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Liu L, Xu Y, Yang L, Jiang Z, Li X. Analysis of the mechanism of action of Euphorbia fischeriana Steud on cirrhosis based on network pharmacology. Medicine (Baltimore) 2023; 102:e35118. [PMID: 37713886 PMCID: PMC10508540 DOI: 10.1097/md.0000000000035118] [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: 04/07/2023] [Accepted: 08/17/2023] [Indexed: 09/17/2023] Open
Abstract
This study aimed to employ network pharmacology to elucidate the mechanism by which Euphorbia fischeriana Steud (EFS) exhibits the efficacy on cirrhosis. The compounds and targets of EFS were retrieved from Traditional Chinese Medicine Integrated Database and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Next, these compounds and targets were analyzed based on protein-protein interaction (PPI) network. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling network was established based on KEGG database. We constructed a compound-compound target-intersection target-pathway PPI network, including 20 compounds, 19 intersection targets between compound targets and EFS targets. Among the 20 compounds, 8-Isopentenyl-kaempferol has the most targets, with 27 targets, followed by 3,4',5-Trihydroxy-7-methoxy-8-isopentenylflavone, Formononetin, Isoxanthohumol, and Isokurarinone with potential targets of 26, 22, 18, and 14, respectively. Top 5 targets are HSP90AA1, PTGS2, NOS2, MAPK14, and PPARG. KEGG pathway enrichment analysis showed that pathways such as Hepatitis B, Hepatitis C, Lipid and atherosclerosis, and AGE-RAGE signaling pathway in diabetic complications were closely related to the infection and abnormal metabolism of the liver. The application of network pharmacology could identify potential targets of EFS with a low false-positive rate and provide novel insight into the mechanism of action of EFS on cirrhosis.
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Affiliation(s)
- Lu Liu
- Department of Pharmacy, The First Hospital of Qiqihar, Qiqihaer, PR China
| | - Yinliang Xu
- Department of Pharmacy, The First Hospital of Qiqihar, Qiqihaer, PR China
| | - Liu Yang
- Department of Pharmacy, The First Hospital of Qiqihar, Qiqihaer, PR China
| | - Zhenzhong Jiang
- Department of Pharmacy, The First Hospital of Qiqihar, Qiqihaer, PR China
| | - Xiaoyan Li
- Department of Pharmacy, The First Hospital of Qiqihar, Qiqihaer, PR China
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Samarasinghe SM, Hewage AS, Siriwardana RC, Tennekoon KH, Niriella MA, De Silva S. Genetic and metabolic aspects of non-alcoholic fatty liver disease (NAFLD) pathogenicity. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2023; 24:53. [DOI: 10.1186/s43042-023-00433-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 08/21/2023] [Indexed: 01/03/2025] Open
Abstract
Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease showing a rising prevalence globally. Genetic predisposition plays a key role in the development and progression of the disease pathogenicity.
Main body
This paper summarizes genetic associations based on their influence on several metabolic aspects such as lipid metabolism, glucose metabolism, hepatic iron accumulation and cholesterol metabolism toward the NAFLD pathogenicity. Furthermore, we present variations in some epigenetic characters and the microRNA profile with regard to NAFLD.
Conclusion
As reported in many studies, the PNPLA3 rs738409 variant seems to be significantly associated with NAFLD susceptibility. Other gene variants like TM6SF2 rs58542926, MBOAT7 rs641738 and GCKR variants also appear to be more prevalent among NAFLD patients. We believe these genetic variants may provide insights into new trends in developing noninvasive biomarkers and identify their suitability in clinical practice in the future.
Graphical abstract
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Xie R, Tang S, Yang Y. Associations of peroxisome proliferator-activated receptor-γ Pro12Ala polymorphism with non-alcoholic fatty liver disease: A meta-analysis. J Diabetes Complications 2022; 36:108261. [PMID: 36055011 DOI: 10.1016/j.jdiacomp.2022.108261] [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: 05/19/2022] [Revised: 06/30/2022] [Accepted: 07/07/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND Polymorphisms in peroxisome proliferator-activated receptor-γ pro12Ala (PPAR-γ Pro12Ala) have been associated with Non-alcoholic Fatty Liver Disease (NAFLD) in several studies. However, the results of these studies are not entirely consistent. Thus, we performed a meta-analysis to investigate the association between the PPAR-γ Pro12Ala polymorphisms and NAFLD. METHODS Studies were identified by searching PubMed database and manual assessment of the cited references in the retrieved articles. Study-specific relative risks (RRs) and 95 % confidence intervals (CIs) were estimated using a random-effect model. Study quality was assessed using the Newcastle-Ottawa scale. RESULTS Relevant medical researches show that 11 studies have been conducted on the analysis of NAFLD for meta-analysis, with a total of 2404 cases and 3959 participating controls. Meta-analysis results show that PPAR-γ Pro12Ala polymorphism and NALAD Ala alleles[no association between dominance model (OR = 0.968, 95%CI: 0.734-1.276, P = 0.815); Pro/Ala vs. Pro/Pro (OR = 0.930, 95 % CI: 0.701-1.233, P = 0.612); Ala/Ala vs. Pro/Pro (OR = 1.220, 95 % CI: 0.668-2.230, P = 0.518); recessive model (OR = 0.907, 95 % CI: 0.516-1.596, P = 0.736)]. Moreover, stratification by ethnicity also revealed that no matter it is in Caucasian populations or in Asian populations, NAFLD has no association with the PPAR-γ Pro12Ala polymorphism. CONCLUSIONS According to the meta-analysis, both in Asians and Caucasian populations, the PPAR-γ Pro12Ala polymorphism can't be demonstrated to have any link with susceptibility to NAFLD.
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Affiliation(s)
- Rong Xie
- The Gastroenterology Department of the First Hospital of Nanning, Nanning, Guangxi Province 530022, PR China
| | - Shaobo Tang
- The Gastroenterology Department of the First Hospital of Nanning, Nanning, Guangxi Province 530022, PR China.
| | - Yanna Yang
- The Ultrasonography of Maternal and Children Health Hospital of Guangxi, Guangxi Province 530022, PR China
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Qiao M, Yang JH, Zhu Y, Hu JP. Association of sorting and assembly machinery component 50 homolog gene polymorphisms with nonalcoholic fatty liver disease susceptibility. Medicine (Baltimore) 2022; 101:e29958. [PMID: 35866791 PMCID: PMC9302252 DOI: 10.1097/md.0000000000029958] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Sorting and assembly machinery component 50 homolog (SAMM50) gene single-nucleotide polymorphisms (SNPs) have been connected with the susceptibility of nonalcoholic fatty liver disease (NAFLD), but with inconsistent results across the current evidence. The present work was schemed to explore the association between SAMM50 gene SNPs and NAFLD vulnerability via meta-analysis. METHODS PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang were retrieved for eligible literature previous to June 10, 2021. The odds ratios (ORs) of the dichotomic variables and the standardized mean difference of quantitative variables with corresponding 95% confidence intervals (95% CIs) were computed to evaluate the strength of the associations. The quality of included studies was assessed using Newcastle-Ottawa Scale (NOS). RESULTS In total, 8 case-control studies encompassing 6297 NAFLD patients and 7306 disease-free controls in this meta-analysis. Ultimately, this analysis included 8, 6, and 5 studies for rs2143571, rs3761472, and rs738491 polymorphisms respectively. The pooled data revealed that the 3 polymorphisms had conspicuous associations with NAFLD susceptibility: rs2143571, A vs. G, OR=1.51, 95% CI, 1.37-1.66, P < .01; rs3761472, A vs. G, OR=1.50, 95% CI, 1.35-1.67, P < .01; rs738491, A vs. G, OR=1.51, 95% CI, 1.40-1.63, P < .01. CONCLUSION This meta-analysis suggests that rs2143571, rs3761472, and rs738491 polymorphisms of the SAMM50 gene are appreciably associated with augmented risk of NAFLD vulnerability. It will provide the latest evidence to support the susceptibility of SAMM50 gene polymorphisms and NAFLD, and provide strategies for the prevention and treatment of NAFLD.
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Affiliation(s)
- Ming Qiao
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jian-hua Yang
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yi Zhu
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jun-ping Hu
- College of Pharmacy, Xinjiang Medical University, Urumqi, China
- * Correspondence: Jun-ping Hu, College of Pharmacy, Xinjiang Medical University, 137 Liyushan Avenue, Xinshi District, Urumqi, Xinjiang 830017, China (e-mail: )
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Su Y, Liu Z, Yang L, Li Y, Jiang S, Yao H, Du G. PPARγ gene Pro12Ala variants reduce the risk of obese individuals to non-alcoholic fatty liver: A study in Uygur Chinese population residing in Northwestern China. Clin Res Hepatol Gastroenterol 2020; 44:894-904. [PMID: 32505733 DOI: 10.1016/j.clinre.2020.02.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/02/2020] [Accepted: 02/12/2020] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To investigate the association of polymorphisms of Pro12Ala of peroxisome proliferator-activated receptor gamma (PPARγ) gene with clinical and biochemical parameters in Uygur Chinese population with non-alcoholic fatty liver (NAFLD) METHODS: In this case-control study, we recruited 467 NAFLD cases and 524 controls. Examination of abdominal ultrasound, clinical and biochemical profiles, as well as polymerase chain reaction-restriction fragment length polymorphisms of Pro12Ala of PPARγ gene were performed. The association of PPARγ gene Pro12Ala variants with clinical and biochemical parameters was analyzed. RESULTS There was no statistically significant difference between NAFLD and control groups in the frequencies of genotypic and allele distribution (P>0.05), while significantly difference of genotypic (P=0.032) and allele (P=0.015) distribution was found between NAFLD and control groups in the obese. Using logistics multivariate regression analysis by adjusting age, sex, body mass index, diabetes, hyperuricemia and dyslipidemia, both Pro12Ala and Ala12Ala polymorphisms were not associated with the presence of NAFLD. However, above two polymorphisms were found to be related to NAFLD in obesity group (odds ratio=0.442, P=0.031 and odds ratio=0.039, P=0.010, respectively) CONCLUSION: In Uygur Chinese population, PPARr gene Ala variants reduce the risk of NAFLD in obese individuals.
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Affiliation(s)
- Yinxia Su
- Health Management Institute, Xinjiang Medical University, China; Public Health School of Xinjiang Medical University, China
| | - Zhenhui Liu
- Department of Microrepair and Reconstruction, the First Affiliated Hospital of Xinjiang Medical University, China
| | - Lei Yang
- Department of abdominal ultrasound, the First Affiliated Hospital of Xinjiang Medical University, China
| | - Yuanyuan Li
- Public Health School of Xinjiang Medical University, China
| | - Sheng Jiang
- Department of Endocrinology, the First Affiliated Hospital of Xinjiang Medical University, China
| | - Hua Yao
- Health Management Institute, Xinjiang Medical University, China.
| | - Guoli Du
- Department of Endocrinology, the First Affiliated Hospital of Xinjiang Medical University, China.
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Hu Q, Wei S, Wen J, Zhang W, Jiang Y, Qu C, Xiang J, Zhao Y, Peng X, Ma X. Network pharmacology reveals the multiple mechanisms of Xiaochaihu decoction in the treatment of non-alcoholic fatty liver disease. BioData Min 2020; 13:11. [PMID: 32863886 PMCID: PMC7450930 DOI: 10.1186/s13040-020-00224-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/14/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver (NAFLD) is a chronic disease worldwide, which poses a huge threat to human health. Xiaochaihu decoction is a well-known traditional Chinese medicine prescription. It has been proven effective in treating NAFLD but its mechanism is still unclear. OBJECTIVE Multiple mechanisms of Xiaochaihu decoction are explored by identifying and connecting potential targets and active ingredients in the treatment of NAFLD. METHODS Active ingredients and related targets of seven herbs were collected from TCMSP database. The related targets of NAFLD were obtained from Genes cards database, TDD and OMIM database. The intersected targets of disease targets and drug targets were input into STRING database to construct protein-protein interaction network. DAVID database was used for GO enrichment analysis and KEGG enrichment analysis. RESULTS After screening and removal of duplicates, a total of 145 active ingredients and 105 potential targets were obtained. PPI network manifested that AKT1, IL6, JUN MAPK8 and STAT3 were the key target proteins. The results of GO enrichment analysis mainly involved cytokine receptor binding, cytokine activity, and heme binding. The results of KEGG analysis suggested that the mechanism mainly involved in AGE-RAGE signaling pathway in diabetic complications, Hepatitis C, fluid shear stress and atherosclerosis. The signaling pathways were further integrated as network manner, including AGE-RAGE signaling pathway in diabetic complications, Fluid shear stress and atherosclerosis, Insulin resistance, HIF-1 signaling pathway, Th17 cell differentiation and IL-17 signaling pathway. The network contained immunity regulation, metabolism regulation and oxidative stress regulation. CONCLUSION Xiaochaihu decoction plays a key role in the treatment of NAFLD with multiple targets and pathways. Immunity regulation, metabolism regulation and oxidative stress regulation consist of the crucial regulation cores in mechanism. GRAPHICAL ABSTRACT Design and workflow of this study.
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Affiliation(s)
- Qichao Hu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Shizhang Wei
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
- Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Jianxia Wen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
- Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Wenwen Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Yinxiao Jiang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Caiyan Qu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Junbao Xiang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Yanling Zhao
- Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Xi Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Xiao Ma
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
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Liebig M, Dannenberger D, Vollmar B, Abshagen K. Endogenously increased n-3 PUFA levels in fat-1 transgenic mice do not protect from non-alcoholic steatohepatitis. Hepatobiliary Surg Nutr 2019; 8:447-458. [PMID: 31673534 DOI: 10.21037/hbsn.2019.04.03] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis. Possible reasons for the NAFLD epidemic in industrialized countries are the high intake of pro-inflammatory n-6 polyunsaturated fatty acids (n-6 PUFAs) and low consumption of healthy n-3 PUFAs. Due to their anti-inflammatory properties, n-3 PUFAs may have the potential to alleviate chronic liver disease. Herein, we examined the therapeutic effect of increased n-3 PUFA tissue levels in fat-1 transgenic mice on progressive NASH. Methods Disease was induced in mice by streptozotocin and high fat diet (STZ/HFD) resulting in NASH. NAFLD in 6 and 8 weeks old wild type and fat-1 transgenic STZ/HFD treated mice was analyzed. Unlike all other mammals, fat-1 transgenic mice ubiquitously express an n-3 fatty acid desaturase, which converts n-6 to n-3 PUFAs, leading to increased n-3 and decreased n-6 PUFA tissue contents. Results Liver damage, NAFLD activity score (NAS), hepatic lipid accumulation and inflammation were significantly reduced in fat-1 transgenic STZ/HFD treated mice in the early (6 weeks) but not late (8 weeks) phase of NASH. Simultaneously, mRNA expression of genes involved in fatty acid uptake and storage (Cd36 and Plin3, respectively) was significantly down-regulated in 6 week old but not 8 week old fat-1 transgenic STZ/HFD treated mice. Conclusions Endogenously elevated n-3 PUFA levels in fat-1 transgenic mice transiently delay the onset of STZ/HFD induced NASH but failed to efficiently protect from NASH development.
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Affiliation(s)
- Marie Liebig
- Rudolf-Zenker-Institute for Experimental Surgery, University Medicine Rostock, 18057 Rostock, Germany
| | - Dirk Dannenberger
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany
| | - Brigitte Vollmar
- Rudolf-Zenker-Institute for Experimental Surgery, University Medicine Rostock, 18057 Rostock, Germany
| | - Kerstin Abshagen
- Rudolf-Zenker-Institute for Experimental Surgery, University Medicine Rostock, 18057 Rostock, Germany
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Saremi L, Lotfipanah S, Mohammadi M, Hosseinzadeh H, Fathi-Kazerooni M, Johari B, Saltanatpour Z. The Pro12Ala polymorphism in the PPAR-γ2 gene is not associated with an increased risk of NAFLD in Iranian patients with type 2 diabetes mellitus. Cell Mol Biol Lett 2019; 24:12. [PMID: 30923554 PMCID: PMC6419465 DOI: 10.1186/s11658-019-0138-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Accepted: 01/30/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. Several studies have demonstrated a significant association between Pro12Ala polymorphism of the PPAR-γ2 gene and metabolic disorders. Therefore, this study aimed to evaluate the association of Pro12Ala polymorphism with increased risk of NAFLD in Iranian patients with type 2 diabetes mellitus. METHODS This cross-sectional study was performed on 145 healthy control subjects and 145 NAFLD patients with a history of type 2 diabetes. Pro12Ala polymorphism genotyping was performed using PCR-restriction fragment length polymorphism (RFLP) technique with the Bs1I restriction enzyme. RESULTS Our results demonstrated that CC and GG genotypes of Pro12Ala were found in the participants, but there was no statistically significant difference between NAFLD patients and healthy controls (P = 0.64 and χ2 = 0.21). CONCLUSION This study suggests that Pro12Ala polymorphism of the PPAR-γ2 gene cannot be considered as a risk factor for NAFLD in the Iranian population.
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Affiliation(s)
- Leila Saremi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Shirin Lotfipanah
- Farhangian University, Shahid Mofatteh Teacher Education Paradise, Tehran, Iran
| | - Masumeh Mohammadi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Mina Fathi-Kazerooni
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behrooz Johari
- Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Zohreh Saltanatpour
- Medical Genetic Center, Endocrinology and Metabolism Research Institute (EMRI), Tehran University of Medical Sciences (TUMS), Tehran, Iran
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Kumar A, Shalimar, Walia GK, Gupta V, Sachdeva MP. Genetics of nonalcoholic fatty liver disease in Asian populations. J Genet 2019. [DOI: 10.1007/s12041-019-1071-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Zhu P, Lu H, Jing Y, Zhou H, Ding Y, Wang J, Guo D, Guo Z, Dong C. Interaction Between AGTR1 and PPARγ Gene Polymorphisms on the Risk of Nonalcoholic Fatty Liver Disease. Genet Test Mol Biomarkers 2019; 23:166-175. [PMID: 30793973 DOI: 10.1089/gtmb.2018.0203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
AIMS Nonalcoholic fatty liver disease (NAFLD) is an important public health issue worldwide. Several recent studies have reported that peroxisome proliferator-activated receptor-γ (PPARγ) and angiotensin II type 1 receptor (AGTR1) variants are associated with NAFLD occurrence, but the results have been inconsistent. The aim of this study was to analyze the interactions between PPARγ and AGTR1 polymorphisms and their associations with NAFLD in Chinese adults. METHODS Seven single nucleotide polymorphisms (SNPs) of the PPARγ gene and 5 SNPs of the AGTR1 gene were selected and genotyped in 1591 unrelated Chinese adults. The SNPAssoc package of R was used to examine the relationships between the selected SNPs and NAFLD. RESULTS After adjusting the covariance, the results from the overdominant model showed that participants carrying the T/C genotype of rs2638360 in AGTR1 have a decreased risk of NAFLD compared with those with T/T-C/C genotypes (odds ratio: 0.70, 95% confidence interval: 0.49-1.00). However, our results showed that none of the selected PPARγ variants were significantly associated with the risk of NAFLD after applying a false discovery rate correction. Among the 12 selected SNPs from PPARγ and AGTR1, model-based multifactor dimensionality reduction (MB-MDR) analyses for gene-gene interactions revealed that all the models were significantly associated with the increased risk of NAFLD (p < 0.05) except the 2-, 10-, 11-, and 12-locus models. Further, among the 10 SNPs negatively associated with NAFLD, the four-locus model (rs13431696 and rs3856806 in PPARγ, and rs5182, rs1492100 in ATGR1) and the five-locus model (rs9817428, rs1175543, rs13433696, and rs2920502 in PPARγ, and rs1492100 in ATGR1) were closely related with NAFLD susceptibility (p = 0.019 and p = 0.048, respectively). CONCLUSION Our present study suggests that interactions among multiple AGTR1 and PPARγ polymorphisms are associated with the risk of NAFLD in the Chinese population.
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Affiliation(s)
- Peifu Zhu
- 1 Zhangjiagang First People's Hospital, Suzhou, China
| | | | - Yang Jing
- 3 Department of Epidemiology and Statistics, School of Public Health, Jiangsu Key Laboratory and Translational Medicine for Geriatric Disease, Medical College of Soochow University, Suzhou, China
| | - Hui Zhou
- 4 Suzhou Industrial Park Centers for Disease Control and Prevention, Suzhou, China
| | - Yi Ding
- 4 Suzhou Industrial Park Centers for Disease Control and Prevention, Suzhou, China
| | - Jie Wang
- 3 Department of Epidemiology and Statistics, School of Public Health, Jiangsu Key Laboratory and Translational Medicine for Geriatric Disease, Medical College of Soochow University, Suzhou, China
| | - Daoxia Guo
- 3 Department of Epidemiology and Statistics, School of Public Health, Jiangsu Key Laboratory and Translational Medicine for Geriatric Disease, Medical College of Soochow University, Suzhou, China
| | - Zhirong Guo
- 3 Department of Epidemiology and Statistics, School of Public Health, Jiangsu Key Laboratory and Translational Medicine for Geriatric Disease, Medical College of Soochow University, Suzhou, China
| | - Chen Dong
- 3 Department of Epidemiology and Statistics, School of Public Health, Jiangsu Key Laboratory and Translational Medicine for Geriatric Disease, Medical College of Soochow University, Suzhou, China
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Akhavan Rezayat A, Dadgar Moghadam M, Ghasemi Nour M, Shirazinia M, Ghodsi H, Rouhbakhsh Zahmatkesh MR, Tavakolizadeh Noghabi M, Hoseini B, Akhavan Rezayat K. Association between smoking and non-alcoholic fatty liver disease: A systematic review and meta-analysis. SAGE Open Med 2018; 6:2050312117745223. [PMID: 29399359 PMCID: PMC5788091 DOI: 10.1177/2050312117745223] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2017] [Accepted: 10/16/2017] [Indexed: 12/17/2022] Open
Abstract
Background/aims Non-alcoholic fatty liver disease is one of the most common chronic liver diseases. Some risk factors are known to influence the development of non-alcoholic fatty liver disease, but the effect of tobacco smoking on the progression of non-alcoholic fatty liver disease is controversial. The main goal of this systematic review and meta-analysis is to investigate the association between smoking and non-alcoholic fatty liver disease. Method Electronic databases (PubMed, Scopus, and ISI Web of Science) were searched to find published articles on non-alcoholic fatty liver disease and smoking until December 2016. All relevant studies were screened by inclusion and exclusion criteria and compatible studies were chosen. The Newcastle-Ottawa Scale was used to assess the methodological quality of eligible articles. Subsequently, information was gathered based on the following: author, publication year, keywords, country, inclusion and exclusion criteria, main results, study design, conclusion, and confounder variables (age, body mass index, gender, ethnicity, and diabetes). Finally, analyses were performed using Comprehensive Meta-Analysis Software. Results Data were extracted from 20 observational studies (9 cross-sectional, 6 case-control, 4 cohort studies, and 1 retrospective cohort study). A significant association was observed between smoking and non-alcoholic fatty liver disease with a pooled odds ratio of 1.110 (95% confidence interval, 1.028-1.199), p-value = 0.008. The statistical heterogeneity was medium with an I2 of 40.012%, p-heterogeneity = 0.074. Also there was a significant relation between non-alcoholic fatty liver disease and passive smoking with a pooled odds ratio of 1.380 (95% confidence interval, 1.199-1.588; p-value = 0.001; I2 = 59.41; p-heterogeneity = 0.117). Conclusion Our meta-analysis demonstrated that smoking is significantly associated with non-alcoholic fatty liver disease. Further prospective studies exploring the underlying mechanisms of this association should be pursued. Also passive smoking increases the risk of non-alcoholic fatty liver disease about 1.38-fold. The effects of smoking cigarettes on active smokers (current smoker, former smoker, and total smoker) are less than passive smokers. Further studies are needed to compare the of effects of passive and active smoking on non-alcoholic fatty liver disease.
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Affiliation(s)
- Arash Akhavan Rezayat
- Gastroenterology and Hepatology Research Center, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Malihe Dadgar Moghadam
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Ghasemi Nour
- Gastroenterology and Hepatology Research Center, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Matin Shirazinia
- Gastroenterology and Hepatology Research Center, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamidreza Ghodsi
- Gastroenterology and Hepatology Research Center, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Rouhbakhsh Zahmatkesh
- Gastroenterology and Hepatology Research Center, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Benyamin Hoseini
- Gastroenterology and Hepatology Research Center, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kambiz Akhavan Rezayat
- Gastroenterology and Hepatology Research Center, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
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Wang C, Gong J, Wu H. Development of gene polymorphisms in meditators of nonalcoholic fatty liver disease. Biomed Rep 2017; 7:95-104. [PMID: 28804621 DOI: 10.3892/br.2017.926] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 05/12/2017] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, the morbidity of which closely correlates with diversity of ethnicity, minority, family and location. Its histology spans from simple steatosis, to nonalcoholic steatohepatitis, which ultimately results in fibrosis, cirrhosis and hepatocellular carcinoma. The accelerating prevalence of NAFLD is due to an incremental incidence of metabolic syndrome that is distinguished by dyslipidemia, glucose impairment, obesity, excessive oxidative stress and adipocytokine impairment. Additionally, the pathogenesis of NAFLD is thought to be a multifactorial and complicated disease associated with lifestyle habits, nutritional factors and genetics. However, the pathogenesis and underlying mechanism in the development of NAFLD caused by genetics remains unclear. People have been increasingly emphasizing on the relationship between NAFLD and gene polymorphisms in recent years, with the aim of having a comprehensive elucidation of associated gene polymorphisms influencing the pathogenesis of the disease. In the current article, the authors attempted to critically summarize the most recently identified gene polymorphisms from the facets of glucose metabolism, fatty acid metabolism, oxidative stress and related cytokines in NAFLD that contribute to promoting the progression of the disease.
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Affiliation(s)
- Chun Wang
- Department of General Surgery, Yongchuan Hospital of Traditional Chinese Medicine, Chongqing 402161, P.R. China
| | - Jianping Gong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China
| | - Hao Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common and important chronic liver disease in the world. As the prevalence of obesity increases in adults and children, the incidence of NAFLD has increased rapidly, reaching 17% to 33%. NAFLD is clinically divided into two forms: simple fatty liver (SFL) and non-alcoholic steatohepatitis (NASH), with NASH accounting for 1/3-1/2 of all NAFLD cases. The probability of developing cirrhosis is 0.6%-3.0% in patients with SFL for 10-20 years, and as high as 15%-25% in patients with NASH for 10-15 years. Approximately 1% of cirrhosis cases develop hepatocellular carcinoma each year. The pathogenesis of NAFLD is still not completely clear. It is generally believed that age, sex, obesity, insulin resistance, cytokines, gene polymorphism, and intestinal microflora are involved in the pathogenesis of NAFLD. An in-depth understanding of the pathogenesis of NAFLD can provide a basis for treatment of this disease. In recent years, cytokines or genes have been reported as targets for NAFLD treatment with appreciated effects. Since there is currently no specific treatment for NAFLD, targeted therapy may have a profound impact on the prognosis of the disease.
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Nutrigenomic Functions of PPARs in Obesogenic Environments. PPAR Res 2016; 2016:4794576. [PMID: 28042289 PMCID: PMC5155092 DOI: 10.1155/2016/4794576] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 10/03/2016] [Indexed: 12/26/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that mediate the effects of several nutrients or drugs through transcriptional regulation of their target genes in obesogenic environments. This review consists of three parts. First, we summarize current knowledge regarding the role of PPARs in governing the development of white and brown/beige adipocytes from uncommitted progenitor cells. Next, we discuss the interactions of dietary bioactive molecules, such as fatty acids and phytochemicals, with PPARs for the modulation of PPAR-dependent transcriptional activities and metabolic consequences. Lastly, the effects of PPAR polymorphism on obesity and metabolic outcomes are discussed. In this review, we aim to highlight the critical role of PPARs in the modulation of adiposity and subsequent metabolic adaptation in response to dietary challenges and genetic modifications. Understanding the changes in obesogenic environments as a consequence of PPARs/nutrient interactions may help expand the field of individualized nutrition to prevent obesity and obesity-associated metabolic comorbidities.
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Gao M, Ma Y, Alsaggar M, Liu D. Dual Outcomes of Rosiglitazone Treatment on Fatty Liver. AAPS JOURNAL 2016; 18:1023-31. [PMID: 27125895 DOI: 10.1208/s12248-016-9919-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 04/15/2016] [Indexed: 01/10/2023]
Abstract
In previous studies, it has been reported that rosiglitazone has opposing effects on nonalcoholic fatty liver disease. The purpose of the current study is to test the hypothesis that such opposing effects are related to different levels of peroxisome proliferator-activated receptor gamma (PPAR-γ) in the liver. Using a gene transfer approach and mice fed a high-fat diet (HFD) as an animal model, we demonstrate that mice with low levels of PPAR-γ expression in the liver are resistant to HFD-induced development of fatty liver when treated with rosiglitazone. Conversely, rosiglitazone treatment actually exacerbates liver steatosis in obese mice that have a higher level of PPAR-γ. Mechanistic studies show that an elevated hepatic PPAR-γ level is associated with an increased expression of genes responsible for lipid metabolism in the liver, particularly Cd36, Fabp4, and Mgat1. The concurrent transfer of these three genes into the mouse liver fully recapitulates the phenotypic change induced by the overexpression of PPAR-γ. These results provide evidence in support of the importance of PPAR-γ in the liver when rosiglitazone is considered for the treatment of fatty liver disease. Clinically, our results suggest the necessity of verifying PPAR-γ levels in the liver when rosiglitazone is considered as a treatment option, and indicate that the direct use of rosiglitazone for treatment of nonalcoholic fatty liver may not be desirable when the patient's PPAR-γ level in the liver is significantly elevated.
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Affiliation(s)
- Mingming Gao
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, 30602, USA
| | - Yongjie Ma
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, 30602, USA
| | - Mohammad Alsaggar
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, 30602, USA
| | - Dexi Liu
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, 30602, USA.
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Macaluso FS, Maida M, Petta S. Genetic background in nonalcoholic fatty liver disease: A comprehensive review. World J Gastroenterol 2015; 21:11088-11111. [PMID: 26494964 PMCID: PMC4607907 DOI: 10.3748/wjg.v21.i39.11088] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 06/11/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.
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Sequence variants of peroxisome proliferator-activated receptor-gamma gene and the clinical courses of patients with end-stage renal disease. DISEASE MARKERS 2015; 2015:763459. [PMID: 25784779 PMCID: PMC4345048 DOI: 10.1155/2015/763459] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Accepted: 01/14/2015] [Indexed: 01/25/2023]
Abstract
Background. PPAR-γ single nucleotide polymorphisms (SNPs) reportedly play an important role in determining metabolic risk among diverse population. Whether PPAR-γ SNPs affect the clinical courses in ESRD patients is unknown. Methods. From a multicenter cohort, we identified 698 patients with prevalent ESRD between 2002 and 2003, and other 782 healthy subjects as control. Two PPAR-γ SNPs, Pro12Ala (rs1801282) and C161T (rs3856806), were genotyped and their association with ESRD was examined. Both groups were prospectively followed until 2007, and the predictability of genotypes for the long-term survival of ESRD patients was analyzed. Results. After multivariable-adjusted regression, GG genotype of Pro12Ala was significantly more likely to associate with ESRD (P < 0.001) among patients with non-diabetes-related ESRD. Cox's proportional hazard regression showed that both Pro12Ala and C161T polymorphisms were significant predictors of mortality in ESRD patients with DM (Pro12Ala: GG versus other genotypes, hazard ratio [HR] <0.01; P < 0.001; for C161T, CC versus TT genotypes, HR 2.86; P < 0.001; CT versus TT genotypes, HR 1.93; P < 0.001). Conclusion. This is the first and largest study to evaluate PPAR-γ SNPs in ESRD patients. Further mechanistic study is needed to elucidate the role of PPAR-γ among ESRD patients.
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Lee YH, Bae SC, Song GG. Meta-analysis of associations between the peroxisome proliferator-activated receptor-γ Pro12Ala polymorphism and susceptibility to nonalcoholic fatty liver disease, rheumatoid arthritis, and psoriatic arthritis. Genet Test Mol Biomarkers 2014; 18:341-8. [PMID: 24697566 DOI: 10.1089/gtmb.2013.0503] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
INTRODUCTION The purpose of this study was to examine whether a Proline (Pro)-to-Alanine (Ala) exchange at codon 12 (Pro12Ala) polymorphism of the peroxisome proliferator-activated receptor-gamma (PPARγ) is associated with susceptibility to nonalcoholic fatty liver disease (NAFLD), rheumatoid arthritis (RA), and psoriatic arthritis (PsA). METHODS A meta-analysis was conducted on the association between the PPARγ Pro12Ala polymorphism and NAFLD, RA, and PsA. RESULTS Nine studies, including five on NAFLD, two on RA, and two on PsA, were available for the meta-analysis consisting of 8082 cases and 3790 controls. The meta-analysis revealed no association between the Ala allele of the PPARγ Pro12Ala polymorphism and NAFLD (odds ratios [OR]=0.936, 95% confidence interval [CI]=0.672-1.302, p=0.693). However, stratification by ethnicity indicated an association between the Ala allele and NAFLD in East Asians (OR=0.700, 95% CI=0.496-0.987, p=0.042), but not in Europeans (OR=1.128, 95% CI=0.863-1.475, p=0.378). Analysis using the dominant model showed the same Ala allele pattern in East Asians and Europeans (OR=0.688, 95% CI=0.484-0.978, p=0.037; OR=1.051, 95% CI=0.782-1.413, p=0.742), demonstrating a significant association between the Ala allele and NAFLD in East Asians. The meta-analysis revealed no association between the Ala allele and RA in East Asians (OR=0.467, 95% CI=0.188-1.161, p=0.101), and no association was found between the Ala allele and PsA in Europeans (OR=0.869, 95% CI=0.465-1.627, p=0.662). CONCLUSIONS Our meta-analysis demonstrates that the PPARγ Pro12Ala polymorphism is associated with susceptibility to NAFLD in East Asians, but not in European populations.
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Affiliation(s)
- Young Ho Lee
- 1 Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine , Seoul, Korea
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Ye Z, Wang S, Yang Z, He M, Zhang S, Zhang W, Wen J, Li Q, Huang Y, Wang X, Lu B, Zhang Z, Su Q, Hu R. Serum lipocalin-2, cathepsin S and chemerin levels and nonalcoholic fatty liver disease. Mol Biol Rep 2014; 41:1317-23. [PMID: 24390241 DOI: 10.1007/s11033-013-2977-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 12/24/2013] [Indexed: 12/20/2022]
Abstract
Several novel circulating adipokines are associated with insulin resistance and inflammation. Little information exists in NAFLD about three recently recognized adipokines lipocalin-2, cathepsin S and chemerin. To assess the relationship between serum lipocalin-2, cathepsin S and chemerin levels and the development of non-alcoholic fatty liver in Chinese subjects, we measured serum lipocalin-2, cathepsin S and chemerin levels in 903 Chinese subjects by ELISA. Among the study population, 436 patients are with B-mode ultrasound-proven NAFLD and 467 controls. Levels of lipocalin-2, but not cathepsin S and chemerin, were significantly elevated in NAFLD versus control [lipocalin-2, 89.67 ± 4.47 vs. 68.70 ± 3.65 ng/mL (p < 0.001)]. After stepwise linear regression analysis adjusting for potential cofounders, further revealed that serum lipocalcin-2 was an independent predictor of NAFLD in whole cohort (standardized β = 0.114, t = 2.347, p = 0.02). Lipocalin-2 levels correlated with insulin resistance (homeostasis model assessment of insulin resistance) and inflammation (CRP) in whole cohorts and NAFLD, whereas cathepsin S and chemerin only correlated positively with insulin resistance and inflammation in whole cohorts. Our results indicated that circulating lipocalin-2, produced by adipocytes, are elevated and may contribute to the development of NAFLD. Serum lipocalin-2, which correlates with inflammation and insulin resistance, may have a direct pathogenic link to disease progression.
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Affiliation(s)
- Zi Ye
- Institute of Endocrinology and Diabetology at Fudan University, Huashan Hospital, Fudan University, Shanghai, 200040, China,
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Fan JG. Epidemiology of alcoholic and nonalcoholic fatty liver disease in China. J Gastroenterol Hepatol 2013; 28 Suppl 1:11-17. [PMID: 23855290 DOI: 10.1111/jgh.12036] [Citation(s) in RCA: 213] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/20/2013] [Indexed: 12/12/2022]
Abstract
The prevalence of patients presenting with fatty liver disease (FLD) in China has approximately doubled over the past two decades. At present, FLD, which is typically diagnosed by imaging, is highly prevalent (≈ 27% urban population) in China and is mainly related to obesity and metabolic syndrome (MetS). However, the percentage of alcoholic liver disease (ALD) among patients with chronic liver diseases in clinic is increasing as well, and a synergetic effect exists between heavy alcohol drinking and obesity in ALD. Prevalence figures reveal regional variations, with a median prevalence of ALD and nonalcoholic FLD (NAFLD) of 4.5% and 15.0%, respectively. The prevalence of NAFLD in children is 2.1%, although the prevalence increases to 68.2% among obese children. With the increasing pandemic of obesity and MetS in the general population, China is likely to harbor an increasing reservoir of patients with FLD. The risk factors for FLD resemble to those of Caucasian counterparts, but the ethnic-specific definitions of obesity and MetS are more useful in assessment of Chinese people. Therefore, FLD/NAFLD has become a most common chronic liver disease in China. Public health interventions are needed to halt the worldwide trend of obesity and alcohol abuse to ameliorate liver injury and to improve metabolic health.
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Affiliation(s)
- Jian-Gao Fan
- Department of Gastroenterology, Shanghai Key Laboratory of Children's Digestion and Nutrition, Xin-Hua Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
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Wang J, Guo X, Wu P, Song J, Ye C, Yu S, Zhang J, Dong W. Association between the Pro12Ala polymorphism of PPAR-γ gene and the non-alcoholic fatty liver disease: a meta-analysis. Gene 2013; 528:328-34. [PMID: 23891820 DOI: 10.1016/j.gene.2013.07.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Revised: 07/02/2013] [Accepted: 07/08/2013] [Indexed: 12/18/2022]
Abstract
Several studies have been conducted to examine the association between PPAR-γ2 Pro12Ala polymorphism and non-alcoholic fatty liver disease (NAFLD), but the results remain inconsistent. In this study, a meta-analysis was performed to assess the association of PPAR-γ Pro12Ala polymorphism with NAFLD risk. A total of 8 case-control studies, including 1697 cases and 2427 controls, were selected. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Overall, no evidence has indicated that the Pro12Ala polymorphism was associated with the susceptibility to NAFLD. Besides, stratified analysis with ethnicity also indicated that no significant association between PPAR-γ Pro12Ala and the risk of NAFLD under all for genetic model in both Asian and Caucasian populations was observed. This meta-analysis indicated that the Pro12Ala polymorphism is not associated with NAFLD risk. Large and well-designed studies are warranted to validate our findings.
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Affiliation(s)
- Jun Wang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China
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22
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Sahebkar A. Does PPARγ2 gene Pro12Ala polymorphism affect nonalcoholic fatty liver disease risk? Evidence from a meta-analysis. DNA Cell Biol 2013; 32:188-198. [PMID: 23448101 DOI: 10.1089/dna.2012.1947] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Genetic factors can substantially contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A missense Pro12Ala substitution in the PPARγ2 gene (rs1801282) has been studied in relation with NAFLD risk in different ethnic groups, but findings have been inconclusive. The aim of this was to evaluate the association between rs1801282 and NAFLD through meta-analysis of all relevant published evidence. A systematic search to find eligible studies was performed in Medline, HuGE Navigator, and SCOPUS databases. The strength of association was evaluated using odds ratios with 95% confidence intervals obtained from a random effect approach and under additive, dominant, co-dominant, recessive, and allelic contrast models. Seven studies comprising 1474 cases and 2259 controls met the eligibility criteria and included in the meta-analysis. Combined results did not indicate any predisposing or protective effect for rs1801282 under any of the assessed modes of inheritance. The rate of heterogeneity was generally high due to the inter-study variations in terms of age, gender, and ethnicity. Evidence from the current meta-analysis indicated that rs1801282 variants are not associated with NAFLD risk. Future large-scale studies are required to substantiate the present findings.
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Affiliation(s)
- Amirhossein Sahebkar
- Biotechnology Research Center and School of Pharmacy, Cardiovascular Research Center, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran.
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Cao CY, Li YY, Zhou YJ, Nie YQ, Wan YJY. The C-681G polymorphism of the PPAR-γ gene is associated with susceptibility to non-alcoholic fatty liver disease. TOHOKU J EXP MED 2013; 227:253-62. [PMID: 22820754 DOI: 10.1620/tjem.227.253] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is defined as excessive accumulation of fatty acid in the liver, a common disease in the world. The research of single nucleotide polymorphisms (SNPs) provides a new approach for managing NAFLD. SNPs may increase or decrease the functions of the target genes and their encoding proteins. Peroxisome proliferator-activated receptor (PPAR) plays a key role in modulating metabolism of hepatic triglycerides and consequently magnitude of NAFLD. In this study, we investigated the effect of three SNPs in the PPAR-γ gene i.e. rs10865710 (C-681G), rs7649970 (C-689T) and rs1801282 (C34G, also termed Pro12Ala) on susceptibility to NAFLD. The participants were selected from our epidemiological survey. Totally 169 participants were enrolled in NAFLD group, and 699 healthy subjects were included as controls. PCR-RFLP was applied to detect the SNPs. The G allele frequency of rs10865710 in NAFLD group (41.1%) was significantly higher than that (34.8%) in controls (p = 0.03). Differences in other two loci (rs7649970 and rs1801282) were not statistically significant between the two groups (p > 0.05). This result was confirmed by haplotype analysis. The GCC haplotype (a set of 3 adjacent SNPs in linkage disequilibrium, corresponding to the three alleles of above polymorphisms in order) was a risk factor for the susceptibility to NAFLD (p = 0.03). This study has revealed that the G allele of rs10865710 in the PPAR-γ gene is associated with the increased susceptibility to NAFLD. Our findings may provide novel diagnostic biomarkers and therapeutic targets for NAFLD.
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Affiliation(s)
- Chuang-Yu Cao
- Department of Gastroenterology and Hepatology, Guangzhou Institute of Clinical Medicine, Guangzhou First Municipal People's Hospital, Guangzhou Medical College, Guangzhou, PR China
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Dongiovanni P, Valenti L. Peroxisome proliferator-activated receptor genetic polymorphisms and nonalcoholic Fatty liver disease: any role in disease susceptibility? PPAR Res 2013; 2013:452061. [PMID: 23431284 PMCID: PMC3575610 DOI: 10.1155/2013/452061] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Revised: 11/13/2012] [Accepted: 11/20/2012] [Indexed: 12/21/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) defines a wide spectrum of liver diseases that extend from simple steatosis, that is, increased hepatic lipid content, to nonalcoholic steatohepatitis (NASH), a condition that may progress to cirrhosis with its associated complications. Nuclear hormone receptors act as intracellular lipid sensors that coordinate genetic networks regulating lipid metabolism and energy utilization. This family of transcription factors, in particular peroxisome proliferator-activated receptors (PPARs), represents attractive drug targets for the management of NAFLD and NASH, as well as related conditions such as type 2 diabetes and the metabolic syndrome. The impact on the regulation of lipid metabolism observed for PPARs has led to the hypothesis that genetic variants within the human PPARs genes may be associated with human disease such as NAFLD, the metabolic syndrome, and/or coronary heart disease. Here we review the available evidence on the association between PPARs genetic polymorphism and the susceptibility to NAFLD and NASH, and we provide a meta-analysis of the available evidence. The impact of PPAR variants on the susceptibility to NASH in specific subgroup of patients, and in particular on the response to therapies, especially those targeting PPARs, represents promising new areas of investigation.
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Affiliation(s)
- Paola Dongiovanni
- Section of Internal Medicine, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milano, Italy
| | - Luca Valenti
- Section of Internal Medicine, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milano, Italy
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Videla LA, Pettinelli P. Misregulation of PPAR Functioning and Its Pathogenic Consequences Associated with Nonalcoholic Fatty Liver Disease in Human Obesity. PPAR Res 2012; 2012:107434. [PMID: 23304111 PMCID: PMC3526338 DOI: 10.1155/2012/107434] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Accepted: 11/06/2012] [Indexed: 12/22/2022] Open
Abstract
Nonalcoholic fatty liver disease in human obesity is characterized by the multifactorial nature of the underlying pathogenic mechanisms, which include misregulation of PPARs signaling. Liver PPAR-α downregulation with parallel PPAR-γ and SREBP-1c up-regulation may trigger major metabolic disturbances between de novo lipogenesis and fatty acid oxidation favouring the former, in association with the onset of steatosis in obesity-induced oxidative stress and related long-chain polyunsaturated fatty acid n-3 (LCPUFA n-3) depletion, insulin resistance, hypoadiponectinemia, and endoplasmic reticulum stress. Considering that antisteatotic strategies targeting PPAR-α revealed that fibrates have poor effectiveness, thiazolidinediones have weight gain limitations, and dual PPAR-α/γ agonists have safety concerns, supplementation with LCPUFA n-3 appears as a promising alternative, which achieves both significant reduction in liver steatosis scores and a positive anti-inflammatory outcome. This latter aspect is of importance as PPAR-α downregulation associated with LCPUFA n-3 depletion may play a role in increasing the DNA binding capacity of proinflammatory factors, NF-κB and AP-1, thus constituting one of the major mechanisms for the progression of steatosis to steatohepatitis.
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Affiliation(s)
- Luis A. Videla
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago 7, Chile
| | - Paulina Pettinelli
- Ciencias de la Salud, Nutrición y Dietética, Facultad de Medicina, Pontificia Universidad Católica de Chile, 7820436 Santiago, Chile
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26
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Bhatt SP, Nigam P, Misra A, Guleria R, Luthra K, Pandey RM, Pasha MAQ. Association of peroxisome proliferator activated receptor-γ gene with non-alcoholic fatty liver disease in Asian Indians residing in north India. Gene 2012; 512:143-7. [PMID: 23031808 DOI: 10.1016/j.gene.2012.09.067] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 08/20/2012] [Accepted: 09/12/2012] [Indexed: 02/08/2023]
Abstract
BACKGROUND Genetics of non-alcoholic fatty liver (NAFLD) in Asian Indians has been inadequately studied. We investigated the association of polymorphisms C161T and Pro12Ala of peroxisome proliferator-activated receptor gamma (PPARγ) with clinical and biochemical parameters in Asian Indians with NAFLD. METHODS In this case-control study, 162 NAFLD cases and 173 controls were recruited. Abdominal ultrasound, clinical and biochemical profiles, fasting insulin levels and value of homeostasis model assessment of insulin resistance were determined. Polymerase chain reaction-restriction fragment length polymorphisms of two polymorphisms were performed. The association of these polymorphisms with clinical and biochemical parameters was analysed. RESULTS Higher frequency of Ala and T alleles of PPARγ was obtained in cases. Ala/Ala genotype of PPARγ (Pro12Ala) was associated with significantly higher serum triglycerides (TG), alkaline phosphatase (ALK) and waist-hip ratio in cases as compared to controls. In C161T polymorphism, TT genotype was significantly increased TG (p=0.04), total cholesterol (p=0.01), ALK (p=0.04) and gamma-glutamyl transpeptidase (p=0.007) in cases. The linkage disequilibrium for these two single-nucleotide polymorphisms of PPARγ was differed in cases (D1=0.1; p=0.006) and controls (D1=0.07; p=0.1). Using a multivariate analysis after adjusting for age, sex and body mass index, the presence of NAFLD was linked to these two polymorphisms (odds ratio 1.64 (95% CI: 1.09-2.45, p=0.05)]. CONCLUSION Asian Indians in north India carrying the alleles Ala and T of PPARγ (Pro12Ala and C161T) polymorphisms are predisposed to develop NAFLD.
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Affiliation(s)
- Surya Prakash Bhatt
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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Peyrou M, Ramadori P, Bourgoin L, Foti M. PPARs in Liver Diseases and Cancer: Epigenetic Regulation by MicroRNAs. PPAR Res 2012; 2012:757803. [PMID: 23024649 PMCID: PMC3449131 DOI: 10.1155/2012/757803] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Accepted: 06/27/2012] [Indexed: 12/19/2022] Open
Abstract
Peroxisome-proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that exert in the liver a transcriptional activity regulating a whole spectrum of physiological functions, including cholesterol and bile acid homeostasis, lipid/glucose metabolism, inflammatory responses, regenerative mechanisms, and cell differentiation/proliferation. Dysregulations of the expression, or activity, of specific PPAR isoforms in the liver are therefore believed to represent critical mechanisms contributing to the development of hepatic metabolic diseases, disorders induced by hepatic viral infections, and hepatocellular adenoma and carcinoma. In this regard, specific PPAR agonists have proven to be useful to treat these metabolic diseases, but for cancer therapies, the use of PPAR agonists is still debated. Interestingly, in addition to previously described mechanisms regulating PPARs expression and activity, microRNAs are emerging as new important regulators of PPAR expression and activity in pathophysiological conditions and therefore may represent future therapeutic targets to treat hepatic metabolic disorders and cancers. Here, we reviewed the current knowledge about the general roles of the different PPAR isoforms in common chronic metabolic and infectious liver diseases, as well as in the development of hepatic cancers. Recent works highlighting the regulation of PPARs by microRNAs in both physiological and pathological situations with a focus on the liver are also discussed.
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Affiliation(s)
- Marion Peyrou
- Department of Cell Physiology and Metabolism, Faculty of Medicine, Centre Médical Universiatire (CMU), 1206 Geneva, Switzerland
| | - Pierluigi Ramadori
- Department of Cell Physiology and Metabolism, Faculty of Medicine, Centre Médical Universiatire (CMU), 1206 Geneva, Switzerland
| | - Lucie Bourgoin
- Department of Cell Physiology and Metabolism, Faculty of Medicine, Centre Médical Universiatire (CMU), 1206 Geneva, Switzerland
| | - Michelangelo Foti
- Department of Cell Physiology and Metabolism, Faculty of Medicine, Centre Médical Universiatire (CMU), 1206 Geneva, Switzerland
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Update on pparγ and nonalcoholic Fatty liver disease. PPAR Res 2012; 2012:912351. [PMID: 22966224 PMCID: PMC3431124 DOI: 10.1155/2012/912351] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 07/16/2012] [Indexed: 12/23/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common initial presentation of obesity and insulin resistance. Uninterrupted progression of hepatic lipid accumulation often leads to fatty liver disease and eventually cirrhosis. Insulin resistance is one of the characteristics of type 2 diabetes. Several types of treatment have been employed against type 2 diabetes some of which ameliorate NAFLD. The frequent line of treatment to improve insulin sensitivity is the use of thiazolidinediones (TZD) which activate the nuclear receptor, peroxisome proliferator activated receptor gamma (Pparγ). Although TZDs are proven to be very effective in promoting insulin sensitivity, its actions on Pparγ have been complicated, specifically on NAFLD. According to studies in different models, Pparγ manifests both beneficial and undesirable effects on NAFLD. This paper will focus on the current knowledge of Pparγ and its effect on NAFLD.
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