese University of Hong Kong, Hong Kong, China
| | - Alexis Lau
- Division of Environment and Sustainability, the Hong Kong University of Science and Technology, Hong Kong, China; Department of Civil and Environmental Engineering, the Hong Kong University of Science and Technology, Hong Kong, China
| | - Yu Huang
- Department of Biomedical Science, City University of Hong KongHong Kong, China
| | - Xiang Qian Lao
- Department of Biomedical Science, City University of Hong KongHong Kong, China.
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9
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Cheng WC, Wong PY, Wu CD, Cheng PN, Lee PC, Li CY. Non-linear association between long-term air pollution exposure and risk of metabolic dysfunction-associated steatotic liver disease. Environ Health Prev Med 2024; 29:7. [PMID: 38346730 PMCID: PMC10898959 DOI: 10.1265/ehpm.23-00271] [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: 09/25/2023] [Accepted: 01/08/2024] [Indexed: 02/15/2024] Open
Abstract
BACKGROUND Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) has become a global epidemic, and air pollution has been identified as a potential risk factor. This study aims to investigate the non-linear relationship between ambient air pollution and MASLD prevalence. METHOD In this cross-sectional study, participants undergoing health checkups were assessed for three-year average air pollution exposure. MASLD diagnosis required hepatic steatosis with at least 1 out of 5 cardiometabolic criteria. A stepwise approach combining data visualization and regression modeling was used to determine the most appropriate link function between each of the six air pollutants and MASLD. A covariate-adjusted six-pollutant model was constructed accordingly. RESULTS A total of 131,592 participants were included, with 40.6% met the criteria of MASLD. "Threshold link function," "interaction link function," and "restricted cubic spline (RCS) link functions" best-fitted associations between MASLD and PM2.5, PM10/CO, and O3 /SO2/NO2, respectively. In the six-pollutant model, significant positive associations were observed when pollutant concentrations were over: 34.64 µg/m3 for PM2.5, 57.93 µg/m3 for PM10, 56 µg/m3 for O3, below 643.6 µg/m3 for CO, and within 33 and 48 µg/m3 for NO2. The six-pollutant model using these best-fitted link functions demonstrated superior model fitting compared to exposure-categorized model or linear link function model assuming proportionality of odds. CONCLUSION Non-linear associations were found between air pollutants and MASLD prevalence. PM2.5, PM10, O3, CO, and NO2 exhibited positive associations with MASLD in specific concentration ranges, highlighting the need to consider non-linear relationships in assessing the impact of air pollution on MASLD.
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Affiliation(s)
- Wei-Chun Cheng
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Gastroenterology and Hepatology, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan
| | - Pei-Yi Wong
- Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Da Wu
- Department of Geomatics, National Cheng Kung University, Tainan, Taiwan
- National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan
- Innovation and Development Center of Sustainable Agriculture, National Chung Hsing University, Taichung, Taiwan
| | - Pin-Nan Cheng
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Chen Lee
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Yi Li
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan
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10
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Dales R, Mitchell K, Lukina A, Brook J, Karthikeyan S, Cakmak S. Does ambient air pollution influence biochemical markers of liver injury? Findings of a cross-sectional population-based survey. CHEMOSPHERE 2023; 340:139859. [PMID: 37619749 DOI: 10.1016/j.chemosphere.2023.139859] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/25/2023] [Accepted: 08/16/2023] [Indexed: 08/26/2023]
Abstract
BACKGROUND There is limited evidence supporting an adverse effect of ambient air pollution on the liver. OBJECTIVES To test the association between exposure to residential air pollution and serum biochemical indicators of liver injury. METHODS We used a nationally representative sample of 32,989 participants aged 3-79 years old who participated in the Canadian Health Measures Survey between 2007 and 2019. Cross-sectional associations were assessed by generalized linear mixed models incorporating survey-specific sampling weights. RESULTS The joint effect of an interquartile range (IQR) increase in nitrogen dioxide (NO2), ozone (O3) and fine particulate matter (PM2.5) was positively and significantly associated with all measures of liver injury adjusting for age, sex, education, income, smoking, alcohol consumption, body mass index (BMI), total cholesterol, diabetes, hypertension, and physical activity. The ranking of effect sizes from largest to smallest percent increases were 8.72% (95% confidence interval [CI] 7.56, 9.88) for alanine aminotransferase (ALT), 5.54% (95%CI 3.31, 7.77) for gamma-glutamyl transferase (GGT), 4.81% (95%CI 3.87, 5.74) for aspartate aminotransferase (AST), 2.46% (95%CI 0.26, 4.65) for total bilirubin (TBIL) and 1.18% (95%CI 0.62, 1.75) for alkaline phosphatase (ALP). Findings were not significantly different when stratified by age (≤16, >16 yr), sex, smoking (current, other), cholesterol (≤6.18, >6.18 mmol/l) and BMI (<30, ≥30 kg/m2). DISCUSSION These findings suggest that ambient air pollution may have a relatively small impact on the liver, but these changes may have significant impact from a population health perspective, considering the ubiquitous nature of air pollution, or for individuals exposed to very high levels of air pollution.
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Affiliation(s)
- Robert Dales
- Population Studies Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada; University of Ottawa and Ottawa Hospital Research Institute, Canada
| | - Kimberly Mitchell
- Population Studies Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada
| | - Anna Lukina
- Population Studies Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada
| | | | - Subramanian Karthikeyan
- Population Studies Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada
| | - Sabit Cakmak
- Population Studies Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada.
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11
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Patterson WB, Holzhausen E, Chalifour B, Goodrich J, Costello E, Lurmann F, Conti DV, Chen Z, Chatzi L, Alderete TL. Exposure to ambient air pollutants, serum miRNA networks, lipid metabolism, and non-alcoholic fatty liver disease in young adults. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 264:115486. [PMID: 37729806 PMCID: PMC10548742 DOI: 10.1016/j.ecoenv.2023.115486] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/30/2023] [Accepted: 09/13/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND AND AIM Ambient air pollution (AAP) exposure has been associated with altered blood lipids and liver fat in young adults. MicroRNAs regulate gene expression and may mediate these relationships. This work investigated associations between AAP exposure, serum microRNA networks, lipid profiles, and non-alcoholic fatty liver disease (NAFLD) risk in young adults. METHODS Participants were 170 young adults (17-22 years) from the Meta-AIR cohort of the Children's Health Study (CHS). Residential AAP exposure (PM2.5, PM10, NO2, 8-hour maximum O3, redox-weighted oxidative capacity [Oxwt]) was spatially interpolated from monitoring stations via inverse-distance-squared weighting. Fasting serum lipids were assayed. Liver fat was imaged by MRI and NAFLD was defined by ≥ 5.5% hepatic fat fraction. Serum microRNAs were measured via NanoString and microRNA networks were constructed by weighted gene correlation network analysis. The first principal component of each network represented its expression profile. Multivariable mixed effects regression models adjusted for sociodemographic, behavioral, and clinical covariates; baseline CHS town code was a random effect. Effects estimates are scaled to one standard deviation of exposure. Mediation analysis explored microRNA profiles as potential mediators of exposure-outcome associations. DIANA-mirPATH identified overrepresented gene pathways targeted by miRNA networks. RESULTS Prior-month Oxwt was associated with NAFLD (OR=3.45; p = 0.003) and inversely associated with microRNA Network A (β = -0.016; p = 0.026). Prior-year NO2 was associated with non-HDL-cholesterol (β = 7.13; p = 0.01) and inversely associated with miRNA Network A (β = -0.019; p = 0.022). Network A expression was inversely associated with NAFLD (OR=0.35; p = 0.010) and non-HDL-C (β = -6.94 mg/dL; p = 0.035). Network A members miR-199a/b-3p and miR-130a, which both target fatty acid synthase, mediated 21% of the association between prior-month Oxwt exposure with NAFLD (p = 0.048) and 23.3% of the association between prior-year NO2 exposure and non-HDL-cholesterol (p = 0.026), respectively. CONCLUSIONS Exposure to AAP may contribute to adverse lipid profiles and NAFLD risk among young adults via altered expression of microRNA profiles.
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Affiliation(s)
- William B Patterson
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Elizabeth Holzhausen
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Bridget Chalifour
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Jesse Goodrich
- Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA
| | - Elizabeth Costello
- Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA
| | | | - David V Conti
- Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA
| | - Zhanghua Chen
- Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA
| | - Lida Chatzi
- Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA
| | - Tanya L Alderete
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
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12
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Deng P, Tang H, Zhu L, Duan J, Li F, Li Y, Wang J, Wu J, Meng C, Wang W, Yang Y, Chen Z, Wang J, Yuan H, Huang Z, Cai J, Lu Y. Association of long-term ambient fine particulate matter (PM 2.5) and incident non-alcoholic fatty liver disease in Chinese adults. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 329:121666. [PMID: 37080516 DOI: 10.1016/j.envpol.2023.121666] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 04/14/2023] [Accepted: 04/17/2023] [Indexed: 05/03/2023]
Abstract
Air pollution is increasingly recognized as an important environmental risk factor for non-alcoholic fatty liver disease (NAFLD). However, epidemiologic evidence on long-term exposure to high air pollution concentrations with incident NAFLD is still very limited. Here, we constructed a population-based dynamic cohort involving 17,106 subjects who were enrolled between 2005 and 2013 and subsequently followed until 2017, combined with a high-resolution ambient fine particulate matter ≤2.5 μm (PM2.5) dataset, to investigate the association of long-term PM2.5 exposure (cumulative annual average levels ranged from 36.67 to 111.16 μg/m3) with NAFLD incidence (N = 4,640). We estimated the adjusted hazard ratio (HR) for incident NAFLD among those exposed to the highest quartile of PM2.5 was 2.04 [95% confidence interval (CI), 1.80-2.30] compared with individuals exposed to the lowest quartile of PM2.5. The dose-response relationships for PM2.5 are non-linear for NAFLD across the exposure distribution. Further stratified analyses revealed that lean (<23 kg/m2), younger (<40-year-old), and women individuals appeared more vulnerable to the harmful effects of PM2.5 exposure. Our study suggests a greater long-term high ambient PM2.5 exposure is associated with an increased risk of NAFLD in Chinese adults, particularly in specific groups, including lean, women, and younger people.
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Affiliation(s)
- Peizhi Deng
- Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China; Department of Endoscopy and Laser, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510062, China
| | - Haibo Tang
- Department of Metabolic and Bariatric Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Liyong Zhu
- Department of Metabolic and Bariatric Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Jingwen Duan
- Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Fei Li
- Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Yalan Li
- Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Jie Wang
- Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Jingjing Wu
- Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Changjiang Meng
- Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Wei Wang
- Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Yiping Yang
- Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Zhiheng Chen
- Health Management Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Jiangang Wang
- Health Management Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Hong Yuan
- Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China; Department of Cardiology, The Third Xiangya Hospital of Central South University Changsha, 410013, China
| | - Zhijun Huang
- Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China; National-Local Joint Engineering Laboratory of Drug Clinical Evaluation Technology, Central South University, Changsha, 410013, China
| | - Jingjing Cai
- Department of Cardiology, The Third Xiangya Hospital of Central South University Changsha, 410013, China
| | - Yao Lu
- Clinical Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China; Department of Cardiology, The Third Xiangya Hospital of Central South University Changsha, 410013, China; School of Life Course Sciences, King's College London, London, WC2R 2LS, United Kingdom.
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13
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Wen Q, Liu T, Yu Y, Zhang Y, Yang Y, Zheng R, Li L, Chen R, Wang S. Self-Reported Primary Cooking Fuels Use and Risk of Chronic Digestive Diseases: A Prospective Cohort Study of 0.5 Million Chinese Adults. ENVIRONMENTAL HEALTH PERSPECTIVES 2023; 131:47002. [PMID: 37011136 PMCID: PMC10069757 DOI: 10.1289/ehp10486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 02/22/2023] [Accepted: 03/02/2023] [Indexed: 06/19/2023]
Abstract
BACKGROUND Household air pollution (HAP) from inefficient combustion of solid fuels is a major health concern worldwide. However, prospective evidence on the health impacts of solid cooking fuels and risks of chronic digestive diseases remains scarce. OBJECTIVES We explored the effects of self-reported primary cooking fuels on the incidence of chronic digestive diseases. METHODS The China Kadoorie Biobank recruited 512,726 participants 30-79 years of age from 10 regions across China. Information on primary cooking fuels at the current and previous two residences was collected via self-reporting at baseline. Incidence of chronic digestive diseases was identified through electronic linkage and active follow-up. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of self-reported long-term cooking fuel patterns and weighted duration of self-reported solid cooking fuel use with chronic digestive diseases incidence. Linear trend was tested by assigning the medians of weighted duration in each group and then taking those as continuous variables in the models. Subgroup analyses were undertaken across the baseline characteristics of participants. RESULTS During 9.1 ± 1.6 y of follow-up, 16,810 new cases of chronic digestive diseases were documented, among which 6,460 were diagnosed as cancers. Compared with long-term cleaner fuel use, self-reported long-term use of solid cooking fuels (i.e., coal, wood) was associated with elevated risks of chronic digestive diseases (HR = 1.08 ; 95% CI: 1.02, 1.13), including nonalcoholic fatty liver disease (NAFLD) (HR = 1.43 ; 95% CI: 1.10, 1.87), hepatic fibrosis/cirrhosis (HR = 1.35 ; 95% CI: 1.05, 1.73), cholecystitis (HR = 1.19 ; 95% CI: 1.07, 1.32), and peptic ulcers (HR = 1.15 ; 95% CI: 1.00, 1.33). The longer the weighted duration of self-reported solid cooking fuel use, the higher the risks of chronic digestive diseases, hepatic fibrosis/cirrhosis, peptic ulcers, and esophageal cancer (p Trend < 0.05 ). The aforementioned associations were modified by sex and body mass index (BMI). Positive associations of always solid cooking fuel use with chronic digestive disease, hepatic fibrosis/cirrhosis, NAFLD, and cholecystitis were observed among women but not men. The longer the weighted duration of self-reported solid cooking fuel use, the higher the risk of NAFLD among those with a BMI ≥ 28 kg / m 2 . DISCUSSION Long-term self-reported solid cooking fuels use was associated with higher risks of chronic digestive diseases. The positive association of HAP from solid cooking fuels with chronic digestive diseases indicates for an imminent promotion of cleaner fuels as public health interventions. https://doi.org/10.1289/EHP10486.
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Affiliation(s)
- Qiaorui Wen
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
| | - Tanxin Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
| | - Yuelin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
| | - Yunjing Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
| | - Yingzi Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
| | - Rongshou Zheng
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liming Li
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
| | - Ru Chen
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shengfeng Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
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14
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Galvan-Martinez DH, Bosquez-Mendoza VM, Ruiz-Noa Y, Ibarra-Reynoso LDR, Barbosa-Sabanero G, Lazo-de-la-Vega-Monroy ML. Nutritional, pharmacological, and environmental programming of NAFLD in early life. Am J Physiol Gastrointest Liver Physiol 2023; 324:G99-G114. [PMID: 36472341 DOI: 10.1152/ajpgi.00168.2022] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the main liver disease worldwide, and its prevalence in children and adolescents has been increasing in the past years. It has been demonstrated that parental exposure to different conditions, both preconceptionally and during pregnancy, can lead to fetal programming of several metabolic diseases, including NAFLD. In this article, we review some of the maternal and paternal conditions that may be involved in early-life programing of adult NAFLD. First, we describe the maternal nutritional factors that have been suggested to increase the risk of NAFLD in the offspring, such as an obesogenic diet, overweight/obesity, and altered lipogenesis. Second, we review the association of certain vitamin supplementation and the use of some drugs during pregnancy, for instance, glucocorticoids, with a higher risk of NAFLD. Furthermore, we discuss the evidence showing that maternal-fetal pathologies, including gestational diabetes mellitus (GDM), insulin resistance (IR), and intrauterine growth restriction (IUGR), as well as the exposure to environmental contaminants, and the impact of microbiome changes, are important factors in early-life programming of NAFLD. Finally, we review how paternal preconceptional conditions, such as exercise and diet (particularly obesogenic diets), may impact fetal growth and liver function. Altogether, the presented evidence supports the hypothesis that both in utero exposure and parental conditions may influence fetal outcomes, including the development of NAFLD in early life and adulthood. The study of these conditions is crucial to better understand the diverse mechanisms involved in NAFLD, as well as for defining new preventive strategies for this disease.
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Affiliation(s)
| | | | - Yeniley Ruiz-Noa
- Health Sciences Division, Medical Sciences Department, University of Guanajuato, Campus Leon, Mexico
| | | | - Gloria Barbosa-Sabanero
- Health Sciences Division, Medical Sciences Department, University of Guanajuato, Campus Leon, Mexico
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15
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Barbieri E, Santoro N, Umano GR. Clinical features and metabolic complications for non-alcoholic fatty liver disease (NAFLD) in youth with obesity. Front Endocrinol (Lausanne) 2023; 14:1062341. [PMID: 36733529 PMCID: PMC9887046 DOI: 10.3389/fendo.2023.1062341] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 01/02/2023] [Indexed: 01/18/2023] Open
Abstract
Pediatric obesity has become in the last forty years the most common metabolic disease in children and adolescents affecting about 25% of the pediatric population in the western world. As obesity worsens, a whole-body insulin resistance (IR) occurs. This phenomenon is more pronounced during adolescence, when youth experience a high degree of insulin resistance due the production of growth hormone. As IR progresses, the blunted control of insulin on adipose tissue lipolysis causes an increased flux of fatty acids with FFA deposition in ectopic tissues and organs such as the liver, leading to the development of NAFLD. In this brief review, we will discuss the clinical implications of IR and NAFLD in the context of pediatric obesity. We will review the pathogenesis and the link between these two entities, the major pathophysiologic underpinnings, including the role of genetics and metagenomics, how these two entities lead to the development of type 2 diabetes, and which are the therapeutic options for NAFLD in youth.
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Affiliation(s)
| | - Nicola Santoro
- Department of Pediatrics, Kansas University Medical Center, Kansas City, KS, United States
- Department of Medicine and Health Sciences, “V. Tiberio” University of Molise, Campobasso, Italy
- Department of Pediatrics, Yale School of Medicine, New Haven, CT, United States
| | - Giuseppina Rosaria Umano
- Department of the Woman, the Child, and General and Specialized Surgery, University of Campania, Luigi Vanvitelli, Naples, Italy
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16
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Lin L, Tian L, Li T, Sun M, Duan J, Yu Y, Sun Z. Microarray analysis of mRNA expression profiles in liver of ob/ob mice with real-time atmospheric PM 2.5 exposure. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:76816-76832. [PMID: 35672633 DOI: 10.1007/s11356-022-21088-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 05/21/2022] [Indexed: 06/15/2023]
Abstract
Epidemiological studies have demonstrated the association between exposure to fine particulate matter (PM2.5) and the onset of non-alcoholic fatty liver disease (NAFLD). However, the potential biological mechanism is largely unknown. Our study was aimed to explore the impact of PM2.5 on the transcriptome level in the liver of ob/ob mice by atmosphere PM2.5 whole-body dynamic exposure system, and meanwhile preliminarily investigated the effects of metformin intervention in this process. More than three thousand differentially expressed genes (DEGs) was screened out by microarray analysis (p < 0.05, |FC|> 1.5). KEGG pathway enrichment analysis showed that these DEGs were mainly enriched in cancers, infectious diseases, and signal transduction, and the most significant pathways were thyroid hormone signaling pathway, chronic myeloid leukemia and metabolic pathways. Then, 12 hub genes were gained through weighted gene correlation network analysis (WGCNA) and verified by qRT-PCR. The expression of 5 genes in darkslateblue module (cd53, fcer1g, cd68, ctss, laptm5) increased after PM2.5 exposure and decreased after metformin intervention. They were related to insulin resistance, glucose and lipid metabolism and other liver metabolism, and also neurodegenerative diseases. This study provided valuable clues and possible protective measures to the liver damage in ob/ob mice caused by PM2.5 exposure, and further research is needed to explore the related mechanism in detail.
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Affiliation(s)
- Lisen Lin
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Li Tian
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Tianyu Li
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Mengqi Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Junchao Duan
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Yang Yu
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China.
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, People's Republic of China.
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China.
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, People's Republic of China.
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Guo B, Guo Y, Nima Q, Feng Y, Wang Z, Lu R, Baimayangji, Ma Y, Zhou J, Xu H, Chen L, Chen G, Li S, Tong H, Ding X, Zhao X. Exposure to air pollution is associated with an increased risk of metabolic dysfunction-associated fatty liver disease. J Hepatol 2022; 76:518-525. [PMID: 34883157 DOI: 10.1016/j.jhep.2021.10.016] [Citation(s) in RCA: 134] [Impact Index Per Article: 44.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 09/24/2021] [Accepted: 10/14/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Accumulating animal studies have demonstrated the harmful contribution of ambient air pollution (AP) to metabolic dysfunction-associated fatty liver disease (MAFLD), but corresponding epidemiological evidence is limited. We examined the associations between long-term AP exposure and MAFLD prevalence in a Chinese population. METHODS We conducted a cross-sectional study of 90,086 participants recruited in China from 2018 to 2019. MAFLD was assessed based on radiologically diagnosed hepatic steatosis and the presence of overweight/obese status, diabetes mellitus, or metabolic dysregulation. Residence-specific levels of air pollutants, including particulate matter with aerodynamic diameters of ≤1 μm (PM1), ≤2.5 μm (PM2.5), and ≤10 μm (PM10), and nitrogen dioxide (NO2), were estimated by validated spatiotemporal models. We used logistic regression models to examine the AP-MAFLD associations and further evaluated potential effect modifications by demographics, lifestyle, central obesity, and diabetes status. RESULTS Increased exposure levels to all 4 air pollutants were significantly associated with increased odds of MAFLD, with odds ratios (ORs) of 1.13 (95% CI 1.10-1.17), 1.29 (1.25-1.34), 1.11 (1.09-1.14), and 1.15 (1.12-1.17) for each 10 μg/m3 increase in PM1, PM2.5, PM10, and NO2, respectively. Further stratified analyses revealed that individuals who are male, alcohol drinkers, and current and previous smokers, those who consume a high-fat diet, and those with central obesity experience more significant adverse effects from AP exposure than other individuals. CONCLUSIONS This study provides evidence that long-term exposure to ambient PM1, PM2.5, PM10, and NO2 may increase the odds of MAFLD in the real world. These effects may be exacerbated by unhealthy lifestyle habits and central obesity. LAY SUMMARY We conducted an epidemiological study on the potential effect of ambient air pollution on the risk of metabolic dysfunction-associated fatty liver disease (MAFLD) in approximately 90 thousand adults in China. We found that long-term exposure to ambient air pollution may increase the odds of MAFLD, especially in individuals who are male, smokers, and alcohol drinkers, those who consume a high-fat diet, and those with central obesity.
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Affiliation(s)
- Bing Guo
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuming Guo
- Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Qucuo Nima
- Tibet Center for Disease Control and Prevention, Lhasa, Tibet, China
| | - Yuemei Feng
- Department of Epidemiology and Health Statistics, School of Public Health, Kunming Medical University, Kunming, Yunnan, China
| | - Ziyun Wang
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, China
| | - Rong Lu
- Chengdu Center for Disease Control and Prevention, Chengdu, Sichuan, China
| | | | - Yue Ma
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Junmin Zhou
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Huan Xu
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lin Chen
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Gongbo Chen
- Guangdong Provincial Engineering Technology Research Center of Environmental and Health Risk Assessment; Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shanshan Li
- Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Huan Tong
- Department of Gastroenterology; Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China.
| | - Xianbin Ding
- Chongqing Municipal Center for Disease Control and Prevention, Chongqing, China.
| | - Xing Zhao
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China.
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18
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Du T, Fang Q, Zhang Z, Zhu C, Xu R, Chen G, Wang Y. Lentinan Protects against Nonalcoholic Fatty Liver Disease by Reducing Oxidative Stress and Apoptosis via the PPARα Pathway. Metabolites 2022; 12:metabo12010055. [PMID: 35050176 PMCID: PMC8780611 DOI: 10.3390/metabo12010055] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 01/02/2022] [Accepted: 01/05/2022] [Indexed: 02/07/2023] Open
Abstract
Lentinan (LNT), a type of polysaccharide derived from Lentinus edodes, has manifested protective effects during liver injury and hepatocellular carcinoma, but little is known about its effects on nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate whether LNT can affect the progression of NAFLD and the associated mechanisms. C57BL/6J mice were fed a normal chow diet or a high-fat diet (HFD) with or without LNT (6 mg/kg/d). AML12 cells were exposed to 200 μM palmitate acid (PA) with or without LNT (5 μg/mL). After 21 wk of the high-fat diet, LNT significantly decreased plasma triglyceride levels and liver lipid accumulation, reduced excessive reactive oxygen species production, and subsequently attenuated hepatic apoptosis in NAFLD mice. These effects were associated with increased PPARα levels, a decreased Bax/Bcl-2 ratio, and enhancement of the antioxidant defense system in vivo. Similar effects were also observed in cultured cells. More importantly, these protective effects of LNT on palmitate acid-treated AML12 cells were almost abolished by PPARα knockdown. In conclusion, this study demonstrates that LNT may ameliorate hepatic steatosis and decrease oxidative stress and apoptosis by activating the PPARα pathway and is a potential drug target for NAFLD.
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Affiliation(s)
- Tingyi Du
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (T.D.); (Q.F.); (Z.Z.); (C.Z.)
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Qin Fang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (T.D.); (Q.F.); (Z.Z.); (C.Z.)
| | - Zhihao Zhang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (T.D.); (Q.F.); (Z.Z.); (C.Z.)
| | - Chuanmeng Zhu
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (T.D.); (Q.F.); (Z.Z.); (C.Z.)
| | - Renfan Xu
- Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Guangzhi Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (T.D.); (Q.F.); (Z.Z.); (C.Z.)
- Correspondence: (G.C.); (Y.W.); Tel./Fax: +86-27-6937-8422 (G.C. & Y.W.)
| | - Yan Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (T.D.); (Q.F.); (Z.Z.); (C.Z.)
- Correspondence: (G.C.); (Y.W.); Tel./Fax: +86-27-6937-8422 (G.C. & Y.W.)
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Garcia E, Stratakis N, Valvi D, Maitre L, Varo N, Aasvang GM, Andrusaityte S, Basagana X, Casas M, de Castro M, Fossati S, Grazuleviciene R, Heude B, Hoek G, Krog NH, McEachan R, Nieuwenhuijsen M, Roumeliotaki T, Slama R, Urquiza J, Vafeiadi M, Vos MB, Wright J, Conti DV, Berhane K, Vrijheid M, McConnell R, Chatzi L. Prenatal and childhood exposure to air pollution and traffic and the risk of liver injury in European children. Environ Epidemiol 2021; 5:e153. [PMID: 34131614 PMCID: PMC8196121 DOI: 10.1097/ee9.0000000000000153] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 03/25/2021] [Indexed: 11/26/2022] Open
Abstract
Nonalcoholic fatty liver disease is the most prevalent pediatric chronic liver disease. Experimental studies suggest effects of air pollution and traffic exposure on liver injury. We present the first large-scale human study to evaluate associations of prenatal and childhood air pollution and traffic exposure with liver injury. METHODS Study population included 1,102 children from the Human Early Life Exposome project. Established liver injury biomarkers, including alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and cytokeratin-18, were measured in serum between ages 6-10 years. Air pollutant exposures included nitrogen dioxide, particulate matter <10 μm (PM10), and <2.5 μm. Traffic measures included traffic density on nearest road, traffic load in 100-m buffer, and inverse distance to nearest road. Exposure assignments were made to residential address during pregnancy (prenatal) and residential and school addresses in year preceding follow-up (childhood). Childhood indoor air pollutant exposures were also examined. Generalized additive models were fitted adjusting for confounders. Interactions by sex and overweight/obese status were examined. RESULTS Prenatal and childhood exposures to air pollution and traffic were not associated with child liver injury biomarkers. There was a significant interaction between prenatal ambient PM10 and overweight/obese status for alanine aminotransferase, with stronger associations among children who were overweight/obese. There was no evidence of interaction with sex. CONCLUSION This study found no evidence for associations between prenatal or childhood air pollution or traffic exposure with liver injury biomarkers in children. Findings suggest PM10 associations maybe higher in children who are overweight/obese, consistent with the multiple-hits hypothesis for nonalcoholic fatty liver disease pathogenesis.
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Affiliation(s)
- Erika Garcia
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA
| | - Nikos Stratakis
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA
| | - Damaskini Valvi
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Léa Maitre
- NA, ISGlobal, Universitat Pompeu Fabra (UPF), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - Nerea Varo
- Clinical Biochemistry Department, Clínica Universidad de Navarra, Pamplona, Spain
| | - Gunn Marit Aasvang
- Department of Environmental Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Sandra Andrusaityte
- Department of Environmental Sciences, Vytautas Magnus University, Kaunas, Lithuania
| | - Xavier Basagana
- NA, ISGlobal, Universitat Pompeu Fabra (UPF), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - Maribel Casas
- NA, ISGlobal, Universitat Pompeu Fabra (UPF), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - Montserrat de Castro
- NA, ISGlobal, Universitat Pompeu Fabra (UPF), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - Serena Fossati
- NA, ISGlobal, Universitat Pompeu Fabra (UPF), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | | | - Barbara Heude
- NA, Université de Paris, Centre for Research in Epidemiology and Statistics (CRESS), INSERM, INRAE, Paris, France
| | - Gerard Hoek
- Department Population Health Sciences, Utrecht University, Utrecht, Netherlands
| | - Norun Hjertager Krog
- Department of Environmental Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Rosemary McEachan
- Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, United Kingdom
| | - Mark Nieuwenhuijsen
- NA, ISGlobal, Universitat Pompeu Fabra (UPF), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - Theano Roumeliotaki
- Department of Social Medicine, University of Crete, Heraklion, Crete, Greece
| | - Rémy Slama
- Department of Prevention and Treatment of Chronic Diseases, Institute for Advanced Biosciences (IAB), INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
| | - Jose Urquiza
- NA, ISGlobal, Universitat Pompeu Fabra (UPF), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - Marina Vafeiadi
- Department of Social Medicine, University of Crete, Heraklion, Crete, Greece
| | - Miriam B. Vos
- Department of Pediatrics, Emory University, Atlanta, GA
| | - John Wright
- Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, United Kingdom
| | - David V. Conti
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA
| | - Kiros Berhane
- Department of Biostatistics, Columbia University, New York, NY
| | - Martine Vrijheid
- NA, ISGlobal, Universitat Pompeu Fabra (UPF), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - Rob McConnell
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA
| | - Lida Chatzi
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA
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Rajesh Y, Sarkar D. Association of Adipose Tissue and Adipokines with Development of Obesity-Induced Liver Cancer. Int J Mol Sci 2021; 22:ijms22042163. [PMID: 33671547 PMCID: PMC7926723 DOI: 10.3390/ijms22042163] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/20/2022] Open
Abstract
Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.
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Affiliation(s)
- Yetirajam Rajesh
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Massey Cancer Center, Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA
- Correspondence: ; Tel.: +1-804-827-2339
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21
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A cohort study on long-term exposure to air pollution and incidence of liver cirrhosis. Environ Epidemiol 2020; 4:e109. [PMID: 33778350 PMCID: PMC7941789 DOI: 10.1097/ee9.0000000000000109] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 07/08/2020] [Indexed: 01/06/2023] Open
Abstract
Cirrhosis is an advanced liver disease affecting millions of people worldwide, involving high healthcare costs. Despite experimental evidence suggesting a possible role of airborne pollutants in liver diseases, epidemiological studies are lacking. We aimed at investigating the association between exposure to air pollutants and incidence of cirrhosis in a large population-based cohort in Rome. Methods We used an administrative cohort established from the 2001 census. We included all adults of 30 years of age or older who were free of cirrhosis, resulting in a study population of over 1.2 million subjects. Follow-up of the subjects ended on 31 December 2015. We ascertained incident cases of cirrhosis from regional mortality and hospital discharge registries using a validated algorithm. We assessed exposure of the subjects to PM10, PM coarse, PM2.5, PM2.5 absorbance, NO2, NOx, and PM metal components at their residential address using Land Use Regression models. We used Cox regression models, adjusted for relevant covariates, to estimate the association between air pollution exposure and cirrhosis incidence. Results We observed 10,111 incident cases of cirrhosis, with a crude incidence rate of 67 × 100,000 person-years. Long-term exposure to all pollutants tested was significantly associated with cirrhosis, e.g., PM10 (hazard ratios [HR], 1.05; 95% confidence interval [CI], 1.01-1.09, per 10 µg/m3 increments), PM coarse (HR, 1.11; 95% CI, 1.05-1.17, per 10 µg/m3 increments), PM2.5 (HR, 1.08; 95% CI, 1.03-1.13, per 5 µg/m3 increments), and NO2 (HR, 1.03; 95% CI, 1.02-1.05, per 10 µg/m3 increments). The associations were robust in secondary analyses. Conclusions Our findings suggest a possible contribution of air pollution to the development of cirrhosis.
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Hepatocyte Injury and Hepatic Stem Cell Niche in the Progression of Non-Alcoholic Steatohepatitis. Cells 2020; 9:cells9030590. [PMID: 32131439 PMCID: PMC7140508 DOI: 10.3390/cells9030590] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/21/2020] [Accepted: 02/27/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by lipid accumulation in hepatocytes in the absence of excessive alcohol consumption. The global prevalence of NAFLD is constantly increasing. NAFLD is a disease spectrum comprising distinct stages with different prognoses. Non-alcoholic steatohepatitis (NASH) is a progressive condition, characterized by liver inflammation and hepatocyte ballooning, with or without fibrosis. The natural history of NAFLD is negatively influenced by NASH onset and by the progression towards advanced fibrosis. Pathogenetic mechanisms and cellular interactions leading to NASH and fibrosis involve hepatocytes, liver macrophages, myofibroblast cell subpopulations, and the resident progenitor cell niche. These cells are implied in the regenerative trajectories following liver injury, and impairment or perturbation of these mechanisms could lead to NASH and fibrosis. Recent evidence underlines the contribution of extra-hepatic organs/tissues (e.g., gut, adipose tissue) in influencing NASH development by interacting with hepatic cells through various molecular pathways. The present review aims to summarize the role of hepatic parenchymal and non-parenchymal cells, their mutual influence, and the possible interactions with extra-hepatic tissues and organs in the pathogenesis of NAFLD.
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Braillon A. Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma: Crying Wolf or Promoting Healthy Living? Clin Gastroenterol Hepatol 2019; 17:2383. [PMID: 31004760 DOI: 10.1016/j.cgh.2019.04.029] [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: 03/13/2019] [Revised: 03/23/2019] [Accepted: 04/10/2019] [Indexed: 02/07/2023]
Affiliation(s)
- Alain Braillon
- Department of Medicine, University Hospital, Amiens, France
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25
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Zhang Z, Guo C, Chang LY, Bo Y, Lin C, Tam T, Hoek G, Wong MCS, Chan TC, Lau AKH, Lao XQ. Long-term exposure to ambient fine particulate matter and liver enzymes in adults: a cross-sectional study in Taiwan. Occup Environ Med 2019; 76:488-494. [DOI: 10.1136/oemed-2019-105695] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 05/07/2019] [Accepted: 05/18/2019] [Indexed: 12/17/2022]
Abstract
ObjectivesAnimal experiments indicate that exposure to particulate matter (PM) can induce hepatotoxic effects but epidemiological evidence is scarce. We aimed to investigate the associations between long-term exposure to PM air pollution and liver enzymes, which are biomarkers widely used for liver function assessment.MethodsA cross-sectional analysis was performed among 351 852 adult participants (mean age: 40.1 years) who participated in a standard medical screening programme in Taiwan. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT) levels were measured. A satellite-based spatio-temporal model was used to estimate the concentrations of ambient fine particles (PM with an aerodynamic diameter ≤2.5 µm, PM2.5) at each participant’s address. Linear and logistic regression models were used to investigate the associations between PM2.5 and the liver enzymes with adjustment for a wide range of potential confounders.ResultsAfter adjustment for confounders, every 10 µg/m3 increment in 2-year average PM2.5 concentration was associated with 0.02%(95% CI: −0.04% to 0.08%), 0.61% (95% CI: 0.51% to 0.70%) and 1.60% (95% CI: 1.50% to 1.70%) increases in AST, ALT and GGT levels, respectively. Consistently, the odds ratios of having elevated liver enzymes (>40 IU/L) per 10 µg/m3 PM2.5 increment were 1.06 (95% CI: 1.04 to 1.09), 1.09 (95% CI: 1.07 to 1.10) and 1.09 (95% CI: 1.07 to 1.11) for AST, ALT and GGT, respectively.ConclusionsLong-term exposure to PM2.5 was associated with increased levels of liver enzymes, especially ALT and GGT. More studies are needed to confirm our findings and to elucidate the underlying mechanisms.
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Bassler J, Ducatman A, Elliott M, Wen S, Wahlang B, Barnett J, Cave MC. Environmental perfluoroalkyl acid exposures are associated with liver disease characterized by apoptosis and altered serum adipocytokines. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2019; 247:1055-1063. [PMID: 30823334 PMCID: PMC6404528 DOI: 10.1016/j.envpol.2019.01.064] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 01/13/2019] [Accepted: 01/16/2019] [Indexed: 01/09/2023]
Abstract
Exposures to perfluoroalkyl substances (PFAS) including perfluoroalkyl acids (PFAAs) are associated with increased liver enzymes in cohort studies including the C8 Health Study. In animal models, PFAAs disrupt hepatic lipid metabolism and induce apoptosis to cause nonalcoholic fatty liver disease (NAFLD). PFAAs are immunotoxic and inhibit pro-inflammatory cytokine release from stimulated leukocytes in vitro. This cross-sectional study tests the hypothesis that environmental PFAAs are associated with increased hepatocyte apoptosis and decreased pro-inflammatory cytokines in serum. Biomarkers previously associated with PFAS exposures and/or NAFLD were evaluated as secondary endpoints. Two hundred adult C8 Health Study participants were included. Measured serum biomarkers included: perfluorohexane sulfonate (PFHxS); perfluorooctanoic acid (PFOA); perfluorooctane sulfonate (PFOS); perfluorononanoic acid (PFNA); cytokeratin 18 M30 (CK18 M30, hepatocyte apoptosis); adipocytokines; insulin; and cleaved complement 3 (C3a). Confounder-adjusted linear regression models determined associations between PFAS and disease biomarkers with cut-offs determined by classification and regression tree analysis. CK18 M30 was positively associated with PFHxS (β = 0.889, p = 0.042); PFOA (β = 2.1, p = 0.005); and PFNA (β = 0.567, p = 0.03). Tumor necrosis factor α (TNFα) was inversely associated with PFHxS (β = -0.799, p = 0.001); PFOA (β = - 1.242, p = 0.001); and PFOS (β = -0.704, p < 0.001). Interleukin 8 was inversely associated with PFOS and PFNA. PFAAs were also associated with sexually dimorphic adipocytokine and C3a responses. Overall, PFAA exposures were associated with the novel combination of increased biomarkers of hepatocyte apoptosis and decreased serum TNFα. These data support previous findings from cohorts and experimental systems that PFAAs may cause liver injury while downregulated some aspects of the immune response. Further studies of PFAAs in NAFLD are warranted and should evaluate sex differences.
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Affiliation(s)
- John Bassler
- Department of Biostatistics, West Virginia University School of Public Health, Morgantown, WV, 26506, USA
| | - Alan Ducatman
- Department of Occupational and Environmental Health, West Virginia University School of Public Health, Morgantown, WV, 26506, USA
| | - Meenal Elliott
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, WV, 26506, USA
| | - Sijin Wen
- Department of Biostatistics, West Virginia University School of Public Health, Morgantown, WV, 26506, USA
| | - Banrida Wahlang
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - John Barnett
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, WV, 26506, USA
| | - Matthew C Cave
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40202, USA; Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
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Kanda T, Matsuoka S, Yamazaki M, Shibata T, Nirei K, Takahashi H, Kaneko T, Fujisawa M, Higuchi T, Nakamura H, Matsumoto N, Yamagami H, Ogawa M, Imazu H, Kuroda K, Moriyama M. Apoptosis and non-alcoholic fatty liver diseases. World J Gastroenterol 2018; 24:2661-2672. [PMID: 29991872 PMCID: PMC6034146 DOI: 10.3748/wjg.v24.i25.2661] [Citation(s) in RCA: 208] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 06/04/2018] [Accepted: 06/21/2018] [Indexed: 02/06/2023] Open
Abstract
The number of patients with nonalcoholic fatty liver diseases (NAFLD) including nonalcoholic steatohepatitis (NASH), has been increasing. NASH causes cirrhosis and hepatocellular carcinoma (HCC) and is one of the most serious health problems in the world. The mechanism through which NASH progresses is still largely unknown. Activation of caspases, Bcl-2 family proteins, and c-Jun N-terminal kinase-induced hepatocyte apoptosis plays a role in the activation of NAFLD/NASH. Apoptotic hepatocytes stimulate immune cells and hepatic stellate cells toward the progression of fibrosis in the liver through the production of inflammasomes and cytokines. Abnormalities in glucose and lipid metabolism as well as microbiota accelerate these processes. The production of reactive oxygen species, oxidative stress, and endoplasmic reticulum stress is also involved. Cell death, including apoptosis, seems very important in the progression of NAFLD and NASH. Recently, inhibitors of apoptosis have been developed as drugs for the treatment of NASH and may prevent cirrhosis and HCC. Increased hepatocyte apoptosis may distinguish NASH from NAFLD, and the improvement of apoptosis could play a role in controlling the development of NASH. In this review, the association between apoptosis and NAFLD/NASH are discussed. This review could provide their knowledge, which plays a role in seeing the patients with NAFLD/NASH in daily clinical practice.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Motomi Yamazaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Toshikatsu Shibata
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Kazushige Nirei
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroshi Takahashi
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Tomohiro Kaneko
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mariko Fujisawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Teruhisa Higuchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hitomi Nakamura
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroaki Yamagami
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroo Imazu
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Kazumichi Kuroda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
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