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Souza M, Al-Sharif L, Diaz I, Mantovani A, Villela-Nogueira CA. Global Epidemiology and Implications of PNPLA3 I148M Variant in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-analysis. J Clin Exp Hepatol 2025; 15:102495. [PMID: 39882540 PMCID: PMC11773032 DOI: 10.1016/j.jceh.2024.102495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 12/18/2024] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND & AIMS PNPLA3 rs738409 variant is a risk factor for onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to assess its global prevalence, clinical and histological characteristics, and long-term outcomes in patients with MASLD. METHODS PubMed and Embase databases were searched until December 30, 2023, for observational studies on PNPLA3 genotyped adults with MASLD. Proportions were pooled using a generalized linear mixed model with Clopper-Pearson intervals. Continuous and dichotomous variables were analyzed using the DerSimonian-Laird method. International Prospective Register of Systematic Reviews registration number: CRD42023449838. RESULTS A total of 109 studies involving 118,302 individuals with MASLD were identified. The overall minor allele frequency of the G allele [MAF(G)] at PNPLA3 was 0.45 (95% confidence interval [CI]: 0.43; 0.48) with high heterogeneity (I2 = 98%). The highest MAF(G) was found in Latin America (0.63) and the lowest in Europe (0.38). No African countries were identified. Carriers of the PNPLA3 variant had reduced adiposity, altered fat metabolism, and worse liver damage/histology than noncarriers. There was significant heterogeneity in the clinical/histological analyses (I2 > 50%). Only the PNPLA3 GG genotype was associated with higher mortality and liver-related events with no heterogeneity (I2 = 0%). Metaregressions showed the influence of adiposity, age, diabetes mellitus, and glucose on some PNPLA3 expression parameters. Overall, there was a moderate risk of bias in the included studies. CONCLUSIONS This study reveals the global pattern of PNPLA3 and its clinical, histological, and outcome implications in MASLD. Patients with MASLD and PNPLA3 variant have different clinical features and worse liver severity, and only PNPLA3 GG has a higher risk of mortality and liver outcomes. Our findings highlight the importance of PNPLA3 genotyping in clinical trials and advocate for personalized medicine approaches.
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Affiliation(s)
- Matheus Souza
- Department of Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Ivanna Diaz
- Department of Internal Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY, United States
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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Shen HC, Pan MH, Huang CJ, Yeh HY, Yang HI, Lin YH, Huang CC, Lee KC, Yang YY, Hou MC. Multiple genetic polymorphisms are associated with the risk of metabolic syndrome, fatty liver, and airflow limitation: A Taiwan Biobank study. Gene 2024; 927:148660. [PMID: 38866261 DOI: 10.1016/j.gene.2024.148660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/30/2024] [Accepted: 06/05/2024] [Indexed: 06/14/2024]
Abstract
BACKGROUND Links have been reported between the airflow limitation and both metabolic syndrome (MetS) and fatty liver (FL). Additionally, associations between genetic factors and risks of MetS, FL, and airflow limitation have been identified separately in different studies. Our study aims to simultaneously explore the association between specific single nucleotide polymorphisms (SNPs) of certain genes and the risk of the three associated diseases. METHODS In this retrospective cross-sectional nationwide study, 150,709 participants from the Taiwan Biobank (TWB) were enrolled. We conducted a genotype-phenotype association analysis of nine SNPs on seven genes (ApoE-rs429358, MBOAT7-rs641738, LEPR-rs1805096, APOC3-rs2854116, APOC3-rs2854117, PPP1R3B-rs4240624, PPP1R3B-rs4841132, TM6SF2-rs58542926, and IFNL4-rs368234815) using data from the TWB1.0 and TWB2.0 genotype dataset. Participants underwent a series of assessments including questionnaires, blood examinations, abdominal ultrasounds, and spirometry examinations. RESULTS MetS was associated with FL and airflow limitation. ApoE-rs429358, LEPR-rs1805096, APOC3-rs2854116, APOC3-rs2854117, PPP1R3B-rs4240624, PPP1R3B-rs4841132, and TM6SF2-rs58542926 were significantly associated with the risk of MetS. The cumulative impact of T alleles of ApoE-rs429358 and TM6SF2-rs58542926 on the risk of FL was observed (p-value for trend < 0.001). Individuals without MetS and airflow limitation carrying LEPR-rs1805096 G_G genotype exhibited a reduction in the forced expiratory volume in 1 s percentage prediction (Coefficient -35, 95 % confidence interval (CI) -69.7- -0.4), low forced vital capacity percentage prediction (Coefficient -41.6, 95 % CI -82.6- -0.6), and low vital capacity percentage prediction (Coefficient -42.2, 95 % CI -84.2- -0.1). CONCLUSIONS MetS significantly correlated with FL and airflow limitation. Multiple SNPs were notably associated with MetS. Specifically, T alleles of ApoE-rs429358 and TM6SF2-rs58542926 cumulatively increased the risk of FL. LEPR-rs1805096 shows a trend-wise association with pulmonary function, which is significant in patients without MetS or airflow limitation.
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Affiliation(s)
- Hsiao-Chin Shen
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Mei-Hung Pan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Chih-Jen Huang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Hsiao-Yun Yeh
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan; Doctoral Program of Clinical and Experimental Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Yi-Hsuan Lin
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
| | - Chia-Chang Huang
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; Department of Internal Medicine, Division of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taiwan
| | - Kuei-Chuan Lee
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ying-Ying Yang
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
| | - Ming-Chih Hou
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
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Park YT, Chung EY, Chae CH, Lee YH. Association between serum perfluoroalkyl substances concentrations and non-alcoholic fatty liver disease among Korean adults: a cross-sectional study using the National Environmental Health Survey cycle 4. Ann Occup Environ Med 2024; 36:e10. [PMID: 38872635 PMCID: PMC11168940 DOI: 10.35371/aoem.2024.36.e10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 02/20/2024] [Accepted: 03/28/2024] [Indexed: 06/15/2024] Open
Abstract
Background Perfluoroalkyl substances (PFAS) are widely used in industry and daily life due to their useful properties. They have a long half-life, accumulate in the body, and there is evidence that they are associated with biomarkers of lipid metabolism and liver damage. This may suggest non-alcoholic fatty liver disease (NAFLD) caused by PFAS. However, since there has been no study analyzing the relationship between PFAS and NAFLD in the entire population in Korea. We sought to confirm the relationship between serum PFAS concentration and NAFLD prevalence in Korean adults using the Korean National Environmental Health Survey (KoNEHS) cycle 4. Methods The study was conducted on 2,529 subjects in 2018-2019 among KoNEHS participants. For the diagnosis of NAFLD, the hepatic steatosis index (HSI) was used, and the geometric mean and concentration distribution of serum PFAS were presented. Logistic regression was performed to confirm the increase in the risk of NAFLD due to changes in PFAS concentration, and the odds ratio and 95% confidence interval (CI) were calculated. Results In both adjusted and unadjusted models, an increased odds ratio was observed with increasing serum concentrations of total PFAS and perfluorooctane sulfonate (PFOS) in the non-obese group. In the adjusted model, the odds ratios for serum total PFAS and PFOS were 6.401 (95% CI: 1.883-21.758) and 7.018 (95% CI: 2.688-18.319). Conclusions In this study, a higher risk of NAFLD based on HSI was associated with serum total PFAS, PFOS in non-obese group. Further research based on radiological or histological evidence for NAFLD diagnosis and long-term prospective studies are necessary. Accordingly, it is necessary to find ways to reduce exposure to PFAS in industry and daily life.
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Affiliation(s)
- Yong Tae Park
- Department of Occupational and Environmental Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Eui Yup Chung
- Department of Occupational and Environmental Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Chang Ho Chae
- Department of Occupational and Environmental Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Young Hoon Lee
- Department of Occupational and Environmental Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
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Reinshagen M, Kabisch S, Pfeiffer AF, Spranger J. Liver Fat Scores for Noninvasive Diagnosis and Monitoring of Nonalcoholic Fatty Liver Disease in Epidemiological and Clinical Studies. J Clin Transl Hepatol 2023; 11:1212-1227. [PMID: 37577225 PMCID: PMC10412706 DOI: 10.14218/jcth.2022.00019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/16/2022] [Accepted: 03/21/2023] [Indexed: 07/03/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome and type 2 diabetes and independently contributes to long-term complications. Being often asymptomatic but reversible, it would require population-wide screening, but direct diagnostics are either too invasive (liver biopsy), costly (MRI) or depending on the examiner's expertise (ultrasonography). Hepatosteatosis is usually accommodated by features of the metabolic syndrome (e.g. obesity, disturbances in triglyceride and glucose metabolism), and signs of hepatocellular damage, all of which are reflected by biomarkers, which poorly predict NAFLD as single item, but provide a cheap diagnostic alternative when integrated into composite liver fat indices. Fatty liver index, NAFLD LFS, and hepatic steatosis index are common and accurate indices for NAFLD prediction, but show limited accuracy for liver fat quantification. Other indices are rarely used. Hepatic fibrosis scores are commonly used in clinical practice, but their mandatory reflection of fibrotic reorganization, hepatic injury or systemic sequelae reduces sensitivity for the diagnosis of simple steatosis. Diet-induced liver fat changes are poorly reflected by liver fat indices, depending on the intervention and its specific impact of weight loss on NAFLD. This limited validity in longitudinal settings stimulates research for new equations. Adipokines, hepatokines, markers of cellular integrity, genetic variants but also simple and inexpensive routine parameters might be potential components. Currently, liver fat indices lack precision for NAFLD prediction or monitoring in individual patients, but in large cohorts they may substitute nonexistent imaging data and serve as a compound biomarker of metabolic syndrome and its cardiometabolic sequelae.
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Affiliation(s)
- Mona Reinshagen
- Department of Endocrinology and Metabolism, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany
- Deutsches Zentrum für Diabetesforschung e.V., Geschäftsstelle am Helmholtz-Zentrum München, Neuherberg, Germany
| | - Stefan Kabisch
- Department of Endocrinology and Metabolism, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany
- Deutsches Zentrum für Diabetesforschung e.V., Geschäftsstelle am Helmholtz-Zentrum München, Neuherberg, Germany
| | - Andreas F.H. Pfeiffer
- Department of Endocrinology and Metabolism, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany
- Deutsches Zentrum für Diabetesforschung e.V., Geschäftsstelle am Helmholtz-Zentrum München, Neuherberg, Germany
| | - Joachim Spranger
- Department of Endocrinology and Metabolism, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany
- Deutsches Zentrum für Diabetesforschung e.V., Geschäftsstelle am Helmholtz-Zentrum München, Neuherberg, Germany
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Cazac GD, Lăcătușu CM, Mihai C, Grigorescu ED, Onofriescu A, Mihai BM. New Insights into Non-Alcoholic Fatty Liver Disease and Coronary Artery Disease: The Liver-Heart Axis. Life (Basel) 2022; 12:1189. [PMID: 36013368 PMCID: PMC9410285 DOI: 10.3390/life12081189] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 07/28/2022] [Accepted: 07/29/2022] [Indexed: 12/17/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the hepatic expression of the metabolic syndrome and is the most prevalent liver disease. NAFLD is associated with liver-related and extrahepatic morbi-mortality. Among extrahepatic complications, cardiovascular disease (CVD) is the primary cause of mortality in patients with NAFLD. The most frequent clinical expression of CVD is the coronary artery disease (CAD). Epidemiological data support a link between CAD and NAFLD, underlain by pathogenic factors, such as the exacerbation of insulin resistance, genetic phenotype, oxidative stress, atherogenic dyslipidemia, pro-inflammatory mediators, and gut microbiota. A thorough assessment of cardiovascular risk and identification of all forms of CVD, especially CAD, are needed in all patients with NAFLD regardless of their metabolic status. Therefore, this narrative review aims to examine the available data on CAD seen in patients with NAFLD, to outline the main directions undertaken by the CVD risk assessment and the multiple putative underlying mechanisms implicated in the relationship between CAD and NAFLD, and to raise awareness about this underestimated association between two major, frequent and severe diseases.
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Affiliation(s)
- Georgiana-Diana Cazac
- Unit of Diabetes, Nutrition and Metabolic Diseases, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Cristina-Mihaela Lăcătușu
- Unit of Diabetes, Nutrition and Metabolic Diseases, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Cătălina Mihai
- Institute of Gastroenterology and Hepatology, “Sf. Spiridon” Emergency Hospital, 700111 Iași, Romania
- Unit of Medical Semiology and Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Elena-Daniela Grigorescu
- Unit of Diabetes, Nutrition and Metabolic Diseases, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Alina Onofriescu
- Unit of Diabetes, Nutrition and Metabolic Diseases, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Bogdan-Mircea Mihai
- Unit of Diabetes, Nutrition and Metabolic Diseases, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iași, Romania
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Adnan M, Wajid A, Noor W, Batool A, Aasim M, Abbas K, Ain Q. Sociodemographic and genetic determinants of nonalcoholic fatty liver disease in type 2 diabetes mellitus patients. J Genet Eng Biotechnol 2022; 20:68. [PMID: 35486295 PMCID: PMC9054952 DOI: 10.1186/s43141-022-00349-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 04/18/2022] [Indexed: 11/10/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) showed significant association with PNPLA3 rs738409 polymorphism in unrelated individuals. However, it is still unknown whether the relationship of NAFLD with PNPLA3 variant exists or not among subjects with type 2 diabetes mellitus (T2DM). Therefore, the study aimed to evaluate sociodemographic and genetic determinants of NAFLD in type 2 diabetics. METHODS The cross-sectional analytical study was conducted at the Department of Molecular Biology, Virtual University of Pakistan, Lahore, Pakistan, during 2019-2020. A total of 153 known cases of T2DM were enrolled using convenience sampling. After excluding patients (n = 24) with HCV, alcoholism, or missing information, data from 129 eligible diabetics with and without NAFLD were analyzed using SPSS. Odds ratios using crosstabs and adjusted odds ratios using binary and multinomial logistic regression were calculated to measure the risk of NAFLD. RESULTS Adults 18-35 years were 7.0%, 36-55 years were 64.3%, ≥ 56 years were 28.7%, and females were 66.7%. A total of 41.1% of patients had obesity, 52.7% had NAFLD, and 29.05% carried mutant G allele of rs738409 polymorphism. Among overall diabetics, NAFLD showed association with female (OR = 2.998, p = 0.007), illiterate (OR = 3.067, p = 0.005), and obese (OR = 2.211, p = 0.046) but not with PNPLA3 genotype under any model (all p = > 0.05). Among obese diabetics, NAFLD showed association with female (AOR = 4.010, p = 0.029), illiterate (AOR = 3.506, p = 0.037), GG + CG/CC (AOR = 3.303, p = 0.033), and GG/CG + CC (AOR = 4.547, p = 0.034) using binary regression and with female (AOR = 3.411, p = 0.051), illiterate (AOR = 3.323, p = 0.048), GG + CG/CC (AOR = 3.270, p = 0.029), and GG/CG + CC (AOR = 4.534, p = 0.024) using multinomial regression. CONCLUSIONS NAFLD and obesity were the most common comorbid diseases of T2DM. Gender female, being illiterate, and PNPLA3 rs738409 polymorphism were significant risk factors of NAFLD among obese diabetic patients.
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Affiliation(s)
- Muhammad Adnan
- Health Research Institute, National Institute of Health, Lahore, Pakistan. .,Department of Molecular Biology, Virtual University of Pakistan, Lahore, Pakistan.
| | - Abdul Wajid
- Department of Molecular Biology, Virtual University of Pakistan, Lahore, Pakistan
| | - Wasif Noor
- Diabetes Clinic, Sir Ganga Ram Hospital, Lahore, Pakistan
| | - Andleeb Batool
- Department of Zoology, Government College University, Lahore, Pakistan
| | - Muhammad Aasim
- Health Research Institute, National Institute of Health, Lahore, Pakistan
| | - Kamran Abbas
- Department of Molecular Biology, Virtual University of Pakistan, Lahore, Pakistan
| | - Quratul Ain
- Department of Molecular Biology, Virtual University of Pakistan, Lahore, Pakistan
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Zheng YT, Xiao TM, Wu CX, Cheng JY, Li LY. Correlation of Adiponectin Gene Polymorphisms rs266729 and rs3774261 With Risk of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2022; 13:798417. [PMID: 35399941 PMCID: PMC8983824 DOI: 10.3389/fendo.2022.798417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 02/22/2022] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Increasing evidence has suggested an association of adiponectin gene polymorphisms rs1501299, rs2241766, rs266729 and rs3774261 with risk of nonalcoholic fatty liver disease (NAFLD). This correlation has been extensively meta-analyzed for the first two polymorphisms, but not the second two. METHODS The PubMed, EMBASE, Google Scholar, and China National Knowledge Infrastructure databases were searched for relevant literature. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS A total of 10 case-control studies on rs266729 (2,619 cases and 1,962 controls) and 3 case-control studies on rs3774261 (562 cases and 793 controls) were included. Meta-analysis showed that rs266729 was associated with significantly higher NAFLD risk based on the following five models: allelic, OR 1.72, 95% CI 1.34-2.21, P < 0.001; recessive, OR 2.35, 95% CI 1.86-2.95, P < 0.001; dominant, OR 1.84, 95% CI 1.34-2.53, P < 0.001; homozygous, OR 2.69, 95% CI 1.84-3.92, P < 0.001; and heterozygous, OR 1.72, 95% CI 1.28-2.32, P < 0.001. This association between rs266729 and NAFLD risk remained significant for all five models among studies with Asian, Chinese and Caucasian samples. The rs2241766 polymorphism was associated with significantly higher NAFLD risk according to the recessive model (OR 1.87, 95% CI 1.15-3.04, P = 0.01). CONCLUSION Polymorphisms rs266729 and rs3774261 in the adiponectin gene may be risk factors for NAFLD. These findings may pave the way for novel therapeutic strategies, but they should be verified in large, well-designed studies.
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Main Risk Factors of Type 2 Diabetes Mellitus with Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2021; 2021:7764817. [PMID: 34691178 PMCID: PMC8528616 DOI: 10.1155/2021/7764817] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/15/2021] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD) is a pathological metabolic disease characterized by high ketone lipid based on abnormal lipid metabolism. Compared with patients with single T2DM or NAFLD, T2DM complicated with NAFLD has more complicated pathogenic factors and pathological processes. Hepatocellular carcinoma (HCC), the leading malignancy arising from cirrhosis, is the second most lethal cancer globally. The purpose of this study was to clarify the main risk factors of T2DM with NAFLD and HCC. There are many challenges in the diagnosis and treatment of T2DM patients with NAFLD and HCC. The current gold standard is to adjust treatment strategy, optimize metabolic control, and improve liver phenotype. It is necessary to identify further the risk factors driving the progression of T2DM with NAFLD and HCC and evaluate new therapeutic targets, in addition to exploring the syndromic forms of T2DM combined with NAFLD and providing a theoretical basis for early prevention, diagnosis, and treatment of the disease using traditional Chinese medicine (TCM).
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Hasan EM, Abd Al Aziz RA, Sabry D, Badary HA, Gaber Y, Yosry A, Zakaria Z. The association of adiponectin gene polymorphisms with susceptibility and progression of NAFLD in a cohort of Egyptian patients. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00103-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Abstract
Background
Several genetic polymorphisms have been proven to play a key role in the progression of non-alcoholic fatty liver disease (NAFLD) from simple steatosis to NASH with fibrosis. Our aim was to study the effect of single nucleotide polymorphisms (SNPs) in the adiponectin gene, namely rs266729 and rs3774261, on susceptibility to NAFLD and disease progression.
Results
There was a definitive association between polymorphisms of the studied SNPs and NAFLD. Among rs266729, CG was significantly higher among patients than controls showing increased risk for NAFLD (P<0.05). AA genotype of the rs3774261 variant was significantly lower in patients than in controls (P value< 0.001) while AG and GG genotypes were significantly higher in patients than in controls (P value<0.05); A allele was significantly higher among controls (P=0.019) which might have a protective effect. None of the variants correlated significantly with the degree of steatosis. Using multivariate regression analysis, there was no significant correlation with any of the independent risk factors to the degree of steatosis.
Conclusions
There was an association between polymorphisms of the studied SNPs of rs266729 and rs3774261 of the adiponectin gene and NAFLD.
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Niederseer D, Wernly B, Aigner E, Stickel F, Datz C. NAFLD and Cardiovascular Diseases: Epidemiological, Mechanistic and Therapeutic Considerations. J Clin Med 2021; 10:467. [PMID: 33530440 PMCID: PMC7865665 DOI: 10.3390/jcm10030467] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/21/2021] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
Overwhelming evidence suggests an association of cardiovascular disease (CVD) with non-alcoholic fatty liver disease (NAFLD); however, the underlying mechanisms remain largely speculative. It is, however, likely that common mechanisms contribute to the development of CVD and NAFLD, with lifestyle factors such as smoking, sedentary lifestyle with poor nutrition habits and physical inactivity being major candidates. These behavioral factors, on a predisposing genetic background, trigger changes in gut microbiota, inflammation, dyslipidemia and oxidative stress, leading to metabolic syndrome, diabetes and obesity as well as atherosclerosis. Treatment options to counteract both the progression and development of CVD and NAFLD include lifestyle interventions, optimal medical therapy of comorbid conditions and, as final possibility, bariatric surgery. As no causal pharmacotherapy of NAFLD is available, further research is urgently needed to address the unmet need of a growing population with NAFLD and CVD.
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Affiliation(s)
- David Niederseer
- Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
| | - Bernhard Wernly
- Department of Anaesthesiology, Perioperative Medicine and Intensive Care Medicine, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria;
- Center for Public Health and Healthcare Research, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
- Department of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
| | - Elmar Aigner
- First Department of Medicine, Paracelsus Medical University, 5020 Salzburg, Austria;
| | - Felix Stickel
- Department of Gastroenterology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
| | - Christian Datz
- Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University, 5110 Oberndorf, Austria
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Saki S, Saki N, Poustchi H, Malekzadeh R. Assessment of Genetic Aspects of Non-alcoholic Fatty Liver and Premature Cardiovascular Events. Middle East J Dig Dis 2020; 12:65-88. [PMID: 32626560 PMCID: PMC7320986 DOI: 10.34172/mejdd.2020.166] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 03/19/2019] [Indexed: 12/12/2022] Open
Abstract
Recent evidence has demonstrated a strong interplay and multifaceted relationship between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). CVD is the major cause of death in patients with NAFLD. NAFLD also has strong associations with diabetes and metabolic syndrome. In this comprehensive review, we aimed to overview the primary environmental and genetic risk factors of NAFLD, and CVD and also focus on the genetic aspects of these two disorders. NAFLD and CVD are both heterogeneous diseases with common genetic and molecular pathways. We have searched for the latest published articles regarding this matter and tried to provide an overview of recent insights into the genetic aspects of NAFLD and CVD. The common genetic and molecular pathways involved in NAFLD and CVD are insulin resistance (IR), subclinical inflammation, oxidative stress, and atherogenic dyslipidemia. According to an investigation, the exact associations between genomic characteristics of NAFLD and CVD and casual relationships are not fully determined. Different gene polymorphisms have been identified as the genetic components of the NAFLDCVD association. Some of the most documented ones of these gene polymorphisms are patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), adiponectin-encoding gene (ADIPOQ), apolipoprotein C3 (APOC3), peroxisome proliferator-activated receptors (PPAR), leptin receptor (LEPR), sterol regulatory element-binding proteins (SREBP), tumor necrosis factor-alpha (TNF-α), microsomal triglyceride transfer protein (MTTP), manganese superoxide dismutase (MnSOD), membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), and mutation in DYRK1B that substitutes cysteine for arginine at position 102 in kinase-like domain. Further cohort studies with a significant sample size using advanced genomic assessments and next-generation sequencing techniques are needed to shed more light on genetic associations between NAFLD and CVD.
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Affiliation(s)
- Sara Saki
- Tehran University of Medical Sciences, Tehran, Iran
| | - Nader Saki
- Hoveizeh Cohort Study, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hossein Poustchi
- Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Malekzadeh
- Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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12
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Divella R, Daniele A, DE Luca R, Mazzocca A, Ruggieri E, Savino E, Casamassima P, Simone M, Sabba C, Paradiso A. Synergism of Adipocytokine Profile and ADIPOQ/TNF-α Polymorphisms in NAFLD-associated MetS Predict Colorectal Liver Metastases Outgrowth. Cancer Genomics Proteomics 2020; 16:519-530. [PMID: 31659105 DOI: 10.21873/cgp.20154] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 08/20/2019] [Accepted: 08/21/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIM The aim of this study was to evaluate whether the altered profile of adipocytokine and genetic fingerprint in NAFLD-associated metabolic syndrome "cluster" represents synergistic risk factors predicting onset of liver colorectal cancer metastases. MATERIALS AND METHODS A total of 165 colorectal cancer patients were enrolled, 56,3% were with metabolic syndrome/NAFLD. Serum samples were assayed for ADIPOQ, leptin and TNF-a levels by ELISA. ADIPOQ rs266729 C/G and TNF-308 A/G genotypes were analyzed in DNA isolated from whole blood. RESULTS Reduction in adiponectin levels and increase in leptin and TNF-α was shown in patients with liver metastases. This trend was influenced by BMI, MetS/NAFLD, and insulin resistance. ADIPOQ G rs266729 and TNF- 308 A allele are associated with obesity, MetS/NAFLD and insulin resistance. ADIPOQ CG/GG and GA/AA TNF-alpha genotypes confer susceptibility to liver metastases. CONCLUSION Obesity and hepatic steatosis significantly favor the development of colorectal cancer liver metastases and the individual adipocytokines genetic profile may play an important predictive role.
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Affiliation(s)
- Rosa Divella
- Institutional BioBank, Experimental Oncology and Biobank Management Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Antonella Daniele
- Institutional BioBank, Experimental Oncology and Biobank Management Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Raffaele DE Luca
- Department of Surgery Oncology, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy
| | - Eustachio Ruggieri
- Department of Surgery Oncology, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Eufemia Savino
- Clinical Pathology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Porzia Casamassima
- Clinical Pathology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Michele Simone
- Department of Surgery Oncology, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Carlo Sabba
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy
| | - Angelo Paradiso
- Institutional BioBank, Experimental Oncology and Biobank Management Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
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13
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Lian K, Feng YN, Li R, Liu HL, Han P, Zhou L, Li CX, Wang Q. Middle- and high-molecular weight adiponectin levels in relation to nonalcoholic fatty liver disease. J Clin Lab Anal 2019; 34:e23148. [PMID: 31880002 PMCID: PMC7171302 DOI: 10.1002/jcla.23148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 10/21/2019] [Accepted: 11/15/2019] [Indexed: 12/14/2022] Open
Abstract
Objective Adiponectin (APN) circulates as high‐molecular weight (HMW), medium‐molecular weight (MMW), and low‐molecular weight (LMW) forms. Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. Currently, the role of LMW, MMW, and HMW APN remains largely unclear in NAFLD. Methods We examined the variation of these forms and analyzed the related clinical characteristics in NAFLD. A total of 63 male NAFLD patients (mean age: 43.00 ± 6.10 years) and 70 healthy male subjects (mean age: 42.53 ± 7.98 years) were included in the study. Total APN and other clinical characteristics were measured. The changes in HMW, MMW, and LMW APN were determined in NAFLD patients and NAFLD patients on a high‐fat diet, and the association between the groups was further analyzed. Results Decreased levels of total APN and three APN isoforms were found in NAFLD. Significantly decreased levels of HMW (P < .01) and MMW (P < .001) were observed in NAFLD of high‐fat diet patients. In NAFLD patients, height (R = −.270, P = .032) and N‐epsilon‐(carboxymethyl) lysine (R = −.259, P = .040) significantly correlated with total APN. HMW APN was significantly associated with fasting plasma glucose (R = .350, P = .016), alanine aminotransferase (R = −.321, P = .029), and aspartate aminotransferase (R = −.295, P = .045). Additionally, MMW APN was significantly associated with total cholesterol (R = .357, P = .014) and high‐density lipoprotein (R = .556, P < .0001). Low‐density lipoprotein (R = −.283, P = .054) was also clearly associated with LMW APN in NAFLD patients. Conclusion These results suggest that HMW and MMW APN may be involved in the pathogenesis and progression of NAFLD.
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Affiliation(s)
- Kun Lian
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Yu-Nan Feng
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Rong Li
- Department of Geriatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Hao-Lin Liu
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Peng Han
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Lei Zhou
- Department of Clinical Laboratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Cheng-Xiang Li
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Qin Wang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
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14
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Liu J, Xing J, Wang B, Wei C, Yang R, Zhu Y, Qiu H. Correlation Between Adiponectin Gene rs1501299 Polymorphism and Nonalcoholic Fatty Liver Disease Susceptibility: A Systematic Review and Meta-Analysis. Med Sci Monit 2019; 25:1078-1086. [PMID: 30735485 PMCID: PMC6376635 DOI: 10.12659/msm.912737] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Metabolic related nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases around the world. A single nucleotide polymorphism (SNP) rs1501299 (+276G>T) in the adiponectin gene has been recently revealed to be responsible for susceptibility to NAFLD. This meta-analysis intended to assess the association risk of NAFLD and rs1501299 polymorphism. Material/Methods We conducted a literature search on PubMed, Embase, and Cochrane Library databases. All involved studies were selected based on our search criteria. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to quantify the strength of the association. Subgroup analysis considered the effects of ethnicity, subject scope, and source of control. Publication bias was assessed by Begg’s tests. Results Eight qualified case-control studies with 1639 patients and 1426 controls demonstrated a significant correlation between rs1501299 polymorphism in adiponectin and NAFLD under the dominant model (OR=1.18, 95% CI=1.02–1.36), allelic contrast (OR=1.21, 95% CI=1.09–1.36), homozygote comparison (OR=1.63, 95% CI=1.26–2.01) and the recessive allele model (OR=1.58, 95% CI=1.23–2.02) with evident heterogeneity. No association was observed between the risk of NAFLD and the genotypic variants in heterozygote comparison (OR=1.11, 95% CI=0.95–1.29) without heterogeneity. Subgroup analysis suggested that the sample size could be the potential source of heterogeneity. Source of control was not the reason for between-study heterogeneity and further sensitivity analysis and publication bias revealed good consistency and symmetry in the pooling studies. Conclusions Results from our current meta-analysis gave insight into the correlation between rs1501299 polymorphism and the risk of NAFLD, indicating the variant of rs1501299 might be related to increased NAFLD susceptibility.
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Affiliation(s)
- Jiaxing Liu
- Bayi College of People's Liberation Army (PLA), Anhui Medical University, Nanjing, Jiangsu, China (mainland)
| | - Jicheng Xing
- Department of Clinical Laboratory, The 81st Hospital of People's Liberation Army (PLA), Nanjing, Jiangsu, China (mainland)
| | - Bing Wang
- Department of Clinical Laboratory, The 81st Hospital of People's Liberation Army (PLA), Nanjing, Jiangsu, China (mainland)
| | - Changyong Wei
- Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Ruining Yang
- Department of Clinical Laboratory, The 81st Hospital of People's Liberation Army (PLA), Nanjing, Jiangsu, China (mainland)
| | - Yuerong Zhu
- Department of Clinical Laboratory, The 81st Hospital of People's Liberation Army (PLA), Nanjing, Jiangsu, China (mainland)
| | - Hong Qiu
- Department of Clinical Laboratory, The 81st Hospital of People's Liberation Army (PLA), Nanjing, Jiangsu, China (mainland)
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15
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Oliveira RFD, Daniele TMDC, Façanha CFS, Forti ACE, Bruin PFCD, Bruin VMSD. Adiponectin levels and sleep deprivation in patients with endocrine metabolic disorders. ACTA ACUST UNITED AC 2018; 64:1122-1128. [PMID: 30569989 DOI: 10.1590/1806-9282.64.12.1122] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 05/27/2018] [Indexed: 11/22/2022]
Abstract
BACKGROUND Sleep abnormalities are frequent in patients with endocrine metabolic disorders (EMD) such as arterial hypertension, diabetes and obesity. Adiponectin is a peptide largely secreted by adipocytes and has various properties e.g. anti-inflammatory, antioxidant, antiatherogenic, pro-angiogenic, vasoprotective and insulin-sensitizing. Adiponectin inversely relates to body weight and when its concentration decreases, the resistin concentration increases resulting in greater insulin resistance. OBJECTIVE The objective of this study is to examine factors influencing adiponectin levels in a population with EMD. METHODS This was a cross-sectional evaluation of 332 patients (18 to 80y) presenting arterial hypertension, pre-diabetes, diabetes, and/or obesity. Investigation included clinical evaluation of comorbidities, general blood tests and adiponectin measures (ELISA). Chronic sleep deprivation was determined if habitual sleep was <6 hours >4 days/week. RESULTS Arterial hypertension (78.5%), type-2 diabetes (82.3%), and overweight (45.0%)/obesity (38.8%) were frequent. Patients with type-2 diabetes tended to have more chronic sleep deprivation (p=0.05). Adiponectin levels increased with age and were inversely correlated with sagittal abdominal diameter (p=0.04) and fasting insulin (p=0.001). Chronic sleep deprivation was associated with higher adiponectin concentration [OR=1.34; CI=1.13-1.58; p<0.005] and this was maintained after adjustment for gender, age, body mass index, menopause, arterial hypertension, American Diabetes Association classification and physical exercise levels [OR=1.38; 0=1.14-1.66: p=0.001]. CONCLUSION In patients with EMD, adiponectin is influenced not only by obesity but also by age and sleep deprivation. The latter finding may be explained by a compensatory effect or a counter regulation to minimize the harmful effects of sleep deprivation.
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Affiliation(s)
- Roseane Feitosa de Oliveira
- School of Medicine, Universidade Federal do Ceará (UFC). Postgraduate Program in Medical Sciences, UFC, Fortaleza, CE, Brasil
| | - Thiago Medeiros da Costa Daniele
- School of Medicine, Universidade Federal do Ceará (UFC). Postgraduate Program in Medical Sciences, UFC, Fortaleza, CE, Brasil.,Sleep Lab and Biological Rhythms, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
| | - Cristina Figueiredo Sampaio Façanha
- School of Medicine, Universidade Federal do Ceará (UFC). Postgraduate Program in Medical Sciences, UFC, Fortaleza, CE, Brasil.,Sleep Lab and Biological Rhythms, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
| | - Adriana Costa E Forti
- School of Medicine, Universidade Federal do Ceará (UFC). Postgraduate Program in Medical Sciences, UFC, Fortaleza, CE, Brasil
| | - Pedro Felipe Carvalhedo de Bruin
- School of Medicine, Universidade Federal do Ceará (UFC). Postgraduate Program in Medical Sciences, UFC, Fortaleza, CE, Brasil.,Sleep Lab and Biological Rhythms, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
| | - Veralice Meireles Sales de Bruin
- School of Medicine, Universidade Federal do Ceará (UFC). Postgraduate Program in Medical Sciences, UFC, Fortaleza, CE, Brasil.,Sleep Lab and Biological Rhythms, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
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16
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Udomsinprasert W, Honsawek S, Poovorawan Y. Adiponectin as a novel biomarker for liver fibrosis. World J Hepatol 2018; 10:708-718. [PMID: 30386464 PMCID: PMC6206156 DOI: 10.4254/wjh.v10.i10.708] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 08/02/2018] [Accepted: 08/06/2018] [Indexed: 02/06/2023] Open
Abstract
Adiponectin is known to play primary roles in the regulation of systemic glucose homeostasis and lipid metabolism. Interestingly, emerging evidence indicates beneficial effects of adiponectin on liver fibrosis; however, the exact mechanisms of this action remain unclear. Herein, we aimed to summarize the recent findings regarding the role of adiponectin in liver fibrogenesis and update the current comprehensive knowledge regarding usefulness of adiponectin-based treatments in liver fibrosis. Adiponectin has been demonstrated to have an anti-fibrotic action in the liver by blocking the activation of hepatic stellate cell-mediated adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor-alpha pathways, which in turn diminish the expression of pro-fibrotic genes. In addition, hyperadiponectinemia was noted in patients with various chronic liver diseases (CLDs)-related liver fibrosis. An increase in circulating adiponectin levels was also found to be associated with the development of liver fibrosis, indicating a role of adiponectin as a non-invasive biomarker for predicting the progression of liver fibrosis. It is therefore reasonable to speculate that adiponectin may be developed as a new therapeutic candidate for the treatment of liver fibrosis. Nonetheless, future observations are still necessary to fully elucidate the extent of the effects of adiponectin on liver fibrotic outcomes, in order to modify adiponectin as an anti-fibrotic therapy that would speed up fibrosis reversal in patients with CLD.
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Affiliation(s)
- Wanvisa Udomsinprasert
- Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
| | - Sittisak Honsawek
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand.
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17
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John BV, Aiken T, Garber A, Thomas D, Lopez R, Patil D, Konjeti VR, Fung JJ, McCollough AJ, Askar M. Recipient But Not Donor Adiponectin Polymorphisms Are Associated With Early Posttransplant Hepatic Steatosis in Patients Transplanted for Non-Nonalcoholic Fatty Liver Disease Indications. EXP CLIN TRANSPLANT 2018; 16:439-445. [PMID: 29863454 DOI: 10.6002/ect.2018.0070] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVES De novo steatosis after liver transplant is common and can occur in up to one-third of patients who are transplanted for liver disease other than for nonalcoholic fatty liver disease. Genetic factors may influence posttransplant steatosis; in a posttransplant setting, donor or recipient genetic factors could also play roles. Genetic polymorphisms in the adiponectin gene have been associated with metabolic syndrome in the pretransplant setting. We aimed to assess the association between donor and recipient adiponectin polymorphisms and early posttransplant hepatic steatosis identified on liver biopsies. MATERIALS AND METHODS Clinical data were collected for 302 liver transplant patients who underwent protocol biopsies for hepatitis C. Of these, 111 patients had available biopsies and donor/recipient DNA. Patients with grade 1 steatosis or greater (35% of patients) were compared with patients without posttransplant steatosis with respect to clinical features and donor/recipient adiponectin polymorphism genotypes. RESULTS Patients who developed posttransplant steatosis and those without steatosis were similar with respect to individual components of metabolic syndrome. The adiponectin polymorphisms rs1501299 G/G and rs17300539 G/G genotypes in recipients were associated with early posttransplant graft steatosis. We found no associations between graft steatosis and donor adiponectin polymorphisms. CONCLUSIONS Genetic polymorphisms in the adiponectin gene of recipients (but not donors) are associated with early de novo posttransplant hepatic steatosis, independent of components of metabolic syndrome.
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Affiliation(s)
- Binu V John
- From the Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
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18
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Umano GR, Martino M, Santoro N. The Association between Pediatric NAFLD and Common Genetic Variants. CHILDREN-BASEL 2017. [PMID: 28629152 PMCID: PMC5483624 DOI: 10.3390/children4060049] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of obesity. Several studies have shown that genetic predisposition probably plays an important role in its pathogenesis. In fact, in the last few years a large number of genetic studies have provided compelling evidence that some gene variants, especially those in genes encoding proteins regulating lipid metabolism, are associated with intra-hepatic fat accumulation. Here we provide a comprehensive review of the gene variants that have affected the natural history of the disease.
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Affiliation(s)
- Giuseppina Rosaria Umano
- Department of Pediatrics, Yale University, 06520, New Haven, CT, USA.
- Dipartimento della Donna, del Bambino, di Vhirurgia Generale e Specialistica, Universita' della Campania Luigi Vanvitelli, 80138, Napoli, Italy.
| | - Mariangela Martino
- Department of Pediatrics, Yale University, 06520, New Haven, CT, USA.
- Dipartimento di Medicina V. Tiberio, Universita' del Molise, 86100, Campobasso, Italy.
| | - Nicola Santoro
- Department of Pediatrics, Yale University, 06520, New Haven, CT, USA.
- Dipartimento di Medicina V. Tiberio, Universita' del Molise, 86100, Campobasso, Italy.
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19
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Xiao X, Li H, Qi X, Wang Y, Xu C, Liu G, Wen G, Liu J. Zinc alpha2 glycoprotein alleviates palmitic acid-induced intracellular lipid accumulation in hepatocytes. Mol Cell Endocrinol 2017; 439:155-164. [PMID: 27264075 DOI: 10.1016/j.mce.2016.06.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 05/14/2016] [Accepted: 06/02/2016] [Indexed: 12/17/2022]
Abstract
Zinc alpha2 glycoprotein (ZAG) plays an important role in stimulating fat mobilization and lipolysis in adipose tissue, but its role in hepatic lipid metabolism remains unclear. Palmitic acid (PA) was used to stimulate HepG2 cells with ZAG overexpression or ZAG knock down (shRNA). Overexpression of ZAG significantly inhibited lipogenesis, promoted lipolysis and fatty acid β-oxidation, and attenuated PA-induced intracellular fat accumulation. Moreover, ZAG overexpression dramatically stimulated adiponectin expression in HepG2 cells. In contrast, knockdown of ZAG notably inhibited fatty acid β-oxidation, increased lipogenesis and lipid accumulation. Collectively, these data suggest that ZAG has the potential to alleviate hepatosteatosis, making it a promising therapeutic target for fatty liver.
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Affiliation(s)
- Xinhua Xiao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, 421001, People's Republic of China
| | - Han Li
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, 421001, People's Republic of China
| | - Xiaoyan Qi
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, 421001, People's Republic of China
| | - Yadi Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, 421001, People's Republic of China
| | - Canxin Xu
- Department of Pathology & Immunology, Developmental, Regenerative and Stem Cell Biology, Washington University in St. Louis, MO, 63110, United States
| | - Gexin Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, 421001, People's Republic of China
| | - Gebo Wen
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, 421001, People's Republic of China
| | - Jianghua Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, 421001, People's Republic of China.
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20
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Stevenson HL, Utay NS. Hepatic steatosis in HCV-infected persons in the direct-acting antiviral era. Trop Dis Travel Med Vaccines 2016; 2:21. [PMID: 28883965 PMCID: PMC5530934 DOI: 10.1186/s40794-016-0038-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 09/22/2016] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) infects 130-170 million people worldwide. Recently, direct-acting antivirals have been shown to eradicate HCV infection in 90-95 % of non-cirrhotic patients depending on genotype, treatment experience, and regimen used. Similar rates are achieved among compensated cirrhotics, although longer treatment duration and/or ribavirin may be required. HCV uses host lipid metabolism for its lifecycle and can cause hepatic steatosis and insulin resistance. Hepatic steatosis, defined as excessive triglyceride deposition in hepatocytes, affects approximately half of HCV-infected individuals. Genetic factors and co-morbidities can drive further steatosis, which in turn can instigate fibrosis and progression to cirrhosis and hepatocellular carcinoma. Polymorphisms in genes that modulate lipid deposition in hepatocytes such as patatin-like phospholipase domain-containing protein 3 (PNPLA3) and transmembrane six superfamily member 2 (TM6SF2) predispose people to steatosis. Metabolic syndrome, obesity, and insulin resistance are increasing worldwide and further contribute to hepatic steatosis, and alcohol has long been recognized as a cause of lipid deposition in the liver. HIV and antiretroviral drugs, but not HBV, may further drive hepatic steatosis. While many of these factors limit response to interferon-based regimens for treating HCV, responses to direct-acting antivirals appear not to be impaired. The effect of HCV eradication on hepatic steatosis and progression to fibrosis, cirrhosis, and hepatocellular carcinoma warrants further study in the era of direct-acting antivirals.
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Affiliation(s)
- Heather L. Stevenson
- Department of Pathology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555 USA
| | - Netanya S. Utay
- Division of Infectious Diseases, Department of Medicine, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555 USA
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21
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Li XL, Sui JQ, Lu LL, Zhang NN, Xu X, Dong QY, Xin YN, Xuan SY. Gene polymorphisms associated with non-alcoholic fatty liver disease and coronary artery disease: a concise review. Lipids Health Dis 2016; 15:53. [PMID: 26965314 PMCID: PMC4785616 DOI: 10.1186/s12944-016-0221-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 03/04/2016] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease which represents a wide spectrum of hepatic damage. Several studies have reported that NAFLD is a strong independent risk factor for coronary artery disease (CAD). And patients with NAFLD are at higher risk and suggested undergoperiodic cardiovascular risk assessment. Cardiovascular disease (CVD) is responsible for the main cause of death in patients with NAFLD, and is mostly influenced by genetic factors. Both NAFLD and CAD are heterogeneous disease. Common pathways involved in the pathogenesis of NAFLD and CAD includes insulin resistance (IR), atherogenic dyslipidemia, subclinical inflammation, oxidative stress, etc. Genomic characteristics of these two diseases have been widely studied, further research about the association of these two diseases draws attention. The gene polymorphisms of adiponectin-encoding gene (ADIPOQ), leptin receptor (LEPR), apolipoprotein C3 (APOC3), peroxisome proliferator-activated receptors (PPAR), sterol regulatory elementbinding proteins (SREBP), transmembrane 6 superfamily member 2 (TM6SF2), microsomal triglyceride transfer protein (MTTP), tumor necrosis factors-alpha (TNF-α) and manganese superoxide dismutase (MnSOD) have been reported to be related to NAFLD and CAD. In this review, we aimed to provide an overview of recent insights into the genetic basis of NAFLD and CAD.
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Affiliation(s)
- Xiao-Lin Li
- Department of Gastroenterology, Qingdao Municipal Hospital, Dalian Medical University, Qingdao, 266011, China
| | - Jian-Qing Sui
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, 266011, China
| | - Lin-Lin Lu
- Digestive Disease Key Laboratory of Qingdao, Qingdao, 266071, China.,Central Laboratories, Qingdao Municipal Hospital, Qingdao, 266071, China
| | - Nan-Nan Zhang
- Department of Gastroenterology, Qingdao Municipal Hospital, Dalian Medical University, Qingdao, 266011, China
| | - Xin Xu
- Department of Gastroenterology, Qingdao Municipal Hospital, Dalian Medical University, Qingdao, 266011, China
| | - Quan-Yong Dong
- Department of Gastroenterology, Qingdao Municipal Hospital, Dalian Medical University, Qingdao, 266011, China
| | - Yong-Ning Xin
- Department of Gastroenterology, Qingdao Municipal Hospital, Dalian Medical University, Qingdao, 266011, China. .,Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, 266011, China. .,Digestive Disease Key Laboratory of Qingdao, Qingdao, 266071, China.
| | - Shi-Ying Xuan
- Department of Gastroenterology, Qingdao Municipal Hospital, Dalian Medical University, Qingdao, 266011, China. .,Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, 266011, China. .,Digestive Disease Key Laboratory of Qingdao, Qingdao, 266071, China.
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Omentin-1 rs2274907 and resistin rs1862513 polymorphisms influence genetic susceptibility to nonalcoholic fatty liver disease. MOLECULAR BIOLOGY RESEARCH COMMUNICATIONS 2016; 5:11-17. [PMID: 27844016 PMCID: PMC5019329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/30/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an obesity-associated disease and dysregulation of adipokines has an important role in its development. Omentin-1 (ITLN1 protein) and resistin are two adipokine secreted from adipose tissue. Single nucleotide polymorphisms in the adipokine genes may affect expression and activity of the adipokine, and thus play a contributory role in NAFLD pathogenesis. The aim of the present study was to investigate the association between omentin-1 rs2274907 (326A/T) and resistin rs1862513 (-420 C/G) polymorphisms and risk of NAFLD in Iranian patients. This case-control study was done on 282 subjects included 94 patients with NAFLD and 188 healthy peoples. The genotypes were determined using PCR-RFLP method. The frequency of omentin-1 AT genotype in patients with NAFLD was significantly different from that in the control (OR=2.3, 95% CI: 1.3-3.8, P=0.003). A significant association was observed between NAFLD and the GG genotype regarding resistin rs1862513 polymorphism (OR=2.3, 95% CI: 1.1-4.8, P=0.03). In conclusion, Omentin-1 rs2274907 and resistin rs1862513 polymorphisms might be a candidate genetic factor for susceptibility to NAFLD.
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