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Rueter J, Rimbach G, Bilke S, Tholey A, Huebbe P. Readdressing the Localization of Apolipoprotein E (APOE) in Mitochondria-Associated Endoplasmic Reticulum (ER) Membranes (MAMs): An Investigation of the Hepatic Protein-Protein Interactions of APOE with the Mitochondrial Proteins Lon Protease (LONP1), Mitochondrial Import Receptor Subunit TOM40 (TOMM40) and Voltage-Dependent Anion-Selective Channel 1 (VDAC1). Int J Mol Sci 2024; 25:10597. [PMID: 39408926 PMCID: PMC11476584 DOI: 10.3390/ijms251910597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/27/2024] [Accepted: 09/29/2024] [Indexed: 10/20/2024] Open
Abstract
As a component of circulating lipoproteins, APOE binds to cell surface receptors mediating lipoprotein metabolism and cholesterol transport. A growing body of evidence, including the identification of a broad variety of cellular proteins interacting with APOE, suggests additional independent functions. Investigating cellular localization and protein-protein interactions in cultured human hepatocytes, we aimed to contribute to the elucidation of hitherto unnoted cellular functions of APOE. We observed a strong accumulation of APOE in MAMs, equally evident for the two major isoforms APOE3 and APOE4. Using mass spectrometry proteome analyses, novel and previously noted APOE interactors were identified, including the mitochondrial proteins TOMM40, LONP1 and VDAC1. All three interactors were present in MAM fractions, which we think initially facilitates interactions with APOE. LONP1 is a protease with chaperone activity, which migrated to MAMs in response to ER stress, displaying a reinforced interaction with APOE. We therefore hypothesize that APOE may help in the unfolded protein response (UPR) by acting as a co-chaperone in cooperation with LONP1 at the interface of mitochondria and ER membranes. The interaction of APOE with the integral proteins TOMM40 and VDAC1 may point to the formation of bridging complexes connecting mitochondria with other organelles.
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Affiliation(s)
- Johanna Rueter
- Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Strasse 6, 24118 Kiel, Germany; (J.R.); (G.R.)
| | - Gerald Rimbach
- Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Strasse 6, 24118 Kiel, Germany; (J.R.); (G.R.)
| | - Stephanie Bilke
- Institute of Experimental Medicine, University of Kiel, Niemannsweg 11, 24105 Kiel, Germany
| | - Andreas Tholey
- Institute of Experimental Medicine, University of Kiel, Niemannsweg 11, 24105 Kiel, Germany
| | - Patricia Huebbe
- Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Strasse 6, 24118 Kiel, Germany; (J.R.); (G.R.)
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Huebbe P, Bilke S, Rueter J, Schloesser A, Campbel G, Glüer CC, Lucius R, Röcken C, Tholey A, Rimbach G. Human APOE4 Protects High-Fat and High-Sucrose Diet Fed Targeted Replacement Mice against Fatty Liver Disease Compared to APOE3. Aging Dis 2024; 15:259-281. [PMID: 37450924 PMCID: PMC10796091 DOI: 10.14336/ad.2023.0530] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 05/30/2023] [Indexed: 07/18/2023] Open
Abstract
Recent genome- and exome-wide association studies suggest that the human APOE ε4 allele protects against non-alcoholic fatty liver disease (NAFLD), while ε3 promotes hepatic steatosis and steatohepatitis. The present study aimed at examining the APOE genotype-dependent development of fatty liver disease and its underlying mechanisms in a targeted replacement mouse model. Male mice expressing the human APOE3 or APOE4 protein isoforms on a C57BL/6J background and unmodified C57BL/6J mice were chronically fed a high-fat and high-sucrose diet to induce obesity. After 7 months, body weight gain was more pronounced in human APOE than endogenous APOE expressing mice with elevated plasma biomarkers suggesting aggravated metabolic dysfunction. APOE3 mice exhibited the highest liver weights and, compared to APOE4, massive hepatic steatosis. An untargeted quantitative proteome analysis of the liver identified a high number of proteins differentially abundant in APOE3 versus APOE4 mice. The majority of the higher abundant proteins in APOE3 mice could be grouped to inflammation and damage-associated response, and lipid storage, amongst others. Results of the targeted qRT-PCR and Western blot analyses contribute to the overall finding that APOE3 as opposed to APOE4 promotes hepatic steatosis, inflammatory- and damage-associated response signaling and fibrosis in the liver of obese mice. Our experimental data substantiate the observation of an increased NAFLD-risk associated with the human APOEε3 allele, while APOEε4 appears protective. The underlying mechanisms of the protection possibly involve a higher capacity of nonectopic lipid deposition in subcutaneous adipose tissue and lower hepatic pathogen recognition in the APOE4 mice.
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Affiliation(s)
- Patricia Huebbe
- Institute of Human Nutrition and Food Science, Kiel University, D-24118 Kiel, Germany.
| | - Stephanie Bilke
- Institute of Experimental Medicine, Proteomics & Bioanalytics, Kiel University, D-24105 Kiel, Germany.
| | - Johanna Rueter
- Institute of Human Nutrition and Food Science, Kiel University, D-24118 Kiel, Germany.
| | - Anke Schloesser
- Institute of Human Nutrition and Food Science, Kiel University, D-24118 Kiel, Germany.
| | - Graeme Campbel
- Section Biomedical Imaging, Department of Radiology and Neuroradiology, Kiel University, D-24118 Kiel, Germany.
| | - Claus-C. Glüer
- Section Biomedical Imaging, Department of Radiology and Neuroradiology, Kiel University, D-24118 Kiel, Germany.
| | - Ralph Lucius
- Anatomical Institute, Kiel University, D-24118 Kiel, Germany.
| | - Christoph Röcken
- Department of Pathology, Kiel University and University Hospital Schleswig-Holstein, Campus Kiel, D-24105 Kiel, Germany.
| | - Andreas Tholey
- Institute of Experimental Medicine, Proteomics & Bioanalytics, Kiel University, D-24105 Kiel, Germany.
| | - Gerald Rimbach
- Institute of Human Nutrition and Food Science, Kiel University, D-24118 Kiel, Germany.
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Fairfield CJ, Drake TM, Pius R, Bretherick AD, Campbell A, Clark DW, Fallowfield JA, Hayward C, Henderson NC, Joshi PK, Mills NL, Porteous DJ, Ramachandran P, Semple RK, Shaw CA, Sudlow CL, Timmers PR, Wilson JF, Wigmore SJ, Harrison EM, Spiliopoulou A. Genome-Wide Association Study of NAFLD Using Electronic Health Records. Hepatol Commun 2022; 6:297-308. [PMID: 34535985 PMCID: PMC8793997 DOI: 10.1002/hep4.1805] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 07/04/2021] [Indexed: 12/20/2022] Open
Abstract
Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10-8 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10-11 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
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Affiliation(s)
- Cameron J. Fairfield
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Thomas M. Drake
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Riinu Pius
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Andrew D. Bretherick
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
| | - Archie Campbell
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
- Centre for Genomic and Experimental MedicineInstitute of Genetics & Molecular MedicineUniversity of EdinburghEdinburghScotland
- Health Data Research UKUniversity of EdinburghEdinburghScotland
| | - David W. Clark
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
| | - Jonathan A. Fallowfield
- Centre for Inflammation ResearchQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - Caroline Hayward
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
| | - Neil C. Henderson
- Centre for Inflammation ResearchQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - Peter K. Joshi
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
| | - Nicholas L. Mills
- Centre for Cardiovascular ScienceQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - David J. Porteous
- Centre for Genomic and Experimental MedicineInstitute of Genetics & Molecular MedicineUniversity of EdinburghEdinburghScotland
| | - Prakash Ramachandran
- Centre for Inflammation ResearchQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - Robert K. Semple
- Centre for Cardiovascular ScienceQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - Catherine A. Shaw
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Cathie L.M. Sudlow
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Paul R.H.J. Timmers
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
| | - James F. Wilson
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
| | - Stephen J. Wigmore
- Department of Clinical SurgeryDivision of Health SciencesUniversity of EdinburghEdingburghScotland
| | - Ewen M. Harrison
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
- Department of Clinical SurgeryDivision of Health SciencesUniversity of EdinburghEdingburghScotland
| | - Athina Spiliopoulou
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
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Liu S, Weng R, Gu X, Li L, Zhong Z. Association between apolipoprotein E gene polymorphism and nonalcoholic fatty liver disease in Southern China: A case-control study. J Clin Lab Anal 2021; 35:e24061. [PMID: 34664321 PMCID: PMC8649370 DOI: 10.1002/jcla.24061] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/03/2021] [Accepted: 10/06/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Apolipoprotein E (ApoE) polymorphisms have been reported to be associated with nonalcoholic fatty liver disease (NAFLD), but the conclusions of studies are inconsistent in different regions. The present study aims to investigate the role of ApoE genotypes on NAFLD in southern China. METHODS A total of 1064 subjects including 372 NAFLD patients and 692 controls who attended Meizhou People's Hospital located in southern China from March 1, 2016 to April 30, 2020 were enrolled in this study. The ApoE genotypes were detected and the laboratory parameters were examined. RESULTS Significant differences were observed between NAFLD patients and controls in the prevalence of ε3/ε3 (p < 0.001) and ε3/ε4 (p = 0.004). NAFLD patients presented higher frequency of ε4 allele than controls (p = 0.013). Logistic regression analysis suggested that ε3/ε3 was an independent risk factor (OR: 1.435, 95% CI: 1.084-1.891, p = 0.010), while ε3/ε4 was an independent protective factor (OR: 0.578, 95% CI: 0.404-0.828, p = 0.003) for development of NAFLD. In addition, allele ε4 showed a protective effect on NAFLD with an adjusted OR of 0.588 (95% CI: 0.420-0.824, p = 0.002). CONCLUSION Our results suggested that ApoE genotype was associated with the development of NAFLD in the population of southern China. Individuals carrying ε3/ε3 were at higher risk of NAFLD, while those carrying ε3/ε4 were at lower risk of NAFLD.
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Affiliation(s)
- Sudong Liu
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou, China.,Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, China.,Research Experiment Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou, China
| | - Ruiqiang Weng
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou, China.,Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, China.,Research Experiment Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou, China
| | - Xiaodong Gu
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou, China.,Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, China.,Research Experiment Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou, China
| | - Lihai Li
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou, China.,Research Experiment Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou, China
| | - Zhixiong Zhong
- Center for Precision Medicine, Meizhou People's Hospital (Huangtang Hospital), Meizhou, China.,Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, China
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5
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Palmer ND, Kahali B, Kuppa A, Chen Y, Du X, Feitosa MF, Bielak LF, O’Connell JR, Musani SK, Guo X, Smith AV, Ryan KA, Eirksdottir G, Allison MA, Bowden DW, Budoff MJ, Carr JJ, Chen YDI, Taylor KD, Correa A, Crudup BF, Halligan B, Yang J, Kardia SLR, Launer LJ, Fu YP, Mosley TH, Norris JM, Terry JG, O’Donnell CJ, Rotter JI, Wagenknecht LE, Gudnason V, Province MA, Peyser PA, Speliotes EK. Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction. Hum Mol Genet 2021; 30:1443-1456. [PMID: 33856023 PMCID: PMC8283205 DOI: 10.1093/hmg/ddab096] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 03/19/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.
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Affiliation(s)
- Nicholette D Palmer
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Bratati Kahali
- Centre for Brain Research, Indian Institute of Science, Bangalore, Karnataka, India
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Annapurna Kuppa
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Yanhua Chen
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Xiaomeng Du
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Mary F Feitosa
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
| | - Lawrence F Bielak
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA
| | - Jeffrey R O’Connell
- Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA
| | - Solomon K Musani
- Department of Medicine, University of Mississippi, Jackson, MS, USA
| | - Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA
| | | | - Kathleen A Ryan
- Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA
| | | | - Matthew A Allison
- Department of Family Medicine and Public Health, University of California, San Diego, CA, USA
| | - Donald W Bowden
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Matthew J Budoff
- Department of Internal Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - J Jeffrey Carr
- Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Yii-Der I Chen
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA
| | - Kent D Taylor
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA
| | - Adolfo Correa
- Department of Medicine, University of Mississippi, Jackson, MS, USA
| | - Breland F Crudup
- Department of Medicine, University of Mississippi, Jackson, MS, USA
| | - Brian Halligan
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Jian Yang
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Sharon L R Kardia
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA
| | - Lenore J Launer
- Laboratory of Epidemiology and Population Sciences, National Institute of Aging, Bethesda, MD, USA
| | - Yi-Ping Fu
- Framingham Heart Study, NHLBI, NIH, Framingham, MA, USA
- Office of Biostatistics Research, NHLBI, NIH, Bethesda, MD, USA
| | - Thomas H Mosley
- Department of Medicine, University of Mississippi, Jackson, MS, USA
| | - Jill M Norris
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - James G Terry
- Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | | | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA
| | - Lynne E Wagenknecht
- Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Vilmundur Gudnason
- Icelandic Heart Association, Kopavogur, Iceland
- Department of Medicine, University of Iceland, Reykjavik 101, Iceland
| | - Michael A Province
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
| | - Patricia A Peyser
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA
| | - Elizabeth K Speliotes
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
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Nascimento JCR, Matos GA, Pereira LC, Mourão AECCB, Sampaio AM, Oriá RB, Toniutto P. Impact of apolipoprotein E genetic polymorphisms on liver disease: An essential review. Ann Hepatol 2021; 19:24-30. [PMID: 31548169 DOI: 10.1016/j.aohep.2019.07.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 07/04/2019] [Accepted: 07/24/2019] [Indexed: 02/07/2023]
Abstract
Cirrhosis is an advanced stage of liver disease, compromising liver function with systemic health implications and poor quality of life. Hepatitis C virus (HCV) infection and alcoholic liver disease are the main causes of this pathology. However, since genetic factors may play a large role in the progression and severity of liver disease, and as apolipoprotein E (apoE) has been recognised to be mainly synthesised in the liver, apoE polymorphism studies are important to better understand the causal mechanisms in liver diseases. In this review, we summarise up-to-date studies addressing how apoE polymorphisms influence liver cirrhosis and liver transplantation outcomes and potential protective mechanisms. Although more clinical studies are needed to support these findings, the apoE ɛ4 allele seems to be protective against the progression of liver cirrhosis in the majority of aetiologies and the postoperative serum apoE phenotype of the transplanted subject receptors was converted to that of the donor, indicating that >90% of apoE in plasma is synthesised in the hepatic system.
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Affiliation(s)
- José C R Nascimento
- Laboratory of Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil; Department of Anesthesia and Liver Transplantation, Fortaleza General Hospital, Fortaleza, CE, Brazil
| | - Gabriella A Matos
- Laboratory of Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Lianna C Pereira
- Laboratory of Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Anderson E C C B Mourão
- Department of Anesthesia and Liver Transplantation, Fortaleza General Hospital, Fortaleza, CE, Brazil
| | - Aline M Sampaio
- Department of Anesthesia and Liver Transplantation, Fortaleza General Hospital, Fortaleza, CE, Brazil
| | - Reinaldo B Oriá
- Department of Anesthesia and Liver Transplantation, Fortaleza General Hospital, Fortaleza, CE, Brazil.
| | - Pierluigi Toniutto
- Hepatology and Liver Transplantation Unit, Department of Medical Area (DAME) Academic Hospital, University of Udine, Italy
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7
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Zhou T, Li H, Zhong H, Zhong Z, Lin S. Association of apoE gene polymorphisms with lipid metabolism in renal diseases. Afr Health Sci 2020; 20:1368-1381. [PMID: 33402986 PMCID: PMC7751546 DOI: 10.4314/ahs.v20i3.43] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Apolipoprotein E (apoE) plays a central role in the metabolism and homeostasis of lipids. ApoE gene encodes three major isoforms: ε2, ε3 a nd ε4 forming six phenotypes: E2E2, E2E3, E2E4, E3E3, E3E3 and E4E4. Disorders of the lipid metabolism and the homeostasis are frequently coexist in renal diseases. The association between gene polymorphisms of apoE and lipid metabolism were not consistent. This meta-analysis was performed to assess the association between gene polymorphisms of apoE and lipid metabolism in renal diseases. METHODS A pre-defined literatures search and selection of eligible relevant investigations were performed to extract and collect data from electronic databases. RESULTS Sixteen articles were enrolled for the analysis of association between apoE gene polymorphisms and lipid metabolism. Subjects with E3E4 had a higher total cholesterol (TC) than those with E3E3, and subjects with E2E3 had a lower TC than those with E3E3. Subjects with ε2, had a lower TC than those with ε3 or ε4, and subjects with ε4 had a higher TC than those with, ε3. Subjects with E2E2, E2E3 or E4E4 had a higher triglyceride (TG) than those with E3E3. Subjects with ε4 had a higher TG than those with ε3. Subjects with ε2, had a higher level of TG than those with non-ε2. Subjects with E3E4 had a slightly lower high-density lipoprotein (HDL) than those with E3E3. E3E4 appeared to be associated with lower levels of HDL. Subjects with E2E2, E2E3 had a notably lower low-density lipoprotein (LDL) than those with E3E3. Subjects with ε2, had a lower LDL than those with ε3 or ε4 ApoE gene polymorphisms were not associated with very low-density lipoprotein, and lipoprotein (a) [Lp(a)]. Subjects with E2E3 or E2E4 had higher apoE levels than those with E3E3, and subjects with E4E4 had lower apoE levels than those with E3E3. CONCLUSION ApoE gene polymorphisms are associated with the expression of TC, TG HDL, LDL, Lp(a) or apoE.
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Affiliation(s)
- Tianbiao Zhou
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, 515041, Shantou, China
| | - Hongyan Li
- Department of Nephrology, Huadu District People's Hospital, Southern Medical University, Guangzhou, China
| | - Hongzhen Zhong
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, 515041, Shantou, China
| | - Zhiqing Zhong
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, 515041, Shantou, China
| | - Shujun Lin
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, 515041, Shantou, China
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8
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van den Berg EH, Corsetti JP, Bakker SJL, Dullaart RPF. Plasma ApoE elevations are associated with NAFLD: The PREVEND Study. PLoS One 2019; 14:e0220659. [PMID: 31386691 PMCID: PMC6684074 DOI: 10.1371/journal.pone.0220659] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 07/20/2019] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is featured by increased plasma very low density lipoproteins (VLDL). The extent to which plasma apolipoprotein E (ApoE) levels are elevated in NAFLD is unclear. We determined whether plasma ApoE is elevated in subjects with suspected NAFLD. Plasma ApoE and genotypes were determined in 6,762 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. A Fatty Liver Index (FLI) ≥ 60 was used as a proxy of NAFLD. A total of 1,834 participants had a FLI ≥ 60, which coincided with increased triglycerides, non-HDL cholesterol, ApoB and ApoE (all P<0.001). In multivariable linear regression analysis, plasma ApoE levels were positively associated with an elevated FLI when taking account of ApoE genotypes and other clinical and laboratory covariates (fully adjusted model: β = 0.201, P<0.001). Stratified analysis for ApoE genotypes (ApoE ε3ε3 homozygotes, ApoE ε2 carriers, and ApoE ε3ε4 and ε4ε4 carriers combined), also showed positive associations of plasma ApoE levels with an elevated FLI in each group (all P<0.001). In conclusion, it is suggested that NAFLD is characterized by increased plasma ApoE levels, even when taking account of the various ApoE genotypes. Increased plasma ApoE may contribute to altered VLDL metabolism and to increased atherosclerosis susceptibility in NAFLD.
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Affiliation(s)
- Eline H. van den Berg
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- * E-mail:
| | - James P. Corsetti
- Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America
| | - Stephan J. L. Bakker
- Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robin P. F. Dullaart
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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9
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Zhou Y, Mägi R, Milani L, Lauschke VM. Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk. J Lipid Res 2018; 59:1987-2000. [PMID: 30076208 PMCID: PMC6168301 DOI: 10.1194/jlr.p086710] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 07/16/2018] [Indexed: 12/13/2022] Open
Abstract
Abnormal plasma apolipoprotein levels are consistently implicated in CVD risk. Although 30% to 60% of their interindividual variability is genetic, common genetic variants explain only 10% to 20% of these differences. Rare genetic variants may be major sources of the missing heritability, yet quantitative evaluations of their contribution to phenotypic variability are lacking. Here, we analyzed whole-genome and whole-exome sequencing data from 138,632 individuals across seven major human populations to present a systematic overview of genetic apolipoprotein variability. We provide population-specific frequencies of 38 clinically important apolipoprotein alleles and identify further 6,875 genetic variants, 33% of which are novel and 98.7% of which are rare with minor allele frequencies <1%. We predicted the functional impact of rare variants and found that their relative importance differed drastically between genes and among ethnicities. Importantly, we validated the clinical relevance of multiple variants with predicted effects by leveraging association data from the CARDIoGRAM (Coronary Artery Disease Genomewide Replication and Meta-analysis) and Global Lipids Genetics consortia. Overall, we provide a consolidated overview of population-specific apolipoprotein genetics as a valuable data resource for scientists and clinicians, estimate the importance of rare genetic variants for the missing heritability of apolipoprotein-associated disease traits, and pinpoint multiple novel apolipoprotein variants with putative population-specific impacts on serum lipid levels.
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Affiliation(s)
- Yitian Zhou
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden
| | - Reedik Mägi
- Estonian Genome Center, University of Tartu, Tartu, Estonia
| | - Lili Milani
- Estonian Genome Center, University of Tartu, Tartu, Estonia
- Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Volker M Lauschke
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden
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10
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Dose J, Nebel A, Piegholdt S, Rimbach G, Huebbe P. Influence of the APOE genotype on hepatic stress response: Studies in APOE targeted replacement mice and human liver cells. Free Radic Biol Med 2016; 96:264-72. [PMID: 27130033 DOI: 10.1016/j.freeradbiomed.2016.04.031] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 04/22/2016] [Accepted: 04/25/2016] [Indexed: 11/29/2022]
Abstract
Apolipoprotein E (APOE) is a multifunctional plasma protein mainly acting in lipid metabolism. Human APOE is polymorphic with three major isoforms (APOE2, APOE3 and APOE4). Up to 75% of the body's APOE is produced by the liver. There is increasing evidence from studies in brain-derived cells that APOE4 affects mitochondrial function and biogenesis as well as stress and inflammatory responses - processes, whose disturbances are considered hallmarks of the ageing process. However, although the liver is the main production site of APOE, knowledge about the impact of the APOE genotype on hepatic stress response-related processes is rather limited. Therefore, we studied biomarkers of oxidative status (glutathione levels, 3-nitrotyrosine adducts, protein carbonyl concentration), ER stress (XBP1(S), BiP, DDIT3), proteasome activity, mitochondrial function (respiratory complexes, ATP levels and mitochondrial membrane potential as well as biomarkers of mitochondrial biogenesis, fission and fusion), autophagy (LC3, LAMP2A), apoptosis (BCL2, BAX, CYCS) and DNA damage in the liver of APOE targeted replacement (TR) mice and in Huh7 hepatocytes overexpressing the APOE3 and the APOE4 isoform, respectively. APOE4 mice exhibited a lower chymotrypsin-like and a higher trypsin-like proteasome activity. Levels of protein carbonyls were moderately higher in liver tissue of APOE4 vs. APOE3 mice. Other biomarkers of oxidative stress were similar between the two genotypes. Under basal conditions, the stress-response pathways investigated appeared largely unaffected by the APOE genotype. However, upon stress induction, APOE4 expressing cells showed lower levels of adenosine triphosphate (ATP) and lower mRNA levels of the ATP-generating complex V of the mitochondrial respiratory chain. Overall, our findings provide evidence for a rather low influence of the APOE genotype on the hepatic stress response processes investigated in this study.
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Affiliation(s)
- Janina Dose
- Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Str. 6, 24118 Kiel, Germany.
| | - Almut Nebel
- Institute of Clinical Molecular Biology, University of Kiel, University Hospital Schleswig-Holstein, Schittenhelmstr. 12, 24105 Kiel, Germany.
| | - Stefanie Piegholdt
- Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Str. 6, 24118 Kiel, Germany.
| | - Gerald Rimbach
- Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Str. 6, 24118 Kiel, Germany.
| | - Patricia Huebbe
- Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Str. 6, 24118 Kiel, Germany.
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11
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Oriá RB, Murray-Kolb LE, Scharf RJ, Pendergast LL, Lang DR, Kolling GL, Guerrant RL. Early-life enteric infections: relation between chronic systemic inflammation and poor cognition in children. Nutr Rev 2016; 74:374-86. [PMID: 27142301 DOI: 10.1093/nutrit/nuw008] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The intestinal microbiota undergoes active remodeling in the first 6 to 18 months of life, during which time the characteristics of the adult microbiota are developed. This process is strongly influenced by the early diet and enteric pathogens. Enteric infections and malnutrition early in life may favor microbiota dysbiosis and small intestinal bacterial overgrowth, resulting in intestinal barrier dysfunction and translocation of intestinal bacterial products, ultimately leading to low-grade, chronic, subclinical systemic inflammation. The leaky gut-derived low-grade systemic inflammation may have profound consequences on the gut-liver-brain axis, compromising normal growth, metabolism, and cognitive development. This review examines recent data suggesting that early-life enteric infections that lead to intestinal barrier disruption may shift the intestinal microbiota toward chronic systemic inflammation and subsequent impaired cognitive development.
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Affiliation(s)
- Reinaldo B Oriá
- R.B. Oriá is with the Laboratory of Tissue Healing, Ontogeny and Nutrition, Institute of Biomedicine and Department of Morphology, Faculty of Medicine, Federal University of Ceará, Ceará, Fortaleza, Brazil. L.E. Murray-Kolb is with The Pennsylvania State University, University Park, Pennsylvania, USA. R.J. Scharf, G. Kolling, and R.L. Guerrant are with the Center for Global Health, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA. L.L. Pendergast is with the School Psychology Program, Temple University, Philadelphia, Pennsylvania, USA. D.R. Lang is with the Foundation for the National Institutes of Health, Bethesda, Maryland, USA.
| | - Laura E Murray-Kolb
- R.B. Oriá is with the Laboratory of Tissue Healing, Ontogeny and Nutrition, Institute of Biomedicine and Department of Morphology, Faculty of Medicine, Federal University of Ceará, Ceará, Fortaleza, Brazil. L.E. Murray-Kolb is with The Pennsylvania State University, University Park, Pennsylvania, USA. R.J. Scharf, G. Kolling, and R.L. Guerrant are with the Center for Global Health, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA. L.L. Pendergast is with the School Psychology Program, Temple University, Philadelphia, Pennsylvania, USA. D.R. Lang is with the Foundation for the National Institutes of Health, Bethesda, Maryland, USA
| | - Rebecca J Scharf
- R.B. Oriá is with the Laboratory of Tissue Healing, Ontogeny and Nutrition, Institute of Biomedicine and Department of Morphology, Faculty of Medicine, Federal University of Ceará, Ceará, Fortaleza, Brazil. L.E. Murray-Kolb is with The Pennsylvania State University, University Park, Pennsylvania, USA. R.J. Scharf, G. Kolling, and R.L. Guerrant are with the Center for Global Health, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA. L.L. Pendergast is with the School Psychology Program, Temple University, Philadelphia, Pennsylvania, USA. D.R. Lang is with the Foundation for the National Institutes of Health, Bethesda, Maryland, USA
| | - Laura L Pendergast
- R.B. Oriá is with the Laboratory of Tissue Healing, Ontogeny and Nutrition, Institute of Biomedicine and Department of Morphology, Faculty of Medicine, Federal University of Ceará, Ceará, Fortaleza, Brazil. L.E. Murray-Kolb is with The Pennsylvania State University, University Park, Pennsylvania, USA. R.J. Scharf, G. Kolling, and R.L. Guerrant are with the Center for Global Health, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA. L.L. Pendergast is with the School Psychology Program, Temple University, Philadelphia, Pennsylvania, USA. D.R. Lang is with the Foundation for the National Institutes of Health, Bethesda, Maryland, USA
| | - Dennis R Lang
- R.B. Oriá is with the Laboratory of Tissue Healing, Ontogeny and Nutrition, Institute of Biomedicine and Department of Morphology, Faculty of Medicine, Federal University of Ceará, Ceará, Fortaleza, Brazil. L.E. Murray-Kolb is with The Pennsylvania State University, University Park, Pennsylvania, USA. R.J. Scharf, G. Kolling, and R.L. Guerrant are with the Center for Global Health, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA. L.L. Pendergast is with the School Psychology Program, Temple University, Philadelphia, Pennsylvania, USA. D.R. Lang is with the Foundation for the National Institutes of Health, Bethesda, Maryland, USA
| | - Glynis L Kolling
- R.B. Oriá is with the Laboratory of Tissue Healing, Ontogeny and Nutrition, Institute of Biomedicine and Department of Morphology, Faculty of Medicine, Federal University of Ceará, Ceará, Fortaleza, Brazil. L.E. Murray-Kolb is with The Pennsylvania State University, University Park, Pennsylvania, USA. R.J. Scharf, G. Kolling, and R.L. Guerrant are with the Center for Global Health, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA. L.L. Pendergast is with the School Psychology Program, Temple University, Philadelphia, Pennsylvania, USA. D.R. Lang is with the Foundation for the National Institutes of Health, Bethesda, Maryland, USA
| | - Richard L Guerrant
- R.B. Oriá is with the Laboratory of Tissue Healing, Ontogeny and Nutrition, Institute of Biomedicine and Department of Morphology, Faculty of Medicine, Federal University of Ceará, Ceará, Fortaleza, Brazil. L.E. Murray-Kolb is with The Pennsylvania State University, University Park, Pennsylvania, USA. R.J. Scharf, G. Kolling, and R.L. Guerrant are with the Center for Global Health, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA. L.L. Pendergast is with the School Psychology Program, Temple University, Philadelphia, Pennsylvania, USA. D.R. Lang is with the Foundation for the National Institutes of Health, Bethesda, Maryland, USA
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12
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Martins IJ. The Role of Clinical Proteomics, Lipidomics, and Genomics in the Diagnosis of Alzheimer's Disease. Proteomes 2016; 4:proteomes4020014. [PMID: 28248224 PMCID: PMC5217345 DOI: 10.3390/proteomes4020014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 03/24/2016] [Accepted: 03/28/2016] [Indexed: 02/07/2023] Open
Abstract
The early diagnosis of Alzheimer’s disease (AD) has become important to the reversal and treatment of neurodegeneration, which may be relevant to premature brain aging that is associated with chronic disease progression. Clinical proteomics allows the detection of various proteins in fluids such as the urine, plasma, and cerebrospinal fluid for the diagnosis of AD. Interest in lipidomics has accelerated with plasma testing for various lipid biomarkers that may with clinical proteomics provide a more reproducible diagnosis for early brain aging that is connected to other chronic diseases. The combination of proteomics with lipidomics may decrease the biological variability between studies and provide reproducible results that detect a community’s susceptibility to AD. The diagnosis of chronic disease associated with AD that now involves genomics may provide increased sensitivity to avoid inadvertent errors related to plasma versus cerebrospinal fluid testing by proteomics and lipidomics that identify new disease biomarkers in body fluids, cells, and tissues. The diagnosis of AD by various plasma biomarkers with clinical proteomics may now require the involvement of lipidomics and genomics to provide interpretation of proteomic results from various laboratories around the world.
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Affiliation(s)
- Ian James Martins
- School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup 6027, Australia.
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13
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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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14
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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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15
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Han JM, Jo AN, Lee SM, Bae HS, Jun DW, Cho YK, Suk KT, Yoon JH, Ahn SB, Cho YJ, Kim SW, Jang EC. Associations between intakes of individual nutrients or whole food groups and non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol 2014; 29:1265-72. [PMID: 24955455 DOI: 10.1111/jgh.12520] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Dietary factors are closely associated with the risk of non-alcoholic fatty liver disease (NAFLD). Asian and Western diets differ in energy-nutrient composition, fatty-acid composition, and main nutritional sources; therefore, the implications would be limited if the Western-oriented study results were applied to Asian patients. We aimed to identify the nutrient and food group intakes of a typical Asian diet and assess their effects on NAFLD risk. METHODS In total, 348 subjects were recruited from 5 participating hospitals. Information on sociodemographic characteristics and health-related behaviors were obtained through face-to-face interviews. NAFLD was diagnosed by ultrasound. Dietary intakes were assessed with a 24-h recall applying a multiple-pass approach and 4-day food records that included 1 or 2 weekend days. RESULTS There were no significant differences in health-related behaviors between the cases and controls except for smoking behavior. The cases had elevated triacylglycerol, fasting glucose, and low-density lipoprotein cholesterol levels compared with the controls. In men, after adjusting for variables, low intakes of vitamin C (odds ratio [OR], 4.23), vitamin K (OR, 3.93), folate (OR, 3.37), omega-3 fatty acids (OR, 2.16), and nuts and seeds (OR, 3.66) were associated with a significantly higher risk for developing NAFLD. In women, vitamin K (OR, 2.54) and vegetable (OR, 4.11) intakes showed a significant beneficial effect for lowering NAFLD risk. CONCLUSIONS Adequate intakes of vitamin C, vitamin K, folate, omega-3 fatty acids, nuts and seeds, and vegetables may help in preventing NAFLD in Korean adults.
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Miele L, Dall’Armi V, Cefalo C, Nedovic B, Arzani D, Amore R, Rapaccini G, Gasbarrini A, Ricciardi W, Grieco A, Boccia S. A case-control study on the effect of metabolic gene polymorphisms, nutrition, and their interaction on the risk of non-alcoholic fatty liver disease. GENES & NUTRITION 2014; 9:383. [PMID: 24402518 PMCID: PMC3968292 DOI: 10.1007/s12263-013-0383-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 12/28/2013] [Indexed: 01/01/2023]
Abstract
The oxidative stress is a key issue in the etiology of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to evaluate the effect of metabolic gene polymorphisms involved in the oxidative stress (GSTT1, GSTM1, SULT1A1, CYP2E1, and 1A1), lifestyle and nutrition aspects, and their interaction, on the risk of NAFLD. We enrolled 294 cases and 359 controls, and collected demographics, anthropometric, lifestyle, and nutrition data. A subgroup of NAFLD provided additional data on nutrients and on physical activity engagement. Each patient provided a blood sample for DNA extraction and genotyping. Clinical and laboratory data were collected from cases. Multivariable analysis shows a significant protective effect of age, gender, and moderate drinking habits on the risk of NAFLD, while an increased risk for greater consumption of fruit and grilled meat or fish. Significant interactions were reported between alcohol consumption, fruit intake, grilled meat and fish, and selected genetic variants. From the subgroup analysis, a moderate/high consumption of fat and/or grilled meat/fish, and a high consumption of white meat increase the risk of NAFLD. Engaging any physical activity at least 1 time/week halves the risk of NAFLD. Besides confirming the beneficial effect of moderate alcohol intake and regular physical activity, and the increased risk associated with high fruit and fat intake, for the first time, we report a detrimental effect of grilled food on NAFLD risk. An effect modification by selected gene variants increases the risk in combination with fruit and grilled food intake.
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Affiliation(s)
- Luca Miele
- />Institute of Internal Medicine, Università Cattolica del Sacro Cuore, Rome, Italy
- />Internal Medicine and Gastroenterology Unit, Complesso Integrato Columbus, Rome, Italy
| | - Valentina Dall’Armi
- />Clinical and Molecular Epidemiology, Area of Systems Approaches and Non Communicable Diseases, IRCCS San Raffaele Pisana, Rome, Italy
| | - Consuelo Cefalo
- />Institute of Internal Medicine, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Bojan Nedovic
- />Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, L.go F. Vito, 00168 Rome, Italy
| | - Dario Arzani
- />Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, L.go F. Vito, 00168 Rome, Italy
| | - Rosarita Amore
- />Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, L.go F. Vito, 00168 Rome, Italy
| | - Gianlodovico Rapaccini
- />Institute of Internal Medicine, Università Cattolica del Sacro Cuore, Rome, Italy
- />Internal Medicine and Gastroenterology Unit, Complesso Integrato Columbus, Rome, Italy
| | - Antonio Gasbarrini
- />Institute of Internal Medicine, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Walter Ricciardi
- />Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, L.go F. Vito, 00168 Rome, Italy
| | - Antonio Grieco
- />Institute of Internal Medicine, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Stefania Boccia
- />Clinical and Molecular Epidemiology, Area of Systems Approaches and Non Communicable Diseases, IRCCS San Raffaele Pisana, Rome, Italy
- />Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, L.go F. Vito, 00168 Rome, Italy
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Apolipoprotein E gene variants on the risk of end stage renal disease. PLoS One 2013; 8:e83367. [PMID: 24349494 PMCID: PMC3862680 DOI: 10.1371/journal.pone.0083367] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 11/01/2013] [Indexed: 11/19/2022] Open
Abstract
Objective End-stage renal disease (ESRD) is a severe health concern over the world. Associations between apolipoprotein E (apoE) gene polymorphisms and the risk of ESRD remained inconclusive. This study aimed to investigate the association between apoE gene polymorphisms and ESRD susceptibility. Methods Databases including PubMed, Embase, Web of Science and the Cochrane Library were searched to find relevant studies. Meta-analysis method was used synthesize the eligible studies. Results Sixteen pertinent case-control studies which included 3510 cases and 13924 controls were analyzed. A significant association was found between ε2 allele and the ESRD risk (odds ratio (OR) = 1.30, 95% confidence interval (CI) 1.15–1.46, P < 0.0001; I2 = 18%, P for heterogeneity = 0.24). The ε2ε3, ε2ε4, ε3ε3, ε3ε4, ε4ε4, ε3 and ε4 were not associated with the susceptibility of ESRD. In the subgroup analysis by ethnicity, there was a statistically significant association between ε2ε3 or ε2 allele and ESRD risk in East Asians (OR = 1.66, 95% CI 1.31–2.10, P < 0.0001; OR = 1.62, 95% CI 1.31–2.01, P < 0.0001, respectively), but not in Caucasians. E2 carriers had higher plasma apoE (mean difference = 16.24 mg/L, 95% CI 7.76-24.73, P = 0.0002) than the (ε3 + ε4) carriers in patients with ESRD. The publication bias was not significant. Conclusion The ε2 allele of apoE gene might increase the risk of ESRD. E2 carriers expressed higher level of plasma apoE in patients with ESRD. More well-designed studies are needed to confirm these associations in the future.
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Zhou TB, Jiang ZP, Yin SS, Qin YH. Relationship between apolipoprotein E gene polymorphism and total cholesterol level in patients with kidney diseases. World J Meta-Anal 2013; 1:138-146. [DOI: 10.13105/wjma.v1.i3.138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2013] [Revised: 06/13/2013] [Accepted: 08/06/2013] [Indexed: 02/05/2023] Open
Abstract
AIM: To evaluate the association between apolipoprotein E (apoE) gene polymorphism and total cholesterol (TC) level in patients with kidney diseases.
METHODS: A predefined literature search was performed to collect data from the electronic databases of PubMed, Embase and the Cochrane Library and eligible relevant studies reporting the association of apoE gene polymorphism with TC level in patients with kidney diseases were recruited for meta-analysis.
RESULTS: Twenty-one studies were identified for the analysis of association between apoE gene polymorphism and TC level in patients with kidney disease. Subjects with E3E4 had a higher TC than those with E3E3 [weighted mean differences (WMD) = 2.14, P = 0.01] and subjects with E2E3 had a lower TC than those with E3E3 (WMD = -1.93, P = 0.01). Subjects with ε2 had a lower TC than those with ε3 (ε2 vs ε3: WMD = -1.23, P = 0.002; ε2 vs ε4: WMD = -2.77, P ﹤0.0001) and subjects with 3 had a lower TC than those with 4 (WMD = -0.79, P = 0.03).
CONCLUSION: Subjects with apoE E3E4 and ε4 had a higher TC level and subjects with apoE E2E3 and ε2 had a higher TC level in patients with kidney disease. However, more well-designed studies should be performed in the future to confirm these findings.
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Dong CQ, Luo YG, Dong K, Chen C, Liu Q, Yang TQ. Relationship between apolipoprotein E gene polymorphism with triglyceride level in patients with renal diseases. Ren Fail 2013; 35:1449-54. [PMID: 24001346 DOI: 10.3109/0886022x.2013.829407] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Apolipoprotein E (apoE), one of the major plasma lipoproteins, plays a major role in the transport and metabolism of lipids by acting as a ligand. apoE gene contains three potential alleles: ϵ2, ϵ3 and ϵ4, forming six genotypes: E2E2, E2E3, E2E4, E3E3, E3E3 and E4E4. Association between apoE gene polymorphism and triglyceride (TG) is still controversial. There was not any meta-analysis to explore the association of apoE gene polymorphism with triglyceride level, and this meta-analysis was performed to evaluate the association between apoE gene polymorphism and triglyceride in patients with renal diseases. A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases. Twenty-four articles were identified for the analysis of association between apoE gene polymorphism and triglyceride level. Subjects with E2E3 or E3E4 had a higher TG than those with E3E3. Subjects with ϵ4 had a higher TG than those with ϵ3. Subjects with ϵ2 had a slightly higher TG than those with ϵ3, although there was no statistical difference. Interestingly, subjects with ϵ4 had a much higher TG than those with ϵ2. In conclusion, E2E3, E3E4 or ϵ4 was associated with higher level of TG. However, more studies should be performed in the future.
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Affiliation(s)
- Chun-Qiang Dong
- Department of Pediatric Surgery, The First Affiliated Hospital of GuangXi Medical University , NanNing , China
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Jiang ZG, Robson SC, Yao Z. Lipoprotein metabolism in nonalcoholic fatty liver disease. J Biomed Res 2012; 27:1-13. [PMID: 23554788 PMCID: PMC3596749 DOI: 10.7555/jbr.27.20120077] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Revised: 08/23/2012] [Accepted: 08/29/2012] [Indexed: 12/18/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), an escalating health problem worldwide, covers a spectrum of pathologies characterized by fatty accumulation in hepatocytes in early stages, with potential progression to liver inflammation, fibrosis, and failure. A close, yet poorly understood link exists between NAFLD and dyslipidemia, a constellation of abnormalities in plasma lipoproteins including triglyceride-rich very low density lipoproteins. Apolipoproteins are a group of primarily liver-derived proteins found in serum lipoproteins; they not only play an extracellular role in lipid transport between vital organs through circulation, but also play an important intracellular role in hepatic lipoprotein assembly and secretion. The liver functions as the central hub for lipoprotein metabolism, as it dictates lipoprotein production and to a significant extent modulates lipoprotein clearance. Lipoprotein metabolism is an integral component of hepatocellular lipid homeostasis and is implicated in the pathogenesis, potential diagnosis, and treatment of NAFLD.
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Affiliation(s)
- Zhenghui Gordon Jiang
- Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA
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Zhou TB, Qin YH, Xu HL. Association of apoE gene expression and its gene polymorphism with nephrotic syndrome susceptibility: a meta-analysis of experimental and human studies. Mol Biol Rep 2012; 39:9347-9354. [PMID: 22760259 DOI: 10.1007/s11033-012-1751-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Accepted: 06/07/2012] [Indexed: 02/07/2023]
Abstract
Apolipoprotein E (apoE) is a major protein in the lipoprotein transport system that plays a well established role in lipids metabolism. apoE gene contains three potential alleles: ε2, ε3 and ε4, forming six genotypes: ε2ε2, ε2ε3, ε2ε4, ε3ε3, ε3ε3 and ε4ε4. The disorder of lipids metabolism is an important feature for nephrotic syndrome (NS). There were some investigations reporting that apoE and its gene polymorphism was associated with NS susceptibility. However, the mechanism was unclear and the association was still controversial. This meta-analysis was performed to evaluate the association between apoE and NS risk in experimental and human studies. A predefined literature search and selection of eligible relevant studies were performed to collect the data from electronic databases, and eligible investigations were synthesized using meta-analysis method. In experimental models, twelve comparisons were included and a definitely positive association was observed between apoE protein expression and NS susceptibility (WMD = 1.88, P < 0.00001). However, in human, there was only two studies included for meta-analysis and a positive association between apoE protein expression and NS susceptibility wasn't found (OR = 108.10, P = 0.32). Interestingly, ε3ε3, ε3ε4, ε3 and ε4 were associated with NS susceptibility (ε3ε3: OR = 0.56, P = 0.002; ε3ε4: OR = 1.91, P = 0.02; ε3: OR = 0.61, P = 0.001; ε4: OR = 1.85, P = 0.009). In conclusion, the apoE gene expression was associated with the NS susceptibility in experimental studies, and the apoE ε3ε3, ε3ε4, ε3 and ε4 were associated with the onset of NS in human studies. This study supported that the disorder of apoE was one of the possible causes for NS risk. However, more studies should be performed to investigate this relationship in the future.
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Affiliation(s)
- Tian-Biao Zhou
- Department of Pediatrics, The First Affiliated Hospital of GuangXi Medical University, Nanning 530021, China
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