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Sato S, Iino C, Sasada T, Furusawa K, Yoshida K, Sawada K, Mikami T, Fukuda S, Nakaji S, Sakuraba H. A 4-year cohort study of the effects of PNPLA3 rs738409 genotypes on liver fat and fibrosis and gut microbiota in a non-fatty liver population. Environ Health Prev Med 2025; 30:17. [PMID: 40074353 PMCID: PMC11925709 DOI: 10.1265/ehpm.24-00365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/07/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Many factors are associated with the development and progression of liver fat and fibrosis; however, genetics and the gut microbiota are representative factors. Moreover, recent studies have indicated a link between host genes and the gut microbiota. This study investigated the effect of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 (C > G), which has been reported to be most involved in the onset and progression of fatty liver, on liver fat and fibrosis in a cohort study related to gut microbiota in a non-fatty liver population. METHODS This cohort study included 214 participants from the health check-up project in 2018 and 2022 who had non-fatty liver with controlled attenuation parameter (CAP) values <248 dB/m by FibroScan and were non-drinkers. Changes in CAP values and liver stiffness measurement (LSM), liver-related items, and gut microbiota from 2018 to 2022 were investigated separately for PNPLA3 rs738409 CC, CG, and GG genotypes. RESULTS Baseline values showed no difference among the PNPLA3 rs738409 genotypes for any of the measurement items. From 2018 to 2022, the PNPLA3 rs738409 CG and GG genotype groups showed a significant increase in CAP and body mass index; no significant change was observed in the CC genotype group. LSM increased in all genotypes, but the rate of increase was highest in the GG genotype, followed by the CG and CC genotypes. Fasting blood glucose levels increased in all genotypes; however, HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) increased significantly only in the GG genotype. HDL (high-density lipoprotein) and LDL (low-density lipoprotein) cholesterol levels significantly increased in all genotypes, whereas triglycerides did not show any significant changes in any genotype. As for the gut microbiota, the relative abundance of Feacalibacterium in the PNPLA3 rs738409 GG genotype decreased by 2% over 4 years, more than 2-fold compared to CC and GG genotypes. Blautia increased significantly in the CC group. CONCLUSION The results suggest that PNPLA3 G-allele carriers of non-fatty liver develop liver fat and fibrosis due to not only obesity and insulin resistance but also the deterioration of gut microbiota, which may require a relatively long course of time, even years.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Chikara Iino
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Takafumi Sasada
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Keisuke Furusawa
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Kenta Yoshida
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Kaori Sawada
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Tatsuya Mikami
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Shinsaku Fukuda
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Shigeyuki Nakaji
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Hirotake Sakuraba
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
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Mu C, Wang S, Wang Z, Tan J, Yin H, Wang Y, Dai Z, Ding D, Yang F. Mechanisms and therapeutic targets of mitochondria in the progression of metabolic dysfunction-associated steatotic liver disease. Ann Hepatol 2024; 30:101774. [PMID: 39701281 DOI: 10.1016/j.aohep.2024.101774] [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: 08/28/2024] [Revised: 12/13/2024] [Accepted: 12/14/2024] [Indexed: 12/21/2024]
Abstract
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) includes liver disease processes from simple fatty liver to nonalcoholic steatohepatitis, which may progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). As the incidence of HCC derived from viral hepatitis decreases, MASLD has emerged as a significant health threat, driven by lifestyle changes and rising obesity rates among patients. The pathogenesis of MASLD is complex, involving factors such as insulin resistance, gut microbiota imbalance, and genetic and epigenetic factors. In recent years, the role of mitochondrial dysfunction in MASLD has gained significant attention, involving β-oxidation imbalance, oxidative stress increase, mitophagy defects, and mitochondrial DNA (mtDNA) mutations. This article reviews the pathophysiological mechanisms of mitochondrial dysfunction in MASLD, diagnostic methods, and potential therapeutic strategies. By synthesizing current research findings, the review aims to highlight the critical role of mitochondrial dysfunction as a target for future diagnostic and therapeutic interventions. This focus could pave the way for innovative clinical strategies, ultimately improving treatment options and patient prognosis in MASLD.
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Affiliation(s)
- Chenyang Mu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China; Department of Medical Genetics, Naval Medical University, Shanghai, China
| | - Sijie Wang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China; Department of Medical Genetics, Naval Medical University, Shanghai, China
| | - Zenghan Wang
- Department of Medical Genetics, Naval Medical University, Shanghai, China
| | - Jian Tan
- Department of Medical Genetics, Naval Medical University, Shanghai, China
| | - Haozan Yin
- Department of Medical Genetics, Naval Medical University, Shanghai, China
| | - Yuefan Wang
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Zhihui Dai
- Department of Medical Genetics, Naval Medical University, Shanghai, China
| | - Dongyang Ding
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Fu Yang
- Department of Medical Genetics, Naval Medical University, Shanghai, China; Shanghai Key Laboratory of Medical Bioprotection, Shanghai, China; Key Laboratory of Biological Defense, Ministry of Education, Shanghai, China.
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Sato S, Iino C, Sasada T, Soma G, Furusawa K, Yoshida K, Sawada K, Mikami T, Fukuda S, Nakaji S, Sakuraba H. An epidemiological study on the factors including genetic polymorphism influencing ALT >30 U/L and liver fibrosis progression in metabolic dysfunction-associated steatotic liver disease among the general population. JGH Open 2024; 8:e70043. [PMID: 39713746 PMCID: PMC11659511 DOI: 10.1002/jgh3.70043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 09/29/2024] [Accepted: 10/07/2024] [Indexed: 12/24/2024]
Abstract
Background and Aim Identifying the factors contributing to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), a lifestyle-related disease, is crucial for preventing future liver-related deaths. This study aimed to epidemiologically investigate factors, including single-nucleotide polymorphisms (SNPs) associated with alanine aminotransferase (ALT) levels >30 U/L and potential risk factors for liver fibrosis, in a general population cohort of patients with MASLD. Methods Among 1059 participants in the health checkup project, 228 who were diagnosed with MASLD were analyzed. Liver fat content and stiffness were measured using FibroScan, and 13 SNPs associated with non-alcoholic fatty liver disease (NAFLD) were measured in addition to other clinical parameters. Results In the multivariate analysis, male sex, younger age, and high triglyceride levels were significant risk factors for ALT levels >30 U/L (P-value < 0.05). Furthermore, among the 13 SNPs measured, only the GG genotypes of patatin-like phospholipase domain-containing 3 gene (PNPLA3) rs738409 and rs2896019 were significant risk factors for ALT levels >30 U/L (P-value 0.004 and 0.007). The GG genotypes of PNPLA3 rs738409 and rs2896019 had higher FibroScan-aspartate aminotransferase (FAST) and APRI scores than the CC + CG and TT + TG genotypes (P-value < 0.05). In addition, multivariate analysis revealed that the GG genotypes of rs738409 and rs2896019 were significant risk factors independent of cardiovascular metabolic risk for patients with MASLD (P-value 0.038 and 0.021). Conclusion An individualized treatment approach is warranted for patients with MASLD due to the influence of various factors on its progression, including genetic factors and lifestyle diseases.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Chikara Iino
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Takafumi Sasada
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Go Soma
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Keisuke Furusawa
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Kenta Yoshida
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Kaori Sawada
- Department of Preemptive MedicineHirosaki University Graduate School of MedicineHirosakiJapan
| | - Tatsuya Mikami
- Department of Preemptive MedicineHirosaki University Graduate School of MedicineHirosakiJapan
| | - Shinsaku Fukuda
- Department of Preemptive MedicineHirosaki University Graduate School of MedicineHirosakiJapan
| | - Shigeyuki Nakaji
- Department of Preemptive MedicineHirosaki University Graduate School of MedicineHirosakiJapan
| | - Hirotake Sakuraba
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
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Korbecki J, Bosiacki M, Kupnicka P, Barczak K, Ziętek P, Chlubek D, Baranowska-Bosiacka I. Biochemistry and Diseases Related to the Interconversion of Phosphatidylcholine, Phosphatidylethanolamine, and Phosphatidylserine. Int J Mol Sci 2024; 25:10745. [PMID: 39409074 PMCID: PMC11477190 DOI: 10.3390/ijms251910745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/01/2024] [Accepted: 10/03/2024] [Indexed: 10/20/2024] Open
Abstract
Phospholipids are crucial structural components of cells. Phosphatidylcholine and phosphatidylethanolamine (both synthesized via the Kennedy pathway) and phosphatidylserine undergo interconversion. The dysregulation of this process is implicated in various diseases. This paper discusses the role of enzymes involved in the interconversion of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine, specifically phosphatidylethanolamine N-methyltransferase (PEMT), phosphatidylserine synthases (PTDSS1 and PTDSS2), and phosphatidylserine decarboxylase (PISD), with a focus on their biochemical properties. Additionally, we describe the effects of the deregulation of these enzymes and their roles in both oncological and non-oncological diseases, including nonalcoholic fatty liver disease (NAFLD), Alzheimer's disease, obesity, insulin resistance, and type II diabetes. Current knowledge on inhibitors of these enzymes as potential therapeutic agents is also reviewed, although in most cases, inhibitors are yet to be developed. The final section of this article presents a bioinformatic analysis using the GEPIA portal to explore the significance of these enzymes in cancer processes.
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Affiliation(s)
- Jan Korbecki
- Department of Anatomy and Histology, Collegium Medicum, University of Zielona Góra, Zyty 28, 65-046 Zielona Góra, Poland;
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.); (P.K.); (D.C.)
| | - Mateusz Bosiacki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.); (P.K.); (D.C.)
| | - Patrycja Kupnicka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.); (P.K.); (D.C.)
| | - Katarzyna Barczak
- Department of Conservative Dentistry and Endodontics, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland;
| | - Paweł Ziętek
- Department of Orthopaedics, Traumatology and Orthopaedic Oncology, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland;
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.); (P.K.); (D.C.)
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.); (P.K.); (D.C.)
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Lan Q, Li X, Fang J, Yu X, Wu ZE, Yang C, Jian H, Li F. Comprehensive biomarker analysis of metabolomics in different syndromes in traditional Chinese medical for prediabetes mellitus. Chin Med 2024; 19:114. [PMID: 39183283 PMCID: PMC11346218 DOI: 10.1186/s13020-024-00983-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 08/16/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Prediabetes mellitus (PreDM) is a high-risk state for developing type 2 diabetes mellitus (T2DM) and often goes undiagnosed, which is closely associated with obesity and characterized by insulin resistance that urgently needs to be treated. PURPOSE To obtain a better understanding of the biological processes associated with both "spleen-dampness" syndrome individuals and those with dysglycaemic control at its earliest stages, we performed a detailed metabolomic analysis of individuals with various early impairments in glycaemic control, the results can facilitate clinicians' decision making and benefit individuals at risk. METHODS According to the diagnostic criteria of TCM patterns and PreDM, patients were divided into 4 groups with 20 cases, patients with syndrome of spleen deficiency with dampness encumbrance and PreDM (PDMPXSK group), patients with syndrome of dampness-heat in the spleen and PreDM (PDMSRYP group), patients with syndrome of spleen deficiency with dampness encumbrance and normal blood glucose (NDMPXSK group), and patients with syndrome of dampness-heat in the spleen and normal blood glucose (NDMSRYP group). Plasma samples from patients were collected for clinical index assessment and untargeted metabolomics using liquid chromatography-mass spectrometry. RESULTS Among patients with the syndrome of spleen deficiency with dampness encumbrance (PXSK), those with PreDM (PDMPXSK group) had elevated levels of 2-hour post-load blood glucose (2-h PG), glycosylated hemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-C), and systolic blood pressure (SBP) than those in the normal blood glucose group (NDMPXSK group, P < 0.01). Among patients with the syndrome of dampness-heat in the spleen (SRYP), the levels of body mass index (BMI), fasting blood glucose (FBG), 2-h PG, HbA1c, and fasting insulin (FINS) were higher in the PreDM group (PDMSRYP group) than those in the normal blood glucose group (NDMSRYP group, P < 0.05). In both TCM syndromes, the plasma metabolomic profiles of PreDM patients were mainly discriminatory from the normal blood glucose controls of the same syndrome in the levels of lipid species, with the PXSK syndrome showing a more pronounced and broader spectrum of alterations than the SRYP syndrome. Changes associated with PreDM common to both syndromes included elevations in the levels of 27 metabolites which were mainly lipid species encompassing glycerophospholipids (GPs), diglycerides (DGs) and triglycerides (TGs), cholesterol and derivatives, and decreases in 5 metabolites consisting 1 DG, 1 TG, 2 N,N-dimethyl phosphatidylethanolamine (PE-NMe2) and iminoacetic acid. Correlation analysis identified significant positive correlations of 3α,7α,12α,25-Tetrahydroxy-5β-cholestane-24-one with more than one glycaemia-related indicators, whereas DG (20:4/20:5) and PC (20:3/14:0) were positively and PC (18:1/14:0) was inversely correlated with more than one lipid profile-related indicators. Based on the value of correlation coefficient, the top three correlative pairs were TG with PC (18:1/14:0) (r = - 0.528), TG with TG (14:0/22:4/22:5) (r = 0.521) and FINS with PE-NMe (15:0/22:4) (r = 0.52). CONCLUSION Our results revealed PreDM patients with different TCM syndromes were characterized by different clinical profiles. Common metabolite markers associated with PreDM shared by the two TCM syndromes were mainly lipid species encompassing GP, GL, cholesterol and derivatives. Our findings were in line with the current view that altered lipid metabolism is a conserved and early event of dysglycaemia. Our study also implied the possible involvement of perturbed bile acid homeostasis and dysregulated PE methylation during development of dysglycaemia.
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Affiliation(s)
- Qin Lan
- Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China
- Outpatient Department, Hongdu Traditional Chinese Medicine Hospital Affiliated to Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, China
| | - Xue Li
- Department of Gastroenterology and Hepatology, Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, and State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jianhe Fang
- Medical Ancient Literature Teaching and Research Office, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China
| | - Xinyu Yu
- Discipline of Chinese and Western Integrative Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Zhanxuan E Wu
- Department of Gastroenterology and Hepatology, Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, and State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Caiyun Yang
- Endocrinology Department II, Hongdu Traditional Chinese Medicine Hospital Affiliated to Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, China
| | - Hui Jian
- Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China.
| | - Fei Li
- Department of Gastroenterology and Hepatology, Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, and State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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Su GM, Guo QW, Shen YL, Cai JJ, Chen X, Lin J, Fang DZ. Association between PEMT rs7946 and blood pressure levels in Chinese adolescents. Blood Press Monit 2024; 29:180-187. [PMID: 38502043 DOI: 10.1097/mbp.0000000000000703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2024]
Abstract
OBJECTIVES This study was to explore blood pressure levels in Chinese adolescents with different genotypes of phosphatidylethanolamine N-methyltransferase (PEMT) gene ( PEMT ) rs7946, as well as effects of dietary intake on blood pressure levels with different genders and different genotypes of PEMT rs7946. METHODS PEMT rs7946 genotypes were identified by PCR-restriction fragment length polymorphism and verified by DNA sequencing. Blood pressure was measured using a standard mercury sphygmomanometer. Dietary intakes were analyzed based on a 3-day diet diary, and dietary components were calculated using computer software. RESULTS A total of 721 high school students (314 males and 407 females) at the age of 16.86 ± 0.59 years were included. The A allele carriers of PEMT rs7946 had increased levels of SBP, DBP, mean arterial pressure (MAP) and pulse pressure (PP) than the GG homozygotes in the female subjects. There were significant interactions between PEMT rs7946 and gender on SBP and MAP levels, regardless of whether an unadjusted or adjusted model was used. When dietary intake was taken into account, fat intake was positively associated with SBP and PP in the male GG homozygotes, while protein intake was positively associated with PP in the female A allele carriers of PEMT rs7946. CONCLUSION This study suggests that PEMT rs7946 is significantly associated with blood pressure levels in human being. There might be interactions among PEMT rs7946, gender, and dietary intake on blood pressure levels in the adolescent population.
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Affiliation(s)
- Guo Ming Su
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
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He Q, Wei Y, Zhu H, Song Y, Chen P, Wang B, Shi H, Qin P. The Mediating Effect of the Choline-to-Betaine Ratio on the Association Between PEMT rs7946 and Digestive System Cancer: A Nested Case-Control Study in a Chinese Population. Curr Dev Nutr 2024; 8:102075. [PMID: 38351975 PMCID: PMC10862518 DOI: 10.1016/j.cdnut.2024.102075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 12/23/2023] [Accepted: 01/02/2024] [Indexed: 02/16/2024] Open
Abstract
Background The enzyme phosphatidylethanolamine N-methyltransferase (PEMT) is responsible for synthesizing phosphatidylcholine by methylating phosphatidylethanolamine. We hypothesized that a polymorphism of the PEMT gene, rs7946, is involved in carcinogenesis. Objectives We aimed to investigate the relationship between PEMT rs7946 and digestive system cancer and examine possible effect modifiers and mediators. Methods We conducted a nested, case-control study within the China H-type Hypertension Registry Study, including 751 cases and 1:1 matched controls. To assess the association of PEMT rs7946 and digestive system cancer, we estimated odds ratios with 95% confidence intervals (CIs) using conditional logistic regression. We used the bootstrap test to examine the potential mediating effects of related metabolites. Results Our results revealed that wild-type homozygous CC genotype carriers of PEMT rs7946 had a significantly increased risk [odds ratio (OR): 1.31; 95% CI: 1.04, 1.66; P = 0.023] compared with the TT/CT combined genotypes. The effect was found to be more pronounced in individuals with a lower choline-to-betaine ratio (<0.412, P-interaction = 0.021). Furthermore, the mediation analysis indicated that the choline-to-betaine ratio played a significant role in mediating 13.55% of the association between PEMT rs7946 and digestive system cancer (P = 0.018). Conclusions Our study suggested that PEMT rs7946 may affect risk of digestive system cancer through direct and indirect pathways, and the choline-to-betaine ratio may partially mediate the indirect effect.This trial was registered at Chinese Clinical Trial Registry as ChiCTR1800017274.
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Affiliation(s)
- Qiangqiang He
- Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
- Shenzhen Evergreen Medical Institute, Shenzhen, China
| | - Yaping Wei
- College of Public Health, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Hehao Zhu
- School of Science, China Pharmaceutical University, Nanjing, China
| | - Yun Song
- Shenzhen Evergreen Medical Institute, Shenzhen, China
| | - Ping Chen
- College of Pharmacy, Jinan University, Guangzhou, China
- Inspection and Testing Center, Key Laboratory of Cancer FSMP for State Market Regulation, Shenzhen, China
| | - Binyan Wang
- Shenzhen Evergreen Medical Institute, Shenzhen, China
- Institute of Biomedicine, Anhui Medical University, Hefei, China
| | - Hanping Shi
- Department of Gastrointestinal Surgery/Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Haidian District, Beijing, China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Haidian District, Beijing, China
- Key Laboratory of Cancer FSMP for State Market Regulation, Haidian District, Beijing, China
| | - Peiwu Qin
- Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, China
- Institute of Biopharmaceutics and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, China
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Chai C, Chen L, Deng MG, Liang Y, Liu F, Nie JQ. Dietary choline intake and non-alcoholic fatty liver disease (NAFLD) in U.S. adults: National Health and Nutrition Examination Survey (NHANES) 2017-2018. Eur J Clin Nutr 2023; 77:1160-1166. [PMID: 37634048 DOI: 10.1038/s41430-023-01336-1] [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: 07/28/2022] [Revised: 08/15/2023] [Accepted: 08/18/2023] [Indexed: 08/28/2023]
Abstract
BACKGROUND Whether there is an association between dietary choline intake and non-alcoholic fatty liver disease (NAFLD) in American adults remains unclear. METHODS Data came from the National Health and Nutrition Examination Survey 2017-2018. Choline intake was defined by the mean amounts of two 24 h dietary recalls, and choline intake was categorized into three groups according to the quartiles: inadequate ( P75). Hepatic steatosis was assessed with FibroScan®, in which VCTE was employed with controlled attenuation to derive the controlled attenuation parameter (CAP), and NAFLD was defined as a CAP score ≥285 dB/m. Multivariable linear regression was performed to assess the linear relationship between choline intake and CAP. Multivariable logistics regression models were conducted to assess the association between choline intake status and NAFLD in the final sample and subgroup analysis was then performed in men and women. RESULTS The amount of dietary choline was inversely associated with CAP score (β = -0.262, 95% CI: -0.280, -0.245). Compared to inadequate choline intake, optimal choline intake was related to a lower risk of NAFLD (OR: 0.705, 95% CI: 0.704-0.706) in the final sample. Subgroup analysis by gender revealed that the highest choline intake status was associated with a lower risk of NAFLD both in females (OR: 0.764, 95% CI: 0.762-0.766), and males (OR: 0.955, 95% CI: 0.953-0.958) when compared to the lowest choline intake. CONCLUSIONS With the latest NHANES data, we found that higher dietary choline was associated with a lower risk of NAFLD in American adults, and such a relationship exists in both females and males.
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Affiliation(s)
- Chen Chai
- Emergency Center, Hubei Clinical Research Center for Emergency and Resuscitation, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
| | - Lin Chen
- Emergency Department, Xiantao First People's Hospital Affiliated to Changjiang University, Xiantao, China
| | - Ming-Gang Deng
- School of Public Health, Wuhan University, Wuhan, 430071, China
| | - Yuehui Liang
- School of Public Health, Wuhan University, Wuhan, 430071, China
| | - Fang Liu
- School of Public Health, Wuhan University, Wuhan, 430071, China
| | - Jia-Qi Nie
- School of Public Health, Wuhan University, Wuhan, 430071, China
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Aggeletopoulou I, Kalafateli M, Tsounis EP, Triantos C. Epigenetic Regulation in Lean Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2023; 24:12864. [PMID: 37629043 PMCID: PMC10454848 DOI: 10.3390/ijms241612864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most prominent cause of chronic liver disease worldwide, is a rapidly growing epidemic. It consists of a wide range of liver diseases, from steatosis to nonalcoholic steatohepatitis, and predisposes patients to liver fibrosis, cirrhosis, and even hepatocellular carcinoma. NAFLD is strongly correlated with obesity; however, it has been extensively reported among lean/nonobese individuals in recent years. Although lean patients demonstrate a lower prevalence of diabetes mellitus, central obesity, dyslipidemia, hypertension, and metabolic syndrome, a percentage of these patients may develop steatohepatitis, advanced liver fibrosis, and cardiovascular disease, and have increased all-cause mortality. The pathophysiological mechanisms of lean NAFLD remain vague. Studies have reported that lean NAFLD demonstrates a close association with environmental factors, genetic predisposition, and epigenetic modifications. In this review, we aim to discuss and summarize the epigenetic mechanisms involved in lean NAFLD and to introduce the interaction between epigenetic patterns and genetic or non genetic factors. Several epigenetic mechanisms have been implicated in the regulation of lean NAFLD. These include DNA methylation, histone modifications, and noncoding-RNA-mediated gene regulation. Epigenetics is an area of special interest in the setting of lean NAFLD as it could provide new insights into the therapeutic options and noninvasive biomarkers that target this under-recognized and challenging disorder.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.)
| | - Maria Kalafateli
- Department of Gastroenterology, General Hospital of Patras, 26332 Patras, Greece;
| | - Efthymios P. Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.)
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.)
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10
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Wu CH, Chang TY, Chen YC, Huang RFS. PEMT rs7946 Polymorphism and Sex Modify the Effect of Adequate Dietary Choline Intake on the Risk of Hepatic Steatosis in Older Patients with Metabolic Disorders. Nutrients 2023; 15:3211. [PMID: 37513629 PMCID: PMC10383596 DOI: 10.3390/nu15143211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/10/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
In humans, PEMT rs7946 polymorphism exerts sex-specific effects on choline requirement and hepatic steatosis (HS) risk. Few studies have explored the interaction effect of the PEMT rs7946 polymorphism and sex on the effect of adequate choline intake on HS risk. In this cross-sectional study, we investigated the association between PEMT polymorphism and adequate choline intake on HS risk. We enrolled 250 older patients with metabolic disorders with (n = 152) or without (n = 98; control) ultrasonically diagnosed HS. An elevated PEMT rs7946 A allele level was associated with a lower HS risk and body mass index in both men and women. Dietary choline intake-assessed using a semiquantitative food frequency questionnaire-was associated with reduced obesity in men only (p for trend < 0.05). ROC curve analysis revealed that the cutoff value of energy-adjusted choline intake for HS diagnosis was 448 mg/day in women (AUC: 0.62; 95% CI: 0.57-0.77) and 424 mg/day in men (AUC: 0.63, 95% CI: 0.57-0.76). In women, GG genotype and high choline intake (>448 mg/day) were associated with a 79% reduction in HS risk (adjusted OR: 0.21; 95% CI: 0.05-0.82); notably, GA or AA genotype was associated with a reduced HS risk regardless of choline intake (p < 0.05). In men, GG genotype and high choline intake (>424 mg/day) were associated with a 3.7-fold increase in HS risk (OR: 3.7; 95% CI: 1.19-11.9). Further adjustments for a high-density lipoprotein level and body mass index mitigated the effect of choline intake on HS risk. Current dietary choline intake may be inadequate for minimizing HS risk in postmenopausal Taiwanese women carrying the PEMT rs7946 GG genotype. Older men consuming more than the recommended amount of choline may have an increased risk of nonalcoholic fatty liver disease; this risk is mediated by a high-density lipoprotein level and obesity.
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Affiliation(s)
- Chien-Hsien Wu
- Ph.D. Program in Nutrition and Food Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan
- Department of Gastroenterology and Hepatology, Taipei Hospital, Ministry of Health and Welfare, New Taipei City 242033, Taiwan
| | - Ting-Yu Chang
- Department of Nutritional Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan
| | - Yen-Chu Chen
- Department of Nutritional Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan
| | - Rwei-Fen S Huang
- Ph.D. Program in Nutrition and Food Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan
- Department of Nutritional Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan
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11
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DiStefano JK. The Role of Choline, Soy Isoflavones, and Probiotics as Adjuvant Treatments in the Prevention and Management of NAFLD in Postmenopausal Women. Nutrients 2023; 15:2670. [PMID: 37375574 DOI: 10.3390/nu15122670] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a prevalent condition among postmenopausal women that can lead to severe liver dysfunction and increased mortality. In recent years, research has focused on identifying potential lifestyle dietary interventions that may prevent or treat NAFLD in this population. Due to the complex and multifactorial nature of NAFLD in postmenopausal women, the disease can present as different subtypes, with varying levels of clinical presentation and variable treatment responses. By recognizing the significant heterogeneity of NAFLD in postmenopausal women, it may be possible to identify specific subsets of individuals who may benefit from targeted nutritional interventions. The purpose of this review was to examine the current evidence supporting the role of three specific nutritional factors-choline, soy isoflavones, and probiotics-as potential nutritional adjuvants in the prevention and treatment of NAFLD in postmenopausal women. There is promising evidence supporting the potential benefits of these nutritional factors for NAFLD prevention and treatment, particularly in postmenopausal women, and further research is warranted to confirm their effectiveness in alleviating hepatic steatosis in this population.
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Affiliation(s)
- Johanna K DiStefano
- Diabetes and Metabolic Disease Research Unit, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
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12
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Sulaiman SA, Dorairaj V, Adrus MNH. Genetic Polymorphisms and Diversity in Nonalcoholic Fatty Liver Disease (NAFLD): A Mini Review. Biomedicines 2022; 11:106. [PMID: 36672614 PMCID: PMC9855725 DOI: 10.3390/biomedicines11010106] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/13/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease with a wide spectrum of liver conditions ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The prevalence of NAFLD varies across populations, and different ethnicities have specific risks for the disease. NAFLD is a multi-factorial disease where the genetics, metabolic, and environmental factors interplay and modulate the disease's development and progression. Several genetic polymorphisms have been identified and are associated with the disease risk. This mini-review discussed the NAFLD's genetic polymorphisms and focusing on the differences in the findings between the populations (diversity), including of those reports that did not show any significant association. The challenges of genetic diversity are also summarized. Understanding the genetic contribution of NAFLD will allow for better diagnosis and management explicitly tailored for the various populations.
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Affiliation(s)
- Siti Aishah Sulaiman
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Jalan Yaa’cob Latiff, Cheras, Kuala Lumpur 56000, Malaysia; (V.D.); (M.N.H.A.)
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13
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Xu R, Pan J, Zhou W, Ji G, Dang Y. Recent advances in lean NAFLD. Biomed Pharmacother 2022; 153:113331. [PMID: 35779422 DOI: 10.1016/j.biopha.2022.113331] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/20/2022] [Accepted: 06/22/2022] [Indexed: 02/09/2023] Open
Abstract
As the predominant type of chronic liver disease, the growing prevalence of nonalcoholic fatty liver disease (NAFLD) has become a concern worldwide. Although obesity plays the most pivotal role in NAFLD, approximately 10-20% of individuals with NAFLD who are not overweight or obese (BMI < 25 kg/m2, or BMI < 23 kg/m2 in Asians) have "lean NAFLD." Lean individuals with NAFLD have a lower prevalence of diabetes, hypertension, hypertriglyceridemia, central obesity, and metabolic syndrome than nonlean individuals with NAFLD, but higher fibrosis scores and rates of cardiovascular morbidity and all-cause mortality in advanced stages. The pathophysiological mechanisms of lean NAFLD remain poorly understood. Studies have shown that lean NAFLD is more correlated with factors such as environmental, genetic susceptibility, and epigenetic regulation. This review will examine the way in which the research progress and characteristic of lean NAFLD, and explore the function of epigenetic modification to provide the basis for the clinical treatment and diagnosis of lean NAFLD.
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Affiliation(s)
- Ruohui Xu
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Jiashu Pan
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Department of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Wenjun Zhou
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Yanqi Dang
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
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14
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Piras IS, Raju A, Don J, Schork NJ, Gerhard GS, DiStefano JK. Hepatic PEMT Expression Decreases with Increasing NAFLD Severity. Int J Mol Sci 2022; 23:ijms23169296. [PMID: 36012560 PMCID: PMC9409182 DOI: 10.3390/ijms23169296] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/12/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
Choline deficiency causes hepatic fat accumulation, and is associated with a higher risk of nonalcoholic fatty liver disease (NAFLD) and more advanced NAFLD-related hepatic fibrosis. Reduced expression of hepatic phosphatidylethanolamine N-methyltransferase (PEMT), which catalyzes the production of phosphatidylcholine, causes steatosis, inflammation, and fibrosis in mice. In humans, common PEMT variants impair phosphatidylcholine synthesis, and are associated with NAFLD risk. We investigated hepatic PEMT expression in a large cohort of patients representing the spectrum of NAFLD, and examined the relationship between PEMT genetic variants and gene expression. Hepatic PEMT expression was reduced in NAFLD patients with inflammation and fibrosis (i.e., nonalcoholic steatohepatitis or NASH) compared to participants with normal liver histology (β = −1.497; p = 0.005). PEMT levels also declined with increasing severity of fibrosis with cirrhosis < incomplete cirrhosis < bridging fibrosis (β = −1.185; p = 0.011). Hepatic PEMT expression was reduced in postmenopausal women with NASH compared to those with normal liver histology (β = −3.698; p = 0.030). We detected a suggestive association between rs7946 and hepatic fibrosis (p = 0.083). Although none of the tested variants were associated with hepatic PEMT expression, computational fine mapping analysis indicated that rs4646385 may impact PEMT levels in the liver. Hepatic PEMT expression decreases with increasing severity of NAFLD in obese individuals and postmenopausal women, and may contribute to disease pathogenesis in a subset of NASH patients.
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Affiliation(s)
- Ignazio S. Piras
- Translational Genomics Research Institute, Phoenix, AZ 85004, USA
| | - Anish Raju
- Translational Genomics Research Institute, Phoenix, AZ 85004, USA
| | - Janith Don
- Translational Genomics Research Institute, Phoenix, AZ 85004, USA
| | | | - Glenn S. Gerhard
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19122, USA
| | - Johanna K. DiStefano
- Translational Genomics Research Institute, Phoenix, AZ 85004, USA
- Correspondence:
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15
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Chew NW, Chong B, Ng CH, Kong G, Chin YH, Xiao W, Lee M, Dan YY, Muthiah MD, Foo R. The genetic interactions between non-alcoholic fatty liver disease and cardiovascular diseases. Front Genet 2022; 13:971484. [PMID: 36035124 PMCID: PMC9399730 DOI: 10.3389/fgene.2022.971484] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 07/19/2022] [Indexed: 12/03/2022] Open
Abstract
The ongoing debate on whether non-alcoholic fatty liver disease (NAFLD) is an active contributor or an innocent bystander in the development of cardiovascular disease (CVD) has sparked interests in understanding the common mediators between the two biologically distinct entities. This comprehensive review identifies and curates genetic studies of NAFLD overlapping with CVD, and describes the colinear as well as opposing correlations between genetic associations for the two diseases. Here, CVD described in relation to NAFLD are coronary artery disease, cardiomyopathy and atrial fibrillation. Unique findings of this review included certain NAFLD susceptibility genes that possessed cardioprotective properties. Moreover, the complex interactions of genetic and environmental risk factors shed light on the disparity in genetic influence on NAFLD and its incident CVD. This serves to unravel NAFLD-mediated pathways in order to reduce CVD events, and helps identify targeted treatment strategies, develop polygenic risk scores to improve risk prediction and personalise disease prevention.
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Affiliation(s)
- Nicholas W.S. Chew
- Department of Cardiology, National University Heart Centre, Singapore, Singapore
- *Correspondence: Nicholas W.S. Chew, ; Roger Foo,
| | - Bryan Chong
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Gwyneth Kong
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Yip Han Chin
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Wang Xiao
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Disease Translational Research Programme, National University Health Systems, Singapore, Singapore
- Genome Institute of Singapore, Agency of Science Technology and Research, Bipolis way, Singapore
| | - Mick Lee
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Disease Translational Research Programme, National University Health Systems, Singapore, Singapore
- Genome Institute of Singapore, Agency of Science Technology and Research, Bipolis way, Singapore
| | - Yock Young Dan
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Mark D. Muthiah
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Roger Foo
- Department of Cardiology, National University Heart Centre, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Disease Translational Research Programme, National University Health Systems, Singapore, Singapore
- Genome Institute of Singapore, Agency of Science Technology and Research, Bipolis way, Singapore
- *Correspondence: Nicholas W.S. Chew, ; Roger Foo,
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16
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Yu J, Xie X, Zhang Y, Jiang F, Wu C. Construction and Analysis of a Joint Diagnosis Model of Random Forest and Artificial Neural Network for Obesity. Front Med (Lausanne) 2022; 9:906001. [PMID: 35677823 PMCID: PMC9168076 DOI: 10.3389/fmed.2022.906001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 04/19/2022] [Indexed: 12/28/2022] Open
Abstract
Obesity is a significant global health concern since it is connected to a higher risk of several chronic diseases. As a consequence, obesity may be described as a condition that reduces human life expectancy and significantly impacts life quality. Because traditional obesity diagnosis procedures have several flaws, it is vital to design new diagnostic models to enhance current methods. More obesity-related markers have been discovered in recent years as a result of improvements and enhancements in gene sequencing technology. Using current gene expression profiles from the Gene Expression Omnibus (GEO) collection, we identified differentially expressed genes (DEGs) associated with obesity and found 12 important genes (CRLS1, ANG, ALPK3, ADSSL1, ABCC1, HLF, AZGP1, TSC22D3, F2R, FXN, PEMT, and SPTAN1) using a random forest classifier. ALPK3, HLF, FXN, and SPTAN1 are the only genes that have never been linked to obesity. We also used an artificial neural network to build a novel obesity diagnosis model and tested its diagnostic effectiveness using public datasets.
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Affiliation(s)
- Jian Yu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoyan Xie
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yun Zhang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Jiang
- Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- *Correspondence: Feng Jiang
| | - Chuyan Wu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Chuyan Wu
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17
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Wang H, Wu Y, Tang W. Methionine cycle in nonalcoholic fatty liver disease and its potential applications. Biochem Pharmacol 2022; 200:115033. [PMID: 35395242 DOI: 10.1016/j.bcp.2022.115033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/31/2022] [Accepted: 03/31/2022] [Indexed: 11/25/2022]
Abstract
As a chronic metabolic disease affecting epidemic proportions worldwide, the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) is not clear yet. There is also a lack of precise biomarkers and specific medicine for the diagnosis and treatment of NAFLD. Methionine metabolic cycle, which is critical for the maintaining of cellular methylation and redox state, is involved in the pathophysiology of NAFLD. However, the molecular basis and mechanism of methionine metabolism in NAFLD are not completely understood. Here, we mainly focus on specific enzymes that participates in methionine cycle, to reveal their interconnections with NAFLD, in order to recognize the pathogenesis of NAFLD from a new angle and at the same time, explore the clinical characteristics and therapeutic strategies.
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Affiliation(s)
- Haoyu Wang
- University of Chinese Academy of Sciences, Beijing, 100049, PR China; Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China
| | - Yanwei Wu
- Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China
| | - Wei Tang
- University of Chinese Academy of Sciences, Beijing, 100049, PR China; Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
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18
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Ishiwata-Kimata Y, Le QG, Kimata Y. Induction and Aggravation of the Endoplasmic-Reticulum Stress by Membrane-Lipid Metabolic Intermediate Phosphatidyl- N-Monomethylethanolamine. Front Cell Dev Biol 2022; 9:743018. [PMID: 35071223 PMCID: PMC8770322 DOI: 10.3389/fcell.2021.743018] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 12/14/2021] [Indexed: 11/13/2022] Open
Abstract
Phosphatidylcholine (PC) is produced via two distinct pathways in both hepatocytes and yeast, Saccharomyces cerevisiae. One of these pathways involves the sequential methylation of phosphatidylethanolamine (PE). In yeast cells, the methyltransferase, Cho2, converts PE to phosphatidylmonomethylethanolamine (PMME), which is further modified to PC by another methyltransferase, Opi3. On the other hand, free choline is utilized for PC production via the Kennedy pathway. The blockage of PC production is well known to cause endoplasmic reticulum (ER) stress and activate the ER-stress sensor, Ire1, to induce unfolded protein response (UPR). Here, we demonstrate that even when free choline is sufficiently supplied, the opi3Δ mutation, but not the cho2 Δ mutation, induces the UPR. The UPR was also found to be induced by CHO2 overexpression. Further, monomethylethanolamine, which is converted to PMME probably through the Kennedy pathway, caused or potentiated ER stress in both mammalian and yeast cells. We thus deduce that PMME per se is an ER-stressing molecule. Interestingly, spontaneously accumulated PMME seemed to aggravate ER stress in yeast cells. Collectively, our findings demonstrate the multiple detrimental effects of the low-abundance phospholipid species, PMME.
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Affiliation(s)
- Yuki Ishiwata-Kimata
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Japan
| | - Quynh Giang Le
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Japan
| | - Yukio Kimata
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Japan
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Martínez-Montoro JI, Cornejo-Pareja I, Gómez-Pérez AM, Tinahones FJ. Impact of Genetic Polymorphism on Response to Therapy in Non-Alcoholic Fatty Liver Disease. Nutrients 2021; 13:4077. [PMID: 34836332 PMCID: PMC8625016 DOI: 10.3390/nu13114077] [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] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 12/13/2022] Open
Abstract
In the last decades, the global prevalence of non-alcoholic fatty liver disease (NAFLD) has reached pandemic proportions with derived major health and socioeconomic consequences; this tendency is expected to be further aggravated in the coming years. Obesity, insulin resistance/type 2 diabetes mellitus, sedentary lifestyle, increased caloric intake and genetic predisposition constitute the main risk factors associated with the development and progression of the disease. Importantly, the interaction between the inherited genetic background and some unhealthy dietary patterns has been postulated to have an essential role in the pathogenesis of NAFLD. Weight loss through lifestyle modifications is considered the cornerstone of the treatment for NAFLD and the inter-individual variability in the response to some dietary approaches may be conditioned by the presence of different single nucleotide polymorphisms. In this review, we summarize the current evidence on the influence of the association between genetic susceptibility and dietary habits in NAFLD pathophysiology, as well as the role of gene polymorphism in the response to lifestyle interventions and the potential interaction between nutritional genomics and other emerging therapies for NAFLD, such as bariatric surgery and several pharmacologic agents.
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Affiliation(s)
- José Ignacio Martínez-Montoro
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.I.M.-M.); (F.J.T.)
- Faculty of Medicine, University of Málaga, 29071 Málaga, Spain
| | - Isabel Cornejo-Pareja
- Instituto de Investigación Biomédica de Málaga (IBIMA), Virgen de la Victoria University Hospital, 29010 Málaga, Spain
- Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ana María Gómez-Pérez
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.I.M.-M.); (F.J.T.)
| | - Francisco J. Tinahones
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.I.M.-M.); (F.J.T.)
- Faculty of Medicine, University of Málaga, 29071 Málaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Virgen de la Victoria University Hospital, 29010 Málaga, Spain
- Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain
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20
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Chen LJ, Lin XX, Guo J, Xu Y, Zhang SX, Chen D, Zhao Q, Xiao J, Lian GH, Peng SF, Guo D, Yang H, Shu Y, Zhou HH, Zhang W, Chen Y. Lrp6 Genotype affects Individual Susceptibility to Nonalcoholic Fatty Liver Disease and Silibinin Therapeutic Response via Wnt/β-catenin-Cyp2e1 Signaling. Int J Biol Sci 2021; 17:3936-3953. [PMID: 34671210 PMCID: PMC8495406 DOI: 10.7150/ijbs.63732] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 09/10/2021] [Indexed: 11/30/2022] Open
Abstract
Background: Nonalcoholic fatty liver disease (NAFLD) is a serious threat to human health worldwide, with a high genetic susceptibility. Rs2302685, a functional germline variant of LRP6, has been recently found to associate with NAFLD risk. This study was aimed to clarify the underlying mechanism associated with rs2302685 risk and its impact on pharmacotherapy in treatment of NAFLD. Methods: Venous blood samples were collected from NAFLD and non-NAFLD patients for SNP genotyping by using mass spectrometry. The Lrp6-floxdel mouse (Lrp6(+/-)) was generated to model the partial function associated with human rs2302685. The liver injury and therapeutic effects of silibinin were compared between Lrp6(+/-) and Lrp6(+/+) mice received a methionine-choline deficient (MCD) diet or normal diet. The effect of Lrp6 functional alteration on Wnt/β-catenin-Cyp2e1 signaling activities was evaluated by a series of cellular and molecular assays. Results: The T allele of LRP6 rs2302685 was confirmed to associate with a higher risk of NAFLD in human subjects. The carriers of rs2302685 had reduced level of AST and ALT as compared with the noncarriers. The Lrp6(+/-) mice exhibited a less severe liver injury induced by MCD but a reduced response to the treatment of silibinin in comparison to the Lrp6(+/+) mice, suggesting Lrp6 as a target of silibinin. Wnt/β-catenin-Cyp2e1 signaling together with ROS generation could be exacerbated by the overexpression of Lrp6, while decreased in response to Lrp6 siRNA or silibinin treatment under NAFLD modeling. Conclusions: The Lrp6 function affects individual susceptibility to NAFLD and the therapeutic effect of silibinin through the Wnt/β-catenin-Cyp2e1 signaling pathway. The present work has provided an underlying mechanism for human individual susceptibility to NAFLD associated with Lrp6 polymorphisms as well as a rationale for the effective use of silibinin in NAFLD patients.
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Affiliation(s)
- Li-Jie Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, P. R. China.,National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, P.R. China
| | - Xiu-Xian Lin
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, P. R. China.,National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, P.R. China
| | - Jing Guo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, P. R. China.,National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, P.R. China
| | - Ying Xu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, P. R. China.,National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, P.R. China
| | - Song-Xia Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, P. R. China.,National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, P.R. China
| | - Dan Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, P. R. China.,National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, P.R. China
| | - Qing Zhao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, P. R. China.,National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, P.R. China
| | - Jian Xiao
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Guang-Hui Lian
- Department of gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Shi-Fang Peng
- Department of Hepatology and Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Dong Guo
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201. USA
| | - Hong Yang
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201. USA
| | - Yan Shu
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201. USA
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, P. R. China.,National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, P.R. China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, P. R. China.,National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, P.R. China
| | - Yao Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, P. R. China.,National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, P.R. China
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21
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Choudhary NS, Duseja A. Genetic and epigenetic disease modifiers: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Transl Gastroenterol Hepatol 2021; 6:2. [PMID: 33409397 DOI: 10.21037/tgh.2019.09.06] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 09/04/2019] [Indexed: 12/12/2022] Open
Abstract
Inter-individual and inter-ethnic differences and difference in the severity and progression of liver disease among patients with non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) suggests the involvement of genetic and epigenetic factors in their pathogenesis. This article reviews the genetic and epigenetic modifiers in patients with NAFLD and ALD. Evidence regarding the genetic and epigenetic disease modifiers of NAFLD and ALD was reviewed by searching the available literature. Both genome wide association studies (GWAS) and candidate gene studies pertaining to the pathogenesis in both diseases were included. Clinical implications of the available information are also discussed. Several studies have shown association of both NAFLD and ALD with I148M PNPLA3 variant. In addition to the higher prevalence of hepatic steatosis, the I148M PNPLA3 variant is also associated with severity of liver disease and risk of hepatocellular carcinoma (HCC). TM6SF2 is the other genetic variant shown to be significantly associated with hepatic steatosis and cirrhosis in patients with NAFLD and ALD. The Membrane bound O-acyltransferase domain-containing 7 (MBOAT7) genetic variant is also associated with both NAFLD and ALD. In addition to these mutations, several variants related to the genes involved in glucose metabolism, insulin resistance, lipid metabolism, oxidative stress, inflammatory pathways, fibrosis have also been shown to be the disease modifiers in patients with NAFLD and ALD. Epigenetics involving several micro RNAs and DNA methylation could also modify the disease course in NAFLD and ALD. In conclusion the available literature suggests that genetics and epigenetics are involved in the pathogenesis of NAFLD and ALD which may affect the disease prevalence, severity and response to treatment in these patients.
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Affiliation(s)
- Narendra Singh Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, The Medicity, Gurgaon, Delhi (NCR), India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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22
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Sall T, Shcherbakova E, Sitkin S, Vakhitov T, Bakulin I, Demyanova E. Molecular mechanisms of non-alcoholic fatty liver disease development. PROFILAKTICHESKAYA MEDITSINA 2021; 24:120. [DOI: 10.17116/profmed202124041120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
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23
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Wang J, Zheng J, Ren X, Wang S, Wang G, Hu B, Yang H, Liu H. Integrative analysis of hepatic metabolomic and transcriptomic data reveals potential mechanism of nonalcoholic steatohepatitis in high-fat diet-fed mice. J Diabetes 2020; 13:390-401. [PMID: 33022884 DOI: 10.1111/1753-0407.13120] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 09/30/2020] [Accepted: 10/04/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Due to the complex pathogenesis, the molecular mechanism of nonalcoholic steatohepatitis (NASH) remains unclear. In this study, we aimed to reveal the comprehensive metabolic and signaling pathways in the occurrence of NASH. METHODS C57BL/6 mice were treated with high-fat diet for 4 months to mimic the NASH phenotype. After the treatment, the physiochemical parameters were evaluated, and the liver tissues were prepared for untargeted metabolomic analysis with ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Then, three relevant Gene Expression Omnibus (GEO) datasets were selected for integrative analysis of differentiated messenger RNA and metabolites. RESULTS The levels of phosphatidylethanolamine (PE) (16:1(9Z)/20:4(5Z,8Z,11Z,14Z)), oleic acid, and sphingomyelin (SM) (d18:0/12:0) were significantly increased, and the content of adenosine was severely reduced in NASH mice. The integrated interpretation of transcriptomic and metabolomic data indicated that the glycerophospholipid metabolism and necroptosis signaling were evidently affected in the development of NASH. The high level of SM (d18:0/12:0) may be related to the expression of acid sphingomyelinase (ASMase), and the elevated arachidonic acid was coordinated with the upregulation of cytosol phospholipase A2 (cPLA2) in the necroptosis pathway. CONCLUSIONS In summary, the inflammatory response, necroptosis, and glycerophospholipid may serve as potential targets for mechanistic exploration and clinical practice in the treatment of NASH.
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Affiliation(s)
- Jinhua Wang
- Jiangsu Province Blood Center, Nanjing, China
| | - Junping Zheng
- College of Life Sciences, Wuchang University of Technology, Wuhan, China
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China
| | - Xianghui Ren
- North China Institute of Computer Technology, Beijing, China
| | - Shaojiang Wang
- North China Institute of Computer Technology, Beijing, China
- Knowledge Engineering Lab, Department of Computer Science and Technology, Tsinghua University, Beijing, China
| | - Guizhou Wang
- School of Economics and Management, University of Chinese Academy of Sciences, Beijing, China
| | - Baifei Hu
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China
| | - Huabing Yang
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China
| | - Hongtao Liu
- College of Life Sciences, Wuchang University of Technology, Wuhan, China
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China
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24
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Radziejewska A, Muzsik A, Milagro FI, Martínez JA, Chmurzynska A. One-Carbon Metabolism and Nonalcoholic Fatty Liver Disease: The Crosstalk between Nutrients, Microbiota, and Genetics. Lifestyle Genom 2019; 13:53-63. [PMID: 31846961 DOI: 10.1159/000504602] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 10/30/2019] [Indexed: 01/02/2023] Open
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Its etiology includes nutritional, genetic, and lifestyle factors. Several mechanisms may link one-carbon metabolism - the associated metabolic pathways of folate, methionine, and choline - to the onset of NAFLD. In this review, we attempted to assess how choline, folate, methionine, and betaine affect NAFLD development, mainly through their role in the secretion of very low-density lipoproteins (VLDL) from the liver. We also reviewed recent articles that have described the relation between microbiota metabolism and NAFLD progression. Moreover, we describe the effect of single-nucleotide polymorphisms (SNP) in genes related to one-carbon metabolism and disease prevalence. We additionally seek SNP identified by genome-wide associations that may increase the risk of this disease. Even though the evidence available is not entirely consistent, it seems that the concentrations of choline, methionine, folate, and betaine may affect the progression of NAFLD. Since there is no effective therapy for NAFLD, further investigations into the link between nutrition, gut microbiota, genetic factors, and NAFLD are still necessary, with a particular emphasis on methyl donors.
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Affiliation(s)
- Anna Radziejewska
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland
| | - Agata Muzsik
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland
| | - Fermín I Milagro
- Department of Nutrition, Food Science and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.,Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - J Alfredo Martínez
- Department of Nutrition, Food Science and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.,Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Agata Chmurzynska
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland,
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25
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Mazidi M, Katsiki N, Mikhailidis DP, Banach M. Adiposity May Moderate the Link Between Choline Intake and Non-alcoholic Fatty Liver Disease. J Am Coll Nutr 2019; 38:633-639. [PMID: 31305223 DOI: 10.1080/07315724.2018.1507011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Background: In animal models, histological and biochemical changes are observed in response to choline deficiency. It is unclear whether dietary choline is linked to non-alcoholic fatty liver disease (NAFLD). Objective: We examined the link among liver tests, fatty liver index (FLI), and choline consumption. Furthermore, we evaluated the impact of adiposity on this association. Method: The National Health and Nutrition Examination Survey (NHANES) was used to obtain data on choline intake and liver function biomarkers. Masked variance and weighting methodology were performed to account for the complex NHANES data. Results: Of the 20,643 participants, 46.8% were men and 45.6% had NAFLD (defined as United States FLI ≥30). In a fully adjusted model (for demographic, dietary, and clinical factors), a significant negative association was found between FLI and choline consumption (β = -0.206, p < 0.001). Participants in the highest quartile (Q4) of choline intake had a 14% lower risk of NAFLD compared with those in the first quartile (Q1). This link was stronger for postmenopausal women; women in Q4 had a 26% lower risk of NAFLD compared with those in Q1. Body mass index (BMI) strongly moderated the link between FLI and choline intake. For example, when choline consumption increased from low (272 mg/d) to high (356 mg/d), FLI decreased from 79.3 to 74.1 in the low BMI category (mean BMI = 22.1 kg/m2) and from 32.1 to 20.6 in the high BMI category (mean BMI =35.9 kg/m2). Conclusions: Our results suggest the presence of a reverse significant association between choline intake and risk of NAFLD. Furthermore, BMI was shown to mediate this relationship since changes in FLI, in relation to choline consumption, were more pronounced in participants with a higher BMI.
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Affiliation(s)
- Mohsen Mazidi
- Key State Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences , Chaoyang , Beijing , China
| | - Niki Katsiki
- Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital , Thessaloniki , Greece
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL) , London , UK
| | - Maciej Banach
- Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz , Poland.,Polish Mother's Memorial Hospital Research Institute (PMMHRI) , Lodz , Poland.,Cardiovascular Research Centre, University of Zielona Gora , Zielona Gora , Poland
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26
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Luo JJ, Cao HX, Yang RX, Zhang RN, Pan Q. PNPLA3 rs139051 is associated with phospholipid metabolite profile and hepatic inflammation in nonalcoholic fatty liver disease. World J Clin Cases 2018; 6:355-364. [PMID: 30283798 PMCID: PMC6163133 DOI: 10.12998/wjcc.v6.i10.355] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 07/27/2018] [Accepted: 08/04/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the effect of PNPLA3 polymorphisms on serum lipidomics and pathological characteristics in nonalcoholic fatty liver disease (NAFLD).
METHODS Thirty-four biopsy-proven NAFLD patients from Northern, Central, and Southern China were subjected to stratification by genotyping their single nucleotide polymorphisms (SNPs) in PNPLA3. Ultra performance liquid chromatographytandem mass spectrometry was then employed to characterize the effects of PNPLA3 SNPs on serum lipidomics. In succession, correlation analysis revealed the association of PNPLA3-related lipid profile and hepatic pathological characteristics on a basis of steatosis, activity, and fibrosis assessment. The variant-based scoring of hepatocyte steatosis, ballooning, lobular inflammation, and liver fibrosis was finally performed so as to uncover the actions of lipidomics-affecting PNPLA3 SNPs in NAFLD-specific pathological alterations.
RESULTS PNPLA3 SNPs (rs139051, rs738408, rs738409, rs 2072906, rs2294918, rs2294919, and rs4823173) demonstrated extensive association with the serum lipidomics, especially phospholipid metabolites [lysophosphatidylcholine (LPC), lysophosphatidylcholine plasmalogen (LPCO), lysophosphatdylethanolamine (LPE), phosphatidylcholine (PC), choline plasmalogen (PCO), phosphatidylethanolamine (PE), ethanolamine plasmalogen (PEO)], of NAFLD patients. PNPLA3 rs139051 (A/A genotype) and rs2294918 (G/G genotype) dominated the up-regulatory effect on phospholipids of LPCs (LPC 17:0, LPC 18:0, LPC 20:0, LPC 20:1, LPC 20:2) and LPCOs (LPC O-16:1, LPC O-18:1). Moreover, subjects with high-level LPCs/LPCOs were predisposed to low-grade lobular inflammation of NAFLD (rho: -0.407 to -0.585, P < 0.05-0.001). The significant correlation of PNPLA3 rs139051 and inflammation grading [A/A vs A/G + G/G: 0.50 (0.00, 1.75) vs 1.50 (1.00, 2.00), P < 0.05] further demonstrated its pathological role based on the modulation of phospholipid metabolite profile.
CONCLUSION The A/A genotype at PNPLA3 rs139051 exerts an up-regulatory effect on serum phospholipids of LPCs and LPCOs, which are associated with low-grade lobular inflammation of NAFLD.
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Affiliation(s)
- Ji-Jun Luo
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Hai-Xia Cao
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Rui-Xu Yang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Rui-Nan Zhang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Qin Pan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
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27
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Luukkonen PK, Zhou Y, Nidhina Haridas PA, Dwivedi OP, Hyötyläinen T, Ali A, Juuti A, Leivonen M, Tukiainen T, Ahonen L, Scott E, Palmer JM, Arola J, Orho-Melander M, Vikman P, Anstee QM, Olkkonen VM, Orešič M, Groop L, Yki-Järvinen H. Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD. J Hepatol 2017; 67:128-136. [PMID: 28235613 DOI: 10.1016/j.jhep.2017.02.014] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 02/07/2017] [Accepted: 02/10/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2EK/KK) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids. METHODS Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs. RESULTS The TM6SF2EK/KK and TM6SF2EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2EK/KK than the TM6SF2EE group (p<0.05). Polyunsaturated fatty acids (PUFA) were deficient in liver and serum TGs and liver PCs but hepatic free fatty acids were relatively enriched in PUFA (p<0.05). Incorporation of PUFA into TGs and PCs in TM6SF2 knockdown hepatocytes was decreased (p<0.05). Hepatic expression of TM6SF2 was decreased in variant carriers, and was co-expressed with genes regulated by PUFAs. CONCLUSIONS Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers.
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Affiliation(s)
- Panu K Luukkonen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
| | - You Zhou
- Minerva Foundation Institute for Medical Research, Helsinki, Finland; Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | | | - Om P Dwivedi
- Institute for Molecular Medicine Finland, Helsinki, Finland
| | | | - Ashfaq Ali
- Steno Diabetes Center, Gentofte, Denmark
| | - Anne Juuti
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Marja Leivonen
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Taru Tukiainen
- Institute for Molecular Medicine Finland, Helsinki, Finland
| | | | - Emma Scott
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Jeremy M Palmer
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Johanna Arola
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | | | | | - Quentin M Anstee
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Vesa M Olkkonen
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Matej Orešič
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
| | - Leif Groop
- Institute for Molecular Medicine Finland, Helsinki, Finland; Lund University, Malmö, Sweden
| | - Hannele Yki-Järvinen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland
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28
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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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29
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van der Veen JN, Kennelly JP, Wan S, Vance JE, Vance DE, Jacobs RL. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2017; 1859:1558-1572. [PMID: 28411170 DOI: 10.1016/j.bbamem.2017.04.006] [Citation(s) in RCA: 956] [Impact Index Per Article: 119.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 03/27/2017] [Accepted: 04/09/2017] [Indexed: 12/11/2022]
Abstract
Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most abundant phospholipids in all mammalian cell membranes. In the 1950s, Eugene Kennedy and co-workers performed groundbreaking research that established the general outline of many of the pathways of phospholipid biosynthesis. In recent years, the importance of phospholipid metabolism in regulating lipid, lipoprotein and whole-body energy metabolism has been demonstrated in numerous dietary studies and knockout animal models. The purpose of this review is to highlight the unappreciated impact of phospholipid metabolism on health and disease. Abnormally high, and abnormally low, cellular PC/PE molar ratios in various tissues can influence energy metabolism and have been linked to disease progression. For example, inhibition of hepatic PC synthesis impairs very low density lipoprotein secretion and changes in hepatic phospholipid composition have been linked to fatty liver disease and impaired liver regeneration after surgery. The relative abundance of PC and PE regulates the size and dynamics of lipid droplets. In mitochondria, changes in the PC/PE molar ratio affect energy production. We highlight data showing that changes in the PC and/or PE content of various tissues are implicated in metabolic disorders such as atherosclerosis, insulin resistance and obesity. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.
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Affiliation(s)
- Jelske N van der Veen
- Group on the Molecular and Cell Biology of Lipids, Canada; Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - John P Kennelly
- Group on the Molecular and Cell Biology of Lipids, Canada; Department of Agricultural, Food and Nutritional Science, 4-002 Li Ka Shing Centre for Heath Research Innovations, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Sereana Wan
- Group on the Molecular and Cell Biology of Lipids, Canada; Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Jean E Vance
- Group on the Molecular and Cell Biology of Lipids, Canada; Department of Medicine, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Dennis E Vance
- Group on the Molecular and Cell Biology of Lipids, Canada; Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - René L Jacobs
- Group on the Molecular and Cell Biology of Lipids, Canada; Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada; Department of Agricultural, Food and Nutritional Science, 4-002 Li Ka Shing Centre for Heath Research Innovations, University of Alberta, Edmonton, AB T6G 2E1, Canada.
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Meikle PJ, Summers SA. Sphingolipids and phospholipids in insulin resistance and related metabolic disorders. Nat Rev Endocrinol 2017; 13:79-91. [PMID: 27767036 DOI: 10.1038/nrendo.2016.169] [Citation(s) in RCA: 325] [Impact Index Per Article: 40.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Obesity, insulin resistance, type 2 diabetes mellitus and cardiovascular disease form a metabolic disease continuum that has seen a dramatic increase in prevalence in developed and developing countries over the past two decades. Dyslipidaemia resulting from hypercaloric diets is a major contributor to the pathogenesis of metabolic disease, and lipid-lowering therapies are the main therapeutic option for this group of disorders. However, the fact that dysfunctional lipid metabolism extends far beyond cholesterol and triglycerides is becoming increasingly clear. Lipidomic studies and mouse models are helping to explain the complex interactions between diet, lipid metabolism and metabolic disease. These studies are not only improving our understanding of this complex biology, but are also identifying potential therapeutic avenues to combat this growing epidemic. This Review examines what is currently known about phospholipid and sphingolipid metabolism in the setting of obesity and how metabolic pathways are being modulated for therapeutic effect.
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Affiliation(s)
- Peter J Meikle
- Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, Australia
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology, University of Utah, 201 Presidents Circle, Salt Lake City, Utah, 84112, USA
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Walker AK. 1-Carbon Cycle Metabolites Methylate Their Way to Fatty Liver. Trends Endocrinol Metab 2017; 28:63-72. [PMID: 27789099 PMCID: PMC5183509 DOI: 10.1016/j.tem.2016.10.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 10/02/2016] [Accepted: 10/04/2016] [Indexed: 01/19/2023]
Abstract
Fatty liver is a complex disease often accompanying metabolic syndrome and Type 2 diabetes mellitus (T2DM). Hepatosteatosis may have roots in multiple metabolic abnormalities. However, metabolic dysfunction in the 1-carbon cycle (1CC), which produces the methyl donor S-adenosylmethionine (SAM) and phosphatidylcholine (PC), induces hepatic lipogenesis in model systems. Human diseases where 1CC or PC synthesis is disrupted, such as alcoholism, congenital lipodystrophy, or cystic fibrosis, often present with fatty liver. Given that the 1CC is clearly linked to this disease, it is critical to understand how the individual metabolites drive mechanisms increasing stored hepatic lipids. In this review, I summarize evidence that ties the 1CC to fatty liver disease along with data proposing mechanisms for increased lipogenesis or decreased lipid export by phosphatidylcholine.
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Phosphatidylethanolamine N-methyltransferase gene rs7946 polymorphism plays a role in risk of nonalcoholic fatty liver disease: evidence from meta-analysis. Pharmacogenet Genomics 2016; 26:88-95. [PMID: 26636496 DOI: 10.1097/fpc.0000000000000193] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Phosphatidylethanolamine N-methyltransferase (PEMT) governs the secretion of hepatic triglycerides in the form of very low-density lipoprotein and has been implicated in nonalcoholic fatty liver disease (NAFLD). Studies on the role of the PEMT rs7946 polymorphism as a genetic modifier of NAFLD have reported inconsistent results. This meta-analysis was carried out to evaluate and summarize the association of PEMT rs7946 with susceptibility to NAFLD. METHODS A comprehensive literature search in Scopus, PubMed, Embase, Science Direct and Google Scholar was performed up to 31 August 2015, followed by data extraction and examination of summary estimates. RESULTS Six independent studies with a total of 792 NAFLD cases and 2722 controls fulfilled the inclusion criteria. Pooled results indicated that the rs7946 A-allele was associated significantly with an increased risk of NAFLD [odds ratio (OR) 1.55, 95% confidence interval (CI) 1.14-2.11, P=0.005]. A significant association was also found in alternative genetic models of inheritance: dominant, recessive and homozygote (OR 1.62, 95% CI 1.10-2.39, P=0.01; OR 1.42, 95% CI 1.12-1.81, P=0.003; and OR 1.64, 95% CI 1.18-2.29, P=0.004, respectively). Subgroup analysis by ethnicity indicated a significant association only in the East-Asians in the additive (OR=2.08, 95% CI 1.12-3.86, P=0.02), recessive (OR=2.94, 95% CI 1.60-5.37, P=0.0005) and homozygote (OR=1.86, 95% CI 1.15-3.01, P=0.01) models. CONCLUSION This study provides evidence of a significant association between the PEMT rs7946 A-allele and a risk of NAFLD, with the effect being more prominent in East-Asians, but not in non-Asians.
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Anstee QM, Seth D, Day CP. Genetic Factors That Affect Risk of Alcoholic and Nonalcoholic Fatty Liver Disease. Gastroenterology 2016; 150:1728-1744.e7. [PMID: 26873399 DOI: 10.1053/j.gastro.2016.01.037] [Citation(s) in RCA: 191] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Revised: 01/17/2016] [Accepted: 01/20/2016] [Indexed: 02/07/2023]
Abstract
Genome-wide association studies and candidate gene studies have informed our understanding of factors contributing to the well-recognized interindividual variation in the progression and outcomes of alcoholic liver disease and nonalcoholic fatty liver disease. We discuss the mounting evidence for shared modifiers and common pathophysiological processes that contribute to development of both diseases. We discuss the functions of proteins encoded by risk variants of genes including patatin-like phospholipase domain-containing 3 and transmembrane 6 superfamily member 2, as well as epigenetic factors that contribute to the pathogenesis of alcoholic liver disease and nonalcoholic fatty liver disease. We also discuss important areas of future genetic research and their potential to affect clinical management of patients.
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Affiliation(s)
- Quentin M Anstee
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
| | - Devanshi Seth
- Centenary Institute of Cancer Medicine, Royal Prince Alfred Hospital, Camperdown, Australia; Drug Health Services, Royal Prince Alfred Hospital, Camperdown, Australia; Central Clinical School, The University of Sydney, Camperdown, Australia
| | - Christopher P Day
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle-upon-Tyne, United Kingdom
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Abstract
Along with the obesity epidemic, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased exponentially. The histological disease spectrum of NAFLD ranges from bland fatty liver (hepatic steatosis), to the concomitant presence of inflammation and ballooning which defines nonalcoholic steatohepatitis (NASH). The latter can progress in a subset to fibrosis, leading ultimately to cirrhosis and hepatocellular carcinoma. The past decade has seen tremendous advances in our understanding of the genetic and epigenetic bases of NAFLD, mainly through the application of high end technology platforms including genome-wide association studies (GWAS). These have helped to define common gene variants (minor allele frequency >5 %) that contribute to the NAFLD phenotype. Looking to the future, these discoveries are expected to lead to improved diagnostics, the personalization of medicine, and a better understanding of the pathophysiological underpinnings that drive the transition from NAFLD to steatohepatitis and fibrosis, leading to the identification of novel therapeutic targets. In this review, we summarize data on the current state of knowledge with regard to the genetic and epigenetic mechanisms for the development of NASH.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, Westmead Millennium Institute, Westmead Hospital, University of Sydney, Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Millennium Institute, Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
- Department of Medicine, Westmead Hospital, Westmead, NSW, 2145, Australia.
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Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis. Sci Rep 2016; 6:21721. [PMID: 26883167 PMCID: PMC4756298 DOI: 10.1038/srep21721] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 01/29/2016] [Indexed: 02/06/2023] Open
Abstract
Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt−/− mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt−/− mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4α resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.
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Sherriff JL, O'Sullivan TA, Properzi C, Oddo JL, Adams LA. Choline, Its Potential Role in Nonalcoholic Fatty Liver Disease, and the Case for Human and Bacterial Genes. Adv Nutr 2016; 7:5-13. [PMID: 26773011 PMCID: PMC4717871 DOI: 10.3945/an.114.007955] [Citation(s) in RCA: 138] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Our understanding of the impact of poor hepatic choline/phosphatidylcholine availability in promoting the steatosis characteristic of human nonalcoholic fatty liver disease (NAFLD) has recently advanced and possibly relates to phosphatidylcholine/phosphatidylethanolamine concentrations in various, membranes as well as cholesterol dysregulation. A role for choline/phosphatidylcholine availability in the progression of NAFLD to liver injury and serious hepatic consequences in some individuals requires further elucidation. There are many reasons for poor choline/phosphatidylcholine availability in the liver, including low intake, estrogen status, and genetic polymorphisms affecting, in particular, the pathway for hepatic de novo phosphatidylcholine synthesis. In addition to free choline, phosphatidylcholine has been identified as a substrate for trimethylamine production by certain intestinal bacteria, thereby reducing host choline bioavailability and providing an additional link to the increased risk of cardiovascular disease faced by those with NAFLD. Thus human choline requirements are highly individualized and biomarkers of choline status derived from metabolomics studies are required to predict those at risk of NAFLD induced by choline deficiency and to provide a basis for human intervention trials.
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Affiliation(s)
- Jill L Sherriff
- School of Public Health, Curtin Health Innovation Research Institute-Metabolic Health, Curtin University, Bentley, Australia;
| | - Therese A O'Sullivan
- School of Exercise and Health Science, Edith Cowan University, Joondalup, Australia
| | - Catherine Properzi
- School of Exercise and Health Science, Edith Cowan University, Joondalup, Australia
| | - Josephine-Lee Oddo
- School of Exercise and Health Science, Edith Cowan University, Joondalup, Australia
| | - Leon A Adams
- School of Medicine and Pharmacology, The University of Western Australia, Nedlands, Australia; and Liver Transplant Unit, Sir Charles Gairdner Hospital, Nedlands, Australia
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37
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring.
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Stepanova M, Henry L, Garg R, Kalwaney S, Saab S, Younossi Z. Risk of de novo post-transplant type 2 diabetes in patients undergoing liver transplant for non-alcoholic steatohepatitis. BMC Gastroenterol 2015; 15:175. [PMID: 26666336 PMCID: PMC4678589 DOI: 10.1186/s12876-015-0407-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Background Non-alcoholic steatohepatitis (NASH) is often seen together with components of metabolic syndrome. The aim of this study was to assess the risk of de novo post-transplant type 2 diabetes (DM) in liver transplant recipients with NASH. Methods All adult patients from the Scientific Registry of Transplant Recipients (2003–2012) transplanted for NASH or cryptogenic cirrhosis (the NASH cohort) without pre-transplant DM were included in this retrospective cross-sectional study. Results Total 2,916 NASH subjects and 14,268 controls with non-HCV related cirrhosis or hepatocellular carcinoma were included. Patients with NASH were, on average, 6 years older, more likely female and overweight/obese. By 5 years post-transplant, 39.8 % NASH vs. 27.0 % controls developed at least one onset of de novo DM; this was observed starting 6 months post-transplant: 22.9 % vs. 16.7 % (relative risk 1.38). Later in follow-up, the relative risk of de novo DM was also higher in NASH: 1.46 by 3 years, 1.47 by 5 years (all p < 0.0001). After exclusion of DM that resolved after the first year, long-term DM remained higher in the NASH cohort: 7.6 % vs. 4.3 %, p < 0.0001. In multivariate analysis, after adjustment for confounders including the use of immunosuppressants, having NASH was independently associated with development of de novo post-transplant DM: adjusted hazard ratio (95 % CI) = 1.29 (1.18–1.42), p < 0.0001. Conclusions Liver transplant recipients with NASH have a higher risk of de novo post-transplant DM. This suggests the presence of an underlying metabolic disorder beyond fatty liver that may be causative for both NASH and type 2 diabetes.
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Affiliation(s)
- Maria Stepanova
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA. .,Betty and Guy Beatty Center for Integrated Research, Inova Health System, Claude Moore Health Education and Research Building, 3rd floor, 3300 Gallows Road, Falls Church, VA, 22042, USA.
| | - Linda Henry
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA.
| | - Rishi Garg
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA.
| | - Shirley Kalwaney
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA.
| | - Sammy Saab
- Department of Medicine, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA, USA.
| | - Zobair Younossi
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA. .,Betty and Guy Beatty Center for Integrated Research, Inova Health System, Claude Moore Health Education and Research Building, 3rd floor, 3300 Gallows Road, Falls Church, VA, 22042, USA.
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Ramos-Lopez O, Martinez-Lopez E, Roman S, Fierro NA, Panduro A. Genetic, metabolic and environmental factors involved in the development of liver cirrhosis in Mexico. World J Gastroenterol 2015; 21:11552-11566. [PMID: 26556986 PMCID: PMC4631960 DOI: 10.3748/wjg.v21.i41.11552] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/29/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis (LC) is a chronic illness caused by inflammatory responses and progressive fibrosis. Globally, the most common causes of chronic liver disease include persistent alcohol abuse, followed by viral hepatitis infections and nonalcoholic fatty liver disease. However, regardless of the etiological factors, the susceptibility and degree of liver damage may be influenced by genetic polymorphisms that are associated with distinct ethnic and cultural backgrounds. Consequently, metabolic genes are influenced by variable environmental lifestyle factors, such as diet, physical inactivity, and emotional stress, which are associated with regional differences among populations. This Topic Highlight will focus on the genetic and environmental factors that may influence the metabolism of alcohol and nutrients in the setting of distinct etiologies of liver disease. The interaction between genes and environment in the current-day admixed population, Mestizo and Native Mexican, will be described. Additionally, genes involved in immune regulation, insulin sensitivity, oxidative stress and extracellular matrix deposition may modulate the degree of severity. In conclusion, LC is a complex disease. The onset, progression, and clinical outcome of LC among the Mexican population are influenced by specific genetic and environmental factors. Among these are an admixed genome with a heterogenic distribution of European, Amerindian and African ancestry; a high score of alcohol consumption; viral infections; a hepatopathogenic diet; and a high prevalence of obesity. The variance in risk factors among populations suggests that intervention strategies directed towards the prevention and management of LC should be tailored according to such population-based features.
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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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Edelman D, Kalia H, Delio M, Alani M, Krishnamurthy K, Abd M, Auton A, Wang T, Wolkoff AW, Morrow BE. Genetic analysis of nonalcoholic fatty liver disease within a Caribbean-Hispanic population. Mol Genet Genomic Med 2015; 3:558-69. [PMID: 26740948 PMCID: PMC4694126 DOI: 10.1002/mgg3.168] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/07/2015] [Accepted: 07/09/2015] [Indexed: 12/18/2022] Open
Abstract
We explored potential genetic risk factors implicated in nonalcoholic fatty liver disease (NAFLD) within a Caribbean–Hispanic population in New York City. A total of 316 individuals including 40 subjects with biopsy‐proven NAFLD, 24 ethnically matched non‐NAFLD controls, and a 252 ethnically mixed random sampling of Bronx County, New York were analyzed. Genotype analysis was performed to determine allelic frequencies of 74 known single‐nucleotide polymorphisms (SNPs) associated with NAFLD risk based on previous genome‐wide association study (GWAS) and candidate gene studies. Additionally, the entire coding region of PNPLA3, a gene showing the strongest association to NAFLD was subjected to Sanger sequencing. Results suggest that both rare and common DNA variations in PNPLA3 and SAMM50 may be correlated with NAFLD in this small population study, while common DNA variations in CHUK and ERLIN1, may have a protective interaction. Common SNPs in ENPP1 and ABCC2 have suggestive association with fatty liver, but with less compelling significance. In conclusion, Hispanic patients of Caribbean ancestry may have different interactions with NAFLD genetic modifiers; therefore, further investigation with a larger sample size, into this Caribbean–Hispanic population is warranted.
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Affiliation(s)
- Deborah Edelman
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
| | - Harmit Kalia
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Maria Delio
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
- Marion Bessin Liver Research CenterAlbert Einstein College of MedicineBronxNew York10461
| | - Mustafa Alani
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Karthik Krishnamurthy
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Mortadha Abd
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Adam Auton
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
| | - Tao Wang
- Department of Epidemiology & Population HealthAlbert Einstein College of MedicineBronxNew York10461
| | - Allan W. Wolkoff
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
- Marion Bessin Liver Research CenterAlbert Einstein College of MedicineBronxNew York10461
- Department of Anatomy and Structural BiologyAlbert Einstein College of MedicineBronxNew York10461
| | - Bernice E. Morrow
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
- Department of Anatomy and Structural BiologyAlbert Einstein College of MedicineBronxNew York10461
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Wood KL, Miller MH, Dillon JF. Systematic review of genetic association studies involving histologically confirmed non-alcoholic fatty liver disease. BMJ Open Gastroenterol 2015; 2:e000019. [PMID: 26462272 PMCID: PMC4599155 DOI: 10.1136/bmjgast-2014-000019] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 01/21/2015] [Accepted: 01/23/2015] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease has an increasing prevalence in Western countries, affecting up to 20% of the population.
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Affiliation(s)
| | - Michael H Miller
- Medical Research Institute, University of Dundee, Ninewells Hospital , Dundee , UK
| | - John F Dillon
- Medical Research Institute, University of Dundee, Ninewells Hospital , Dundee , UK
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Dyson JK, McPherson S, Anstee QM. Republished: Non-alcoholic fatty liver disease: non-invasive investigation and risk stratification. Postgrad Med J 2015; 90:254-66. [PMID: 24737902 DOI: 10.1136/postgradmedj-2013-201620rep] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum of liver disease, from simple steatosis through to cirrhosis. As the worldwide rates of obesity have increased, NAFLD has become the commonest cause of liver disease in many developed countries, affecting up to a third of the population. The majority of patients have simple steatosis that carries a relatively benign prognosis. However, a significant minority have non-alcoholic steatohepatitis, and have increased liver related and cardiovascular mortality. Identifying those at risk of progressive disease is crucial. Liver biopsy remains the gold standard investigation for assessing stage of disease but its invasive nature makes it impractical for widespread use as a prognostic tool. Non-invasive tools for diagnosis and disease staging are required, reserving liver biopsy for those patients where it offers clinically relevant additional information. This review discusses the non-invasive modalities available for assessing steatosis, steatohepatitis and fibrosis. We propose a pragmatic approach for the assessment of patients with NAFLD to identify those at high risk of progressive disease who require referral to specialist services.
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Affiliation(s)
- J K Dyson
- Liver Unit, Newcastle Upon Tyne Hospitals NHS Trust, Freeman Hospital, , Newcastle upon Tyne, UK
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Acid sphingomyelinase-ceramide system in steatohepatitis: a novel target regulating multiple pathways. J Hepatol 2015; 62:219-33. [PMID: 25281863 DOI: 10.1016/j.jhep.2014.09.023] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 09/13/2014] [Accepted: 09/24/2014] [Indexed: 02/07/2023]
Abstract
Steatohepatitis (SH) is an intermediate stage of fatty liver disease and is one of the most common causes of chronic liver disease worldwide that may progress to cirrhosis and liver cancer. SH encompasses alcoholic and non-alcoholic steatohepatitis, the latter being of particular concern as it is associated with obesity and insulin resistance and has become a major cause of liver transplantation. The molecular mechanisms governing the transition from steatosis to SH are not fully understood. Here we discuss emerging data indicating that the acid sphingomyelinase (ASMase), a specific mechanism of ceramide generation, is required for the activation of key pathways that regulate steatosis, fibrosis and lipotoxicity, including endoplasmic reticulum stress, autophagy and lysosomal membrane permeabilization. Moreover, ASMase modulates alterations of the methionine cycle and phosphatidylcholine homeostasis, two crucial events involved in SH that regulate methylation reactions, antioxidant defence and membrane integrity. These new findings suggest that targeting ASMase in combination with restoring methionine metabolism and phosphatidylcholine levels may be of utility in the treatment of SH.
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Yu D, Shu XO, Xiang YB, Li H, Yang G, Gao YT, Zheng W, Zhang X. Higher dietary choline intake is associated with lower risk of nonalcoholic fatty liver in normal-weight Chinese women. J Nutr 2014; 144:2034-40. [PMID: 25320186 PMCID: PMC4230213 DOI: 10.3945/jn.114.197533] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Choline deficiency has been shown to induce liver fat accumulation in both rodent and human studies. However, it is unclear whether dietary choline intake is related to fatty liver in the general population. OBJECTIVE We examined the association between choline intake and nonalcoholic fatty liver. METHODS Participants included 56,195 Chinese women and men, 40-75 y of age, with no or negligible alcohol consumption and with no history of hepatitis, cardiovascular disease, or cancer. All participants reported undergoing liver ultrasonography. Fatty liver was defined by self-report of a physician diagnosis. Habitual dietary intakes were assessed via validated food-frequency questionnaires. RESULTS The average total choline intakes were 289 ± 85 mg/d in women and 318 ± 92 mg/d in men. Major food sources were eggs, soy foods, red meat, fish, and vegetables. A higher choline intake was associated with lower risk of fatty liver; after adjustment for sociodemographic characteristics, lifestyle factors, and other dietary intakes, the ORs (95% CIs) for the highest vs. the lowest quintiles of choline intake were 0.68 (0.59, 0.79) in women and 0.75 (0.60, 0.93) in men (both P-trend < 0.01). The inverse association was attenuated after further adjustment for history of metabolic disease and, in particular, BMI. The corresponding ORs (95% CIs) were 0.88 (0.75, 1.03) in women (P-trend = 0.05) and 0.85 (0.68, 1.06) in men (P-trend = 0.09). Stratified analyses suggested a potential effect modification by obesity status in women; the OR (95% CI) across extreme quintiles was 0.72 (0.57, 0.91) in normal-weight women vs. 1.05 (0.84, 1.31) in overweight or obese women (P-trend = 0.007 vs. 0.99, P-interaction < 0.0001). CONCLUSION Higher dietary choline intake may be associated with lower risk of nonalcoholic fatty liver only in normal-weight Chinese women.
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Affiliation(s)
- Danxia Yu
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; and
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; and
| | - Yong-Bing Xiang
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
| | - Honglan Li
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
| | - Gong Yang
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; and
| | - Yu-Tang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; and
| | - Xianglan Zhang
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; and
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46
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Kalafati IP, Borsa D, Dedoussis GVZ. The Genetics of Nonalcoholic Fatty Liver Disease: Role of Diet as a Modifying Factor. Curr Nutr Rep 2014. [DOI: 10.1007/s13668-014-0085-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Manti S, Romano C, Chirico V, Filippelli M, Cuppari C, Loddo I, Salpietro C, Arrigo T. Nonalcoholic Fatty liver disease/non-alcoholic steatohepatitis in childhood: endocrine-metabolic "mal-programming". HEPATITIS MONTHLY 2014; 14:e17641. [PMID: 24829591 PMCID: PMC4013495 DOI: 10.5812/hepatmon.17641] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 02/13/2014] [Accepted: 02/19/2014] [Indexed: 02/08/2023]
Abstract
CONTEXT Nonalcoholic Fatty Liver Disease (NAFLD) is the major chronic liver disease in the pediatric population. NAFLD includes a broad spectrum of abnormalities (inflammation, fibrosis and cirrhosis), ranging from accumulation of fat (also known as steatosis) towards non-alcoholic steatohepatitis (NASH). The development of NAFLD in children is significantly increased. EVIDENCE ACQUISITION A literature search of electronic databases was undertaken for the major studies published from 1998 to today. The databases searched were: PubMed, EMBASE, Orphanet, Midline and Cochrane Library. We used the key words: "non-alcoholic fatty liver disease, children, non-alcoholic steatohepatitis and fatty liver". RESULTS NAFLD/NASH is probably promoted by "multiple parallel hits": environmental and genetic factors, systemic immunological disorders (oxidative stress, persistent-low grade of inflammation) as well as obesity and metabolic alterations (insulin resistance and metabolic syndrome). However its exact cause still underdiagnosed and unknown. CONCLUSIONS Pediatric NAFLD/NASH is emerging problem. Longitudinal follow-up studies, unfortunately still insufficient, are needed to better understand the natural history and outcome of NAFLD in children. This review focuses on the current knowledge regarding the epidemiology, pathogenesis, environmental, genetic and metabolic factors of disease. The review also highlights the importance of studying the underlying mechanisms of pediatric NAFLD and the need for complete and personalized approach in the management of NAFLD/NASH.
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Affiliation(s)
- Sara Manti
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Claudio Romano
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Valeria Chirico
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Martina Filippelli
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Caterina Cuppari
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Italia Loddo
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Carmelo Salpietro
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Teresa Arrigo
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
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Radwan MM, Radwan BM, Nandipati KC, Hunter WJ, Agrawal DK. Immunological and molecular basis of nonalcoholic steatohepatitis and nonalcoholic fatty liver disease. Expert Rev Clin Immunol 2014; 9:727-38. [PMID: 23971751 DOI: 10.1586/1744666x.2013.816484] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is rising worldwide with the increasing incidence of obesity, Type 2 diabetes mellitus and metabolic syndrome. NASH is currently one of the most common indications of liver transplantation in the United States. The immune system plays a major role in the pathogenesis of NAFLD/NASH. The metabolic changes, associated with obesity and metabolic syndrome, induce immunological responses resulting in NAFLD and further aggravation of the metabolic derangement in a feed-forward loop. Genetic and endocrine factors modulate the immunological and metabolic responses and determine the pathophysiological features of NAFLD. Histologically, NAFLD is a spectrum that ranges from simple hepatic steatosis to severe steatohepatitis, liver cirrhosis and/or hepatocellular carcinoma. Liver cirrhosis and hepatocellular carcinoma are responsible for the morbidity and mortality of the disease. This article is a critical evaluation of our current knowledge of the immunological and molecular basis of the disease.
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Affiliation(s)
- Mohamed M Radwan
- Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA
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Nishimukai M, Maeba R, Yamazaki Y, Nezu T, Sakurai T, Takahashi Y, Hui SP, Chiba H, Okazaki T, Hara H. Serum choline plasmalogens, particularly those with oleic acid in sn-2, are associated with proatherogenic state. J Lipid Res 2014; 55:956-65. [PMID: 24616482 DOI: 10.1194/jlr.p045591] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Serum plasmalogens (Pls) (1-O-alk-1'-enyl-2-acyl glycerophospholipids) are of particular interest for studies on metabolic disorders associated with oxidative stress and chronic inflammation. Serum levels of Pls are known to correlate positively with HDL-cholesterol (HDL-C); however, few studies have examined serum Pls molecular species in association with pathophysiological conditions and their clinical significance. To clarify these, we determined serum levels of individual ether glycerophospholipids in Japanese asymptomatic cohorts (n = 428; 362 male and 66 female subjects) by LC/MS/MS, and examined their correlations with clinical parameters. We found that the proportion of choline Pls (PlsCho) among total serum phospholipids was significantly lower in the male group over 40 years old and was associated with multiple risk parameters more strongly than HDL-C. The abundance of serum PlsCho with oleic acid (18:1) in sn-2 exhibited the strongest positive correlation with serum concentrations of adiponectin and HDL-C, while being inversely associated with waist circumference and the serum levels of TG and small dense LDL-cholesterol. The characterization of serum ether glycerophospholipids verified the specificity of PlsCho, particularly the ones with 18:1 in sn-2, as a sensitive biomarker for the atherogenic state.
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Affiliation(s)
- Megumi Nishimukai
- Division of Applied Bioscience, Research Faculty of Agriculture, Hokkaido University, Sapporo, Hokkaido 060-8589, Japan
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Dongiovanni P, Anstee QM, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des 2014; 19:5219-38. [PMID: 23394097 PMCID: PMC3850262 DOI: 10.2174/13816128113199990381] [Citation(s) in RCA: 162] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 02/01/2013] [Indexed: 02/07/2023]
Abstract
Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome.
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Affiliation(s)
- Paola Dongiovanni
- Department of Pathophysiology and Transplantation, section Internal Medicine, Università degli Studi Milano, UO Medicina Interna1B, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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