|
1
|
Yonis N, Mousa A, Yousef MH, Ghouneimy AM, Dabbish AM, Abdelzaher H, Hussein MA, Ezzeldin S, Adel AA, Mahmoud YH, El-Khazragy N, Abdelnaser A. Cracking the code: lncRNA-miRNA-mRNA integrated network analysis unveiling lncRNAs as promising non-invasive NAFLD biomarkers toward precision diagnosis. Comput Biol Chem 2025; 115:108325. [PMID: 39832417 DOI: 10.1016/j.compbiolchem.2024.108325] [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: 11/13/2024] [Revised: 12/15/2024] [Accepted: 12/22/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) involves abnormal fat accumulation in the liver, mainly as triglycerides. It ranges from steatosis to non-alcoholic steatohepatitis (NASH), which can lead to inflammation, cellular damage, liver fibrosis, cirrhosis, or hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) are crucial for regulating gene expression across various conditions. LncRNAs are emerging as potential putative diagnostic markers for NAFLD-associated HCC. METHODS We used two human and two mouse datasets from the Gene Expression Omnibus to analyze the expression profiles of mRNAs and lncRNAs. We created a network linking lncRNAs, miRNAs, and mRNAs to investigate the relationships among these RNA types. Additionally, we identified NAFLD-related lncRNAs from existing literature. We then quantified the expression levels of four specific lncRNAs, including PVT1, DUBR, SNHG17, and SNHG14, in the serum of 92 Egyptian participants using qPCR. Finally, we performed a Receiver Operating Characteristic analysis to evaluate the diagnostic potential of the candidate lncRNAs. RESULTS Our data suggests that maternally expressed gene 3 (MEG3), H19, and DPPA2 Upstream Binding RNA (DUBR) were significantly upregulated, and plasmacytoma variant translocation 1 (PVT1) was markedly downregulated. PVT1 showed the highest diagnostic accuracy for both NAFLD and NASH. The combined panels of PVT1 +H19 for NAFLD and PVT1 +H19 +DUBR for NASH demonstrated high diagnostic potential. Uniquely, PVT1 can distinguish between NAFLD and NASH. PVT1 exhibited strong diagnostic potential for NAFLD and NASH, individually and in combination with other lncRNAs. CONCLUSION Our study identifies four lncRNAs as putative biomarkers with high specificity and accuracy, individually or combined, for differentiating between NAFLD and NASH. Healthy volunteers with PVT1 possess the highest diagnostic accuracy and significantly discriminate between NAFLD and NASH.
Collapse
Affiliation(s)
- Nouran Yonis
- Institute of Global Health and Human Ecology (IGHHE), School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Ahmed Mousa
- University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt
| | - Mohamed H Yousef
- Biotechnology Graduate Program, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Ahmed M Ghouneimy
- Department of Biology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Areeg M Dabbish
- Biotechnology Graduate Program, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Hana Abdelzaher
- Institute of Global Health and Human Ecology (IGHHE), School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Mohamed Ali Hussein
- Institute of Global Health and Human Ecology (IGHHE), School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt
| | - Shahd Ezzeldin
- Basic Research Department, Proteomics and Metabolomics Research Program, Children's Cancer Hospital 57357 (CCHE-57357), Cairo, Egypt
| | - Abdelmoneim A Adel
- Hematology and Gastroenterology Department, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Egypt
| | - Yosra H Mahmoud
- Hematology and Gastroenterology Department, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Egypt
| | - Nashwa El-Khazragy
- Clinical Pathology and Hematology Department, Faculty of Medicine, Ain Shams University Biomedical Research Department, Cairo 11381, Egypt
| | - Anwar Abdelnaser
- Institute of Global Health and Human Ecology (IGHHE), School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt.
| |
Collapse
|
|
2
|
Moore MP, Wang X, Kennelly JP, Shi H, Ishino Y, Kano K, Aoki J, Cherubini A, Ronzoni L, Guo X, Chalasani NP, Khalid S, Saleheen D, Mitsche MA, Rotter JI, Yates KP, Valenti L, Kono N, Tontonoz P, Tabas I. Low MBOAT7 expression, a genetic risk for MASH, promotes a profibrotic pathway involving hepatocyte TAZ upregulation. Hepatology 2025; 81:576-590. [PMID: 38776184 PMCID: PMC11822724 DOI: 10.1097/hep.0000000000000933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 04/03/2024] [Indexed: 05/24/2024]
Abstract
BACKGROUND AND AIMS The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established metabolic dysfunction-associated steatotic liver disease dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear. APPROACH AND RESULTS We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity and increased IHH mRNA. CONCLUSIONS This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis, adds new insight into an established genetic locus for MASH, and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7.
Collapse
Affiliation(s)
- Mary P Moore
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Xiaobo Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - John Paul Kennelly
- Department of Pathology and Laboratory Medicine, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Hongxue Shi
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Yuki Ishino
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Alessandro Cherubini
- Precisione Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Luisa Ronzoni
- Precisione Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - 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, California, USA
| | - Naga P Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Shareef Khalid
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Center for Non-Communicable Disease, Karachi, Karachi City, Sindh, Pakistan
| | - Danish Saleheen
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Center for Non-Communicable Disease, Karachi, Karachi City, Sindh, Pakistan
| | - Matthew A Mitsche
- Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, 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, California, USA
| | - Katherine P Yates
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Luca Valenti
- Precisione Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
| | - Nozomu Kono
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Ira Tabas
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
- Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, New York, USA
- Columbia University Digestive and Liver Disease Research Center, New York, NY
| |
Collapse
|
|
3
|
Jamialahmadi O, De Vincentis A, Tavaglione F, Malvestiti F, Li-Gao R, Mancina RM, Alvarez M, Gelev K, Maurotti S, Vespasiani-Gentilucci U, Rosendaal FR, Kozlitina J, Pajukanta P, Pattou F, Valenti L, Romeo S. Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease. Nat Med 2024; 30:3614-3623. [PMID: 39653778 PMCID: PMC11645285 DOI: 10.1038/s41591-024-03284-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 08/30/2024] [Indexed: 12/15/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by an excess of lipids, mainly triglycerides, in the liver and components of the metabolic syndrome, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence that MASLD clusters with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity identifying 27 previously unknown genetic loci associated with MASLD (n = 36,394), six replicated in four independent cohorts (n = 3,903). Next, we generated two partitioned polygenic risk scores based on the presence of lipoprotein retention in the liver. The two polygenic risk scores suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease. These findings shed light on the heterogeneity of MASLD and have the potential to improve the prediction of clinical trajectories and inform precision medicine approaches.
Collapse
Grants
- 777377 EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
- 22 2270 Pj Cancerfonden (Swedish Cancer Society)
- R01 DK132775 NIDDK NIH HHS
- 2023-02079 Vetenskapsrådet (Swedish Research Council)
- R01 HG010505 NHGRI NIH HHS
- R01 HL170604 NHLBI NIH HHS
- the Swedish state under the Agreement between the Swedish government and the county councils (the ALF agreement, ALFGBG-965360); Swedish Heart Lung Foundation (20220334); Wallenberg Academy Fellows from the Knut and Alice Wallenberg Foundation (KAW 2017.0203); Novonordisk Distinguished Investigator Grant - Endocrinology and Metabolism (NNF23OC0082114; Novonordisk Project grants in Endocrinology and Metabolism (NNF20OC0063883).
- NIH grants R01HG010505, R01DK132775, and R01HL170604
- Italian Ministry of Health (Ministero della Salute), Ricerca Finalizzata 2016, RF-2016-02364358; Italian Ministry of Health, Ricerca Finalizzata 2021 (TERS) RF-2021-12373889; Italian Ministry of Health (national coordinator) (2023-2026) Ricerca Finalizzata PNRR 2022 (PNRR-MAD-2022-12375656); Italian Ministry of Health (Ministero della Salute), Rete Cardiologica “CV-PREVITAL”; Fondazione Patrimonio Ca’ Granda, “Liver BIBLE” (PR-0361); The European Union, H2020-ICT-2018-20/H2020-ICT-2020-2 programme “Photonics” under grant agreement No. 101016726-REVEAL,Gilead_IN-IT-989-5790;The European Union, HORIZON-MISS-2021-CANCER-02-03 programme “Genial” under grant agreement “101096312#x201D;; Italian Ministry of University and Research, PNRR – M4 - C2 “di R&S su alcune Key Enabling Technologies” “National Center for Gene Therapy and Drugs based on RNA Technology” CN3 Spoke 4, group ASSET: A sex-specific approach to NAFLD targeting.
Collapse
Affiliation(s)
- Oveis Jamialahmadi
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
| | - Antonio De Vincentis
- Operative Unit of Internal Medicine, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Research Unit of Internal Medicine, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Federica Tavaglione
- Operative Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Francesco Malvestiti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Ruifang Li-Gao
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Rosellina M Mancina
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
- Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
- Department of Life Science, Health, and Health Professions, Link Campus University, Rome, Italy
| | - Marcus Alvarez
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Kyla Gelev
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Samantha Maurotti
- Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Umberto Vespasiani-Gentilucci
- Operative Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Frits Richard Rosendaal
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Julia Kozlitina
- The Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Päivi Pajukanta
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA
- Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - François Pattou
- Service de chirurgie générale et endocrinienne, Centre Hospitalier Universitaire de Lille, Lille, France
- European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
- Precision Medicine - Biological Resource Center, Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy.
- Department of Medicine (H7), Karolinska Institute, Huddinge, Stockholm, Sweden.
- Department of Endocrinology, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
| |
Collapse
|
|
4
|
Ebrahimi F, Ebrahimi R, Hagström H, Sundström J, Sun J, Bergman D, Forss A, Ludvigsson JF. Risk of Major Adverse Cardiovascular Outcomes in Families With MASLD: A Population-Based Multigenerational Cohort Study. Circ Cardiovasc Qual Outcomes 2024; 17:e010912. [PMID: 39503614 DOI: 10.1161/circoutcomes.124.010912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 09/16/2024] [Indexed: 11/08/2024]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a risk factor for cardiovascular disease. However, whether family members of individuals with MASLD also share an increased cardiovascular risk is unknown. METHODS We created a nationwide multigenerational cohort study identifying all family members of Swedish adults diagnosed with biopsy-proven MASLD (1969-2017) and of matched general population comparators (by age, sex, calendar year, and county of residence). We calculated incidence rates and used Cox models to calculate adjusted hazard ratios (aHRs) and 95% CIs for incident major adverse cardiovascular events (MACE), including acute myocardial infarction, stroke, hospitalization for heart failure, or cardiovascular death. Cox models were adjusted for education, country of birth, diabetes, hypertension, obesity, dyslipidemia, chronic kidney disease, chronic obstructive pulmonary disease, and the Charlson comorbidity index. RESULTS We identified 22 267 MASLD first-degree relatives (FDRs; parents, siblings, and offspring) and 5687 MASLD spouses, as well as 118 056 comparator FDRs and 29 389 comparator spouses without earlier cardiovascular disease. Overall, the mean age was 41.8 years (SD, 18.0), and 51.5% were females. Over a median of 24.6 years, the incidence rate for MACE was higher in MASLD FDRs than in comparator FDRs (65.0 versus 62.5/10 000 person-years; aHR, 1.06 [95% CI, 1.01-1.11]). MASLD FDRs had higher rates of acute myocardial infarction (23.0 versus 20.9/10 000 person-years; aHR, 1.09 [95% CI, 1.01-1.18]) and cardiovascular death (aHR, 1.09 [95% CI, 1.01-1.18]). Across generations of FDRs, the risk of MACE was uniformly increased with no differences by relationship (ie, parents, siblings, and offspring; Pinteraction>0.05). MASLD spouses were also at an increased risk of MACE (117.6 versus 103.5/10 000 person-years; aHR, 1.09 [95% CI, 1.01-1.18]). CONCLUSIONS First-degree relatives of individuals with biopsy-proven MASLD are at slightly higher risk of incident MACE, but absolute risks do not support early screening for cardiovascular disease. Shared lifestyle factors may be the main contributors, as spouses of MASLD patients also had higher risks of MACE.
Collapse
Affiliation(s)
- Fahim Ebrahimi
- Department of Medical Epidemiology and Biostatistics (F.E., J. Sun, D.B., A.F., J.F.L.), Karolinska Institutet, Stockholm, Sweden
- Department of Gastroenterology and Hepatology, Clarunis University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland (F.E.)
| | - Ramin Ebrahimi
- Division of Cardiology, Department of Internal Medicine B, University Medicine Greifswald, Germany (R.E.)
| | - Hannes Hagström
- Department of Medicine, Huddinge (H.H.), Karolinska Institutet, Stockholm, Sweden
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden (H.H.)
| | - Johan Sundström
- Department of Medical Sciences, Uppsala University, Sweden (J. Sundström)
| | - Jiangwei Sun
- Department of Medical Epidemiology and Biostatistics (F.E., J. Sun, D.B., A.F., J.F.L.), Karolinska Institutet, Stockholm, Sweden
| | - David Bergman
- Department of Medical Epidemiology and Biostatistics (F.E., J. Sun, D.B., A.F., J.F.L.), Karolinska Institutet, Stockholm, Sweden
| | - Anders Forss
- Department of Medical Epidemiology and Biostatistics (F.E., J. Sun, D.B., A.F., J.F.L.), Karolinska Institutet, Stockholm, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics (F.E., J. Sun, D.B., A.F., J.F.L.), Karolinska Institutet, Stockholm, Sweden
- Department of Pediatrics, Örebro University Hospital, Sweden (J.F.L.)
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY (J.F.L.)
| |
Collapse
|
|
5
|
Herrera-Marcos LV, Arbones-Mainar JM, Osada J. Lipoprotein Lipidomics as a Frontier in Non-Alcoholic Fatty Liver Disease Biomarker Discovery. Int J Mol Sci 2024; 25:8285. [PMID: 39125855 PMCID: PMC11311740 DOI: 10.3390/ijms25158285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 07/16/2024] [Accepted: 07/27/2024] [Indexed: 08/12/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by the build-up of fat in the liver of individuals in the absence of alcohol consumption. This condition has become a burden in modern societies aggravated by the lack of appropriate predictive biomarkers (other than liver biopsy). To better understand this disease and to find appropriate biomarkers, a new technology has emerged in the last two decades with the ability to explore the unmapped role of lipids in this disease: lipidomics. This technology, based on the combination of chromatography and mass spectrometry, has been extensively used to explore the lipid metabolism of NAFLD. In this review, we aim to summarize the knowledge gained through lipidomics assays exploring tissues, plasma, and lipoproteins from individuals with NAFLD. Our goal is to identify common features and active pathways that could facilitate the finding of a reliable biomarker from this field. The most frequent observation was a variable decrease (1-9%) in polyunsaturated fatty acids in phospholipids and non-esterified fatty acids in NAFLD patients, both in plasma and liver. Additionally, a reduction in phosphatidylcholines is a common feature in the liver. Due to the scarcity of studies, further research is needed to properly detect lipoprotein, plasma, and tissue lipid signatures of NAFLD etiologies, and NAFLD subtypes, and to define the relevance of this technology in disease management strategies in the push toward personalized medicine.
Collapse
Affiliation(s)
- Luis V. Herrera-Marcos
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Universidad de Zaragoza, E-50013 Zaragoza, Spain; (L.V.H.-M.); (J.O.)
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, E-50013 Zaragoza, Spain
- Instituto de Investigación Sanitaria (IIS) Aragon, E-50009 Zaragoza, Spain
- CIBER Fisiopatología Obesidad y Nutrición (CIBERObn), Instituto Salud Carlos III, E-28029 Madrid, Spain
| | - Jose M. Arbones-Mainar
- Instituto de Investigación Sanitaria (IIS) Aragon, E-50009 Zaragoza, Spain
- CIBER Fisiopatología Obesidad y Nutrición (CIBERObn), Instituto Salud Carlos III, E-28029 Madrid, Spain
- Adipocyte and Fat Biology Laboratory (AdipoFat), Translational Research Unit, University Hospital Miguel Servet, E-50013 Zaragoza, Spain
- Instituto Aragonés de Ciencias de la Salud (IACS), E-50009 Zaragoza, Spain
| | - Jesús Osada
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Universidad de Zaragoza, E-50013 Zaragoza, Spain; (L.V.H.-M.); (J.O.)
- Instituto Agroalimentario de Aragón, CITA-Universidad de Zaragoza, E-50013 Zaragoza, Spain
- Instituto de Investigación Sanitaria (IIS) Aragon, E-50009 Zaragoza, Spain
- CIBER Fisiopatología Obesidad y Nutrición (CIBERObn), Instituto Salud Carlos III, E-28029 Madrid, Spain
| |
Collapse
|
|
6
|
Gato S, García-Fernández V, Gil-Gómez A, Rojas Á, Montero-Vallejo R, Muñoz-Hernández R, Romero-Gómez M. Navigating the Link Between Non-alcoholic Fatty Liver Disease/Non-alcoholic Steatohepatitis and Cardiometabolic Syndrome. Eur Cardiol 2024; 19:e03. [PMID: 38807856 PMCID: PMC11131154 DOI: 10.15420/ecr.2023.26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 12/27/2023] [Indexed: 05/30/2024] Open
Abstract
The global prevalence of non-alcoholic fatty liver disease (NAFLD) is nearly 25% and is increasing rapidly. The spectrum of liver damage in NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis, characterised by the presence of lobular inflammation and hepatocyte ballooning degeneration, with or without fibrosis, which can further develop into cirrhosis and hepatocellular carcinoma. Not only is NAFLD a progressive liver disease, but numerous pieces of evidence also point to extrahepatic consequences. Accumulating evidence suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); in fact, CVDs are the most common cause of mortality in patients with NAFLD. Obesity, type 2 diabetes and higher levels of LDL are common risk factors in both NAFLD and CVD; however, how NAFLD affects the development and progression of CVD remains elusive. In this review, we comprehensively summarise current data on the key extrahepatic manifestations of NAFLD, emphasising the possible link between NAFLD and CVD, including the role of proprotein convertase substilisin/kenin type 9, extracellular vesicles, microbiota, and genetic factors.
Collapse
Affiliation(s)
- Sheila Gato
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
| | - Vanessa García-Fernández
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
| | - Antonio Gil-Gómez
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
| | - Ángela Rojas
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
| | - Rocío Montero-Vallejo
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
| | - Rocío Muñoz-Hernández
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
- Departamento de Fisiología, Facultad de Biología, Universidad de SevillaSeville, Spain
| | - Manuel Romero-Gómez
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSeville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)Madrid, Spain
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen del RocíoSeville, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad de SevillaSeville, Spain
| |
Collapse
|
|
7
|
León-Mengíbar J, Sánchez E, Herrerías F, De La Fuente MC, Santamaría M, Valdivielso JM, Bermúdez-López M, Castro E, Pallarés J, Matias-Guiu X, Vilardell F, Caixàs A, Bueno M, Martí R, Lecube A. Influence of nonalcoholic fatty liver disease severity on carotid adventitial vasa vasorum. Front Endocrinol (Lausanne) 2024; 15:1366015. [PMID: 38774226 PMCID: PMC11106423 DOI: 10.3389/fendo.2024.1366015] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/22/2024] [Indexed: 05/24/2024] Open
Abstract
Introduction Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the world's population and encompasses a spectrum of liver conditions, from non-alcoholic steatohepatitis (NASH) to inflammation and fibrosis. In addition, NAFLD also links to extrahepatic conditions like diabetes or obesity. However, it remains unclear if NAFLD independently correlates with the onset and progression of atherosclerosis. Material and methods This cross-sectional study aimed to explore the relationship between NAFLD severity, assessed via liver biopsy, and early atherosclerosis using adventitial vasa vasorum (VV) density. It included 44 patients with obesity (33 with steatosis, 11 with NASH) undergoing bariatric surgery. Results Results revealed no significant differences in adventitial VV density between steatosis and NASH groups, neither in the mean values [0.759 ± 0.104 vs. 0.780 ± 0.043, P=0.702] nor left-right sides. Similarly, carotid intima-media thickness (cIMT) did not vary between these groups. Additionally, no linear correlation existed between VV density and cIMT. Only gender showed an association with VV density. Conclusion These findings suggest that NASH severity doesn't independently drive early atherosclerosis or affects cIMT. Gender might play a role in early atherosclerotic disease in NAFLD, impacting VV density and cIMT. This highlights the need to consider other risk factors when evaluating cardiovascular risk in NAFLD patients.
Collapse
Affiliation(s)
- Josep León-Mengíbar
- Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova, Lleida, Spain
- Obesity, Diabetes and Metabolism (ODIM) Research Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain
| | - Enric Sánchez
- Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova, Lleida, Spain
- Obesity, Diabetes and Metabolism (ODIM) Research Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain
- Medicine and Surgery Department, University of Lleida, Lleida, Spain
| | - Ferrán Herrerías
- Gastrointestinal Surgery Department, Arnau de Vilanova University Hospital, Lleida, Spain
- Surgery Research Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain
| | - Mari Cruz De La Fuente
- Gastrointestinal Surgery Department, Arnau de Vilanova University Hospital, Lleida, Spain
- Surgery Research Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain
| | - Maite Santamaría
- Gastrointestinal Surgery Department, Arnau de Vilanova University Hospital, Lleida, Spain
- Surgery Research Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain
| | - José Manuel Valdivielso
- Medicine and Surgery Department, University of Lleida, Lleida, Spain
- Vascular and Renal Translational Research Group, Institut de Recerca Biomèdica de Lleida (RBLleida), Lleida, Spain
| | - Marcelino Bermúdez-López
- Medicine and Surgery Department, University of Lleida, Lleida, Spain
- Vascular and Renal Translational Research Group, Institut de Recerca Biomèdica de Lleida (RBLleida), Lleida, Spain
| | - Eva Castro
- Medicine and Surgery Department, University of Lleida, Lleida, Spain
- Vascular and Renal Translational Research Group, Institut de Recerca Biomèdica de Lleida (RBLleida), Lleida, Spain
| | - Judit Pallarés
- Department of Pathology and Molecular Genetics, Arnau de Vilanova University Hospital, Institut de Recerca Biomèdica (IRB) and University of Lleida, Lleida, Spain
| | - Xavier Matias-Guiu
- Department of Pathology and Molecular Genetics, Arnau de Vilanova University Hospital, Institut de Recerca Biomèdica (IRB) and University of Lleida, Lleida, Spain
| | - Felip Vilardell
- Department of Pathology and Molecular Genetics, Arnau de Vilanova University Hospital, Institut de Recerca Biomèdica (IRB) and University of Lleida, Lleida, Spain
| | - Assumpta Caixàs
- Endocrinology and Nutrition Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (IPT-CERCA), Medicine Department, Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Marta Bueno
- Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova, Lleida, Spain
- Obesity, Diabetes and Metabolism (ODIM) Research Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain
| | - Raquel Martí
- Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova, Lleida, Spain
- Obesity, Diabetes and Metabolism (ODIM) Research Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain
| | - Albert Lecube
- Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova, Lleida, Spain
- Obesity, Diabetes and Metabolism (ODIM) Research Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain
- Medicine and Surgery Department, University of Lleida, Lleida, Spain
| |
Collapse
|
|
8
|
Yang W, Ebrahimi F, Romeo S, Holmer M, Vessby J, Ekstedt M, Ludvigsson JF, Shang Y, Hagström H. Risk of major adverse liver outcomes among first-degree relatives of individuals with MASLD. Liver Int 2024; 44:1253-1264. [PMID: 38385564 DOI: 10.1111/liv.15874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/07/2024] [Accepted: 02/08/2024] [Indexed: 02/23/2024]
Abstract
BACKGROUND & AIMS Previous studies have suggested an increased risk of major adverse liver outcomes (MALO) in relatives of patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, granular and longitudinal evidence is lacking on the future risk of MALO among family members of individuals with MASLD. METHODS We identified 3526 first-degree relatives (FDRs) and 11 079 general population comparators to 1328 patients with MASLD diagnosed between 1974 and 2021, with detailed clinical data, including liver histology in 71% of patients. MALO was defined through diagnostic coding for cirrhosis or its complications. Cox regression models were used to estimate adjusted hazard ratios (aHRs) for MALO among FDRs compared to general population comparators. Cumulative incidence accounting for competing risks was calculated. RESULTS During a median follow-up of 13.4 years, there were 65 (2%, 1.12/1000 person-years) and 225 (2%, 1.26/1000 person-years) MALO events in FDRs and general population comparators respectively. After adjusting for demographic factors and comorbidities, FDRs were at no increased risk of MALO (aHR = 0.99, 95% CI: 0.74-1.33). Increased relative rates of MALOs were, however, observed in some subgroups, including parents, although absolute risk estimates were low and comparable to the general population. CONCLUSIONS FDRs of patients with MASLD did not have a higher rate of incident MALO than the general population. Since the absolute risk of MALO in relatives of patients with MASLD was low, these results do not support systematic screening of MASLD-related fibrosis in relatives of patients with MASLD.
Collapse
Affiliation(s)
- Wen Yang
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Fahim Ebrahimi
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Gastroenterology and Hepatology, Clarunis University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Holmer
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
| | - Johan Vessby
- Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden
| | - Mattias Ekstedt
- Department of Gastroenterology and Hepatology, Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Ying Shang
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Hannes Hagström
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
9
|
Chavan SU, Rathi P, Mandot A. Association of GCKR and MBOAT7 genetic polymorphisms with non-alcoholic fatty liver disease. Clin Exp Hepatol 2024; 10:39-46. [PMID: 38765903 PMCID: PMC11100339 DOI: 10.5114/ceh.2024.136326] [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: 07/16/2023] [Accepted: 10/29/2023] [Indexed: 05/22/2024] Open
Abstract
Aim of the study Non-alcoholic fatty liver disease (NAFLD) is one of the most important causes of chronic liver disease (CLD) in both Western and Asian populations. There is wide inter-individual variability in the occurrence of NAFLD and progression to non-alcoholic steatohepatitis (NASH) even after correcting environmental factors, and its true explanation can be provided by heritability. Two such genetic variations, the glucokinase regulator (GCKR) and membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes, in NAFLD patients were studied in the Indian population. Material and methods A cross sectional analytical study was conducted in the Department of Gastroenterology at a tertiary care centre. In total 100 subjects in the age range of 18-65 years were included in the study; 50 were patients with NAFLD including fatty liver, NASH and NASH related cirrhosis, and 50 were healthy subjects (No NAFLD). The polymorphisms rs780094 and rs1260326 for GCKR and rs641738 for MBOAT7 were determined using PCR followed by the PCR-RFLP. Results GCKR rs780094 minor allele A was more common in NAFLD patients (p = 0.00001). Within the spectrum of NAFLD, the A allele was present frequently among cirrhotics as compared to NASH and fatty liver (p = 0.00001). Morbidly obese individuals showed significant association with the homozygous A allele (p = 0.028). These results were not seen with GCKR rs1260326 across all alleles. In MBOAT7 (rs641738) the frequency of the minor allele T for NAFLD was 84% vs. 80% in healthy subjects (p = 0.79). The association of the T allele among the spectrum of NAFLD was not statistically significant (p = 0.79). Conclusions GCKR genetic variant rs780094 was found to be significantly associated with NAFLD. The MBOAT7 (rs641738) genetic variant was not found to be significantly associated with NAFLD.
Collapse
Affiliation(s)
| | - Pravin Rathi
- Bombay Hospital and Research Centre, Mumbai, India
| | - Ameet Mandot
- Bombay Hospital and Research Centre, Mumbai, India
| |
Collapse
|
|
10
|
Soto A, Spongberg C, Martinino A, Giovinazzo F. Exploring the Multifaceted Landscape of MASLD: A Comprehensive Synthesis of Recent Studies, from Pathophysiology to Organoids and Beyond. Biomedicines 2024; 12:397. [PMID: 38397999 PMCID: PMC10886580 DOI: 10.3390/biomedicines12020397] [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: 01/05/2024] [Revised: 02/04/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a widespread contributor to chronic liver disease globally. A recent consensus on renaming liver disease was established, and metabolic dysfunction-associated steatotic liver disease, MASLD, was chosen as the replacement for NAFLD. The disease's range extends from the less severe MASLD, previously known as non-alcoholic fatty liver (NAFL), to the more intense metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH), characterized by inflammation and apoptosis. This research project endeavors to comprehensively synthesize the most recent studies on MASLD, encompassing a wide spectrum of topics such as pathophysiology, risk factors, dietary influences, lifestyle management, genetics, epigenetics, therapeutic approaches, and the prospective trajectory of MASLD, particularly exploring its connection with organoids.
Collapse
Affiliation(s)
- Allison Soto
- Department of Surgery, University of Illinois College of Medicine, Chicago, IL 60607, USA;
| | - Colby Spongberg
- Touro College of Osteopathic Medicine, Great Falls, MT 59405, USA
| | | | - Francesco Giovinazzo
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| |
Collapse
|
|
11
|
Ebrahimi F, Hagström H, Sun J, Bergman D, Shang Y, Yang W, Roelstraete B, Ludvigsson JF. Familial coaggregation of MASLD with hepatocellular carcinoma and adverse liver outcomes: Nationwide multigenerational cohort study. J Hepatol 2023; 79:1374-1384. [PMID: 37647992 DOI: 10.1016/j.jhep.2023.08.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 07/26/2023] [Accepted: 08/17/2023] [Indexed: 09/01/2023]
Abstract
BACKGROUND & AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD) is the fastest growing cause of hepatocellular carcinoma (HCC) worldwide. However, whether family members of individuals with MASLD also share an increased risk of developing HCC is unknown. METHODS This nationwide multigenerational cohort study involved family members of all Swedish adults diagnosed with biopsy-proven MASLD (1969-2017), and matched general population comparators. Using the Swedish Multi-generation Register, we identified 38,018 first-degree relatives (FDRs: parents, siblings, offspring) and 9,381 spouses of patients with MASLD, as well as 197,303 comparator FDRs and 47,572 comparator spouses. We used Cox proportional hazards models to calculate adjusted hazard ratios (aHRs) for HCC, major adverse liver outcomes (cirrhosis, decompensated liver disease or liver transplantation), liver-related mortality, extrahepatic cancer, and non-liver-related mortality. RESULTS Over a median of 17.6 years, the rate of the primary outcome HCC was higher in MASLD FDRs vs. comparator FDRs (13 vs. 8/100,000 person-years [PY]; aHR 1.80, 95% CI 1.36-2.37). The HCC risk was further increased in FDRs of individuals with liver fibrosis/cirrhosis (aHR 2.14, 95% CI 1.07-4.27; PHeterogeneity = 0.03). MASLD FDRs also had higher rates of major adverse liver outcomes (73 vs. 51/100,000 PY; aHR 1.52, 95% CI 1.36-1.69) and liver-related mortality (20 vs. 11/100,000 PY; aHR 2.14, 95% CI 1.67-2.74). MASLD FDRs with any concomitant chronic liver condition experienced accelerated progression of liver disease (aHR 1.47, 95% CI 1.29-1.67). MASLD spouses were at higher risks of major adverse liver outcomes (86 vs. 74/100,000 PY; aHR 1.23, 95% CI 1.01-1.51) and liver-related mortality (25 vs. 19/100,000 PY; aHR 1.93, 95% CI 1.15-3.23), but not of HCC (aHR 1.43, 95% CI 0.87-2.35). CONCLUSIONS There is distinct familial clustering of adverse liver-related outcomes in families of individuals with biopsy-proven MASLD, with higher relative risks of HCC, progressive liver disease, and liver-related mortality, but absolute risks are low. IMPACT AND IMPLICATIONS Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly termed NAFLD) clusters in families with high genetic susceptibility and shared environmental risk factors, but the risks of developing hepatocellular carcinoma and other major liver-related outcomes in family members of individuals with MASLD are largely unknown. This large nationwide multigenerational cohort study involving family members (first-degree relatives and spouses) of individuals with biopsy-proven MASLD and of matched general population comparators found slightly increased risks of hepatocellular carcinoma in first-degree relatives, and of developing cirrhosis and liver-related mortality in all family members of individuals with biopsy-proven MASLD. The findings of this study provide large-scale evidence to inform clinical practice guidelines for recommendations on the early identification of individuals at higher risk of liver-related morbidity and mortality.
Collapse
Affiliation(s)
- Fahim Ebrahimi
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Gastroenterology and Hepatology, Clarunis University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland.
| | - Hannes Hagström
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Jiangwei Sun
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - David Bergman
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Ying Shang
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Wen Yang
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Bjorn Roelstraete
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| |
Collapse
|
|
12
|
Subramaniyan V, Lubau NSA, Mukerjee N, Kumarasamy V. Alcohol-induced liver injury in signalling pathways and curcumin's therapeutic potential. Toxicol Rep 2023; 11:355-367. [PMID: 37868808 PMCID: PMC10585641 DOI: 10.1016/j.toxrep.2023.10.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/30/2023] [Accepted: 10/11/2023] [Indexed: 10/24/2023] Open
Abstract
Confronting the profound public health concern of alcohol-induced liver damage calls for inventive therapeutic measures. The social, economic, and clinical ramifications are extensive and demand a comprehensive understanding. This thorough examination uncovers the complex relationship between alcohol intake and liver damage, with a special emphasis on the pivotal roles of the Toll-like receptor 4 (TLR4)/NF-κB p65 and CYP2E1/ROS/Nrf2 signalling networks. Different alcohol consumption patterns, determined by a myriad of factors, have significant implications for liver health, leading to a spectrum of adverse effects. The TLR4/NF-κB p65 pathway, a principal regulator of inflammation and immune responses, significantly contributes to various disease states when its balance is disrupted. Notably, the TLR4/MD-2-TNF-α pathway has been linked to non-alcohol related liver disease, while NF-κB activation is associated with alcohol-induced liver disease (ALD). The p65 subunit of NF-κB, primarily responsible for the release of inflammatory cytokines, hastens the progression of ALD. Breakthrough insights suggest that curcumin, a robust antioxidant and anti-inflammatory compound sourced from turmeric, effectively disrupts the TLR4/NF-κB p65 pathway. This heralds a new approach to managing alcohol-induced liver damage. Initial clinical trials support curcumin's therapeutic potential, highlighting its ability to substantially reduce liver enzyme levels. The narrative surrounding alcohol-related liver injury is gradually becoming more intricate, intertwining complex signalling networks such as TLR4/NF-κB p65 and CYP2E1/ROS/Nrf2. The protective role of curcumin against alcohol-related liver damage marks the dawn of new treatment possibilities. However, the full realisation of this promising therapeutic potential necessitates rigorous future research to definitively understand these complex mechanisms and establish curcumin's effectiveness and safety in managing alcohol-related liver disorders.
Collapse
Affiliation(s)
- Vetriselvan Subramaniyan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Jalan Lagoon Selatan, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia
- Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu 600077, India
| | - Natasha Sura Anak Lubau
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Jalan Lagoon Selatan, Bandar Sunway, 47500 Subang Jaya, Selangor, Malaysia
| | - Nobendu Mukerjee
- Department of Microbiology, Ramakrishna Mission Vivekananda Centenary Collage, Kolkata, West Bengal 700118, India
- Department of Health Sciences, Novel Global Community and Educational Foundation, Australia
| | - Vinoth Kumarasamy
- Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia
| |
Collapse
|
|
13
|
Akambase JA, Prieto JE, Mattos AZ, Mattos AA, Carrera E, Díaz-Ferrer J, Gallardo P, Curia A, Ballerga EG, Tovo CV, Balderramo D, Debes JD. Epidemiology and risk factors for histopathologic characteristics of non-alcoholic fatty liver disease in South America. Aliment Pharmacol Ther 2023; 58:526-536. [PMID: 37349900 DOI: 10.1111/apt.17615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 06/02/2023] [Accepted: 06/02/2023] [Indexed: 06/24/2023]
Abstract
BACKGROUND The burden of non-alcoholic fatty liver disease (NAFLD) in South America is among the highest in the world. However, the epidemiology and risk factors for NAFLD are insufficiently described in the region. AIM To explore the associations between clinical characteristics and histopathological features of NAFLD METHODS: This was a descriptive study of 2722 patients with NAFLD from 8 medical centres across 5 South American countries. We collected clinical, biochemical and histopathological data using a templated chart. Fibrosis was assessed by elastography or fibrosis scores and confirmed with biopsy when available. We examined associations between histopathological features and clinical characteristics with logistic regression models. Models were adjusted for country, age and sex. RESULTS The median age was 53 years (IQR: 41-62), and 63% were women. Subjects from Brazil had the highest body mass index at 42 kg/m2 . Sixty-seven percent had dyslipidemia, 46% had obesity, 30% had hypertension, 17% had type 2 diabetes mellitus (T2DM) and 34% had metabolic syndrome. Biopsy reports were available for 948 (35%), of which 58% showed fibrosis, 91% steatosis and 65% inflammation; 25% showed significant fibrosis and 27% severe steatosis. Metabolic syndrome, T2DM and hypertension were significantly associated with significant fibrosis (OR = 1.94, p < 0.001; OR = 2.93, p < 0.001 and OR = 1.60, p = 0.003, respectively), severe steatosis (OR = 2.05, p < 0.001; OR = 1.91, p = 0.001 and OR = 2.17, p < 0.001, respectively) and liver inflammation (OR = 1.66, p = 0.007; OR = 2.00, p = 0.002; OR = 1.62, p = 0.001, respectively). CONCLUSIONS In the largest NAFLD cohort study to date from South America, metabolic syndrome, hypertension and T2DM were independently associated with significant fibrosis, severe steatosis, and inflammation. The prevalence of T2DM was lower than the reported global prevalence.
Collapse
Affiliation(s)
- Joseph A Akambase
- Division of Epidemiology and Community Health, School of Medicine, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA
| | - Jhon E Prieto
- Centro de Enfermedades Hepáticas y Digestivas, Bogotá, Colombia
| | - Angelo Z Mattos
- Graduate Program in Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
| | - Angelo A Mattos
- Graduate Program in Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
| | - Enrique Carrera
- Departamento de Gastroenterología y Hepatología, Hospital Eugenio Espejo, Quito, Ecuador
| | - Javier Díaz-Ferrer
- Department of Gastroenterology, Hospital Nacional Edgardo Rebagliati Martins, HNERM, Lima, Peru
| | | | - Andrea Curia
- División Gastroenterology, Hospital de Clínicas José de San Martín - UBA, Buenos Aires, Argentina
| | - Esteban G Ballerga
- División Gastroenterology, Hospital de Clínicas José de San Martín - UBA, Buenos Aires, Argentina
| | - Cristiane V Tovo
- Graduate Program in Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
| | - Domingo Balderramo
- Departamento de Gastroenterología, Hospital Privado Universitario de Córdoba, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, Argentina
| | - Jose D Debes
- Division of Epidemiology and Community Health, School of Medicine, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA
- Department of Medicine, University of MInnesota, Minneapolis, United States
| |
Collapse
|
|
14
|
Zhao J, Xu X, Wei X, Zhang S, Xu H, Wei X, Zhang Y, Zhang J. SAMM50- rs2073082, - rs738491 and - rs3761472 Interactions Enhancement of Susceptibility to Non-Alcoholic Fatty Liver Disease. Biomedicines 2023; 11:2416. [PMID: 37760857 PMCID: PMC10525902 DOI: 10.3390/biomedicines11092416] [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: 07/19/2023] [Revised: 08/05/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND AND AIM Several studies have identified that three SAMM50 polymorphisms (rs2073082, rs738491, rs3761472) are associated with an increased risk of non-alcoholic fatty liver disease (NAFLD). However, the clinical significance of the SAMM50 SNP in relation to NAFLD remains largely unknown. Therefore, we conducted a clinical study and SNP-SNP interaction analysis to further elucidate the effect of the SAMM50 SNP on the progression of NAFLD in the elderly. METHODS A total of 1053 patients over the age of 65 years were recruited. Liver fat and fibrosis were detected by abdominal ultrasound or FibroScan, respectively. Genomic DNA was extracted and then genotyped by Fluidigm 96.96 Dynamic Array. Multivariable logistic regression was used to evaluate the association between NAFLD and SNP. SNP-SNP interactions were analyzed using generalized multivariate dimensionality reduction (GMDR). RESULTS The risk of NAFLD was substantially higher in people who carried SAMM50-rs2073082 G and -rs738491 T alleles (OR, 1.962; 95% CI, 1.448-2.659; p < 0.001; OR, 1.532; 95% CI, 1.246-1.884; p = 0.021, respectively) compared to noncarriers. Carriers of the rs738491 T and rs3761472 G alleles in the cohort showed a significant increase in liver stiffness measurements (LSM). The combination of the three SNPs showed the highest predictive power for NAFLD. The rs2073082 G allele, rs738491 T allele and rs3761472 G carriers had a two-fold higher risk of NAFLD compared to noncarriers. CONCLUSIONS Our research has demonstrated a strong correlation between the genetic polymorphism of SAMM50 and NAFLD in the elderly, which will contribute to a better understanding of the impact of age and genetics on this condition. Additionally, this study provides a potential predictive model for the early clinical warning of NAFLD.
Collapse
Affiliation(s)
- Jinhan Zhao
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (J.Z.); (X.X.); (X.W.); (S.Z.); (H.X.); (X.W.)
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Xiaoyi Xu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (J.Z.); (X.X.); (X.W.); (S.Z.); (H.X.); (X.W.)
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Xinhuan Wei
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (J.Z.); (X.X.); (X.W.); (S.Z.); (H.X.); (X.W.)
| | - Shuang Zhang
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (J.Z.); (X.X.); (X.W.); (S.Z.); (H.X.); (X.W.)
- Menkuang Hospital, Beijing Jingmei Group General Hospital, Beijing Energy Holding Company Limited, Beijing 102399, China
| | - Hangfei Xu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (J.Z.); (X.X.); (X.W.); (S.Z.); (H.X.); (X.W.)
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Xiaodie Wei
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (J.Z.); (X.X.); (X.W.); (S.Z.); (H.X.); (X.W.)
| | - Yang Zhang
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Jing Zhang
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (J.Z.); (X.X.); (X.W.); (S.Z.); (H.X.); (X.W.)
| |
Collapse
|
|
15
|
Wu N, Zhai X, Yuan F, Li J, Li D, Wang J, Zhang L, Shi Y, Ji G, He G, Liu B. Genetic variation in TBC1 domain family member 1 gene associates with the risk of lean NAFLD via high-density lipoprotein. Front Genet 2023; 13:1026725. [PMID: 36712867 PMCID: PMC9877292 DOI: 10.3389/fgene.2022.1026725] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/23/2022] [Indexed: 01/15/2023] Open
Abstract
Objective: Non-alcoholic fatty liver disease (NAFLD) affects almost a quarter of the world's population. Although NAFLD often co-exists with obesity, a substantial proportion of NAFLD patients are lean which is relatively unexplored. This study aimed to examine the association between genetic variation in candidate genes, e.g., TBC1D1 and the risk of lean NAFLD in the elderly Chinese Han population. Methods: This is an extension of the research on physical examination in the Zhanjiang community center including 5387 residents, Shanghai, China, in 2017. According to the classification in adult Asian populations, participants were categorized into four groups: lean NAFLD (BMI <23, n = 106), non-lean NAFLD (BMI ≥23, n = 644), lean non-NAFLD (BMI <23, n = 216) and non-lean non-NAFLD (BMI ≥23, n = 253).116 NAFLD-related candidate genes, which cover 179 single nucleotide polymorphisms (SNPs) were included in the KEGG enrichment analysis. Independent samples t-test was adopted for the group comparison. The associations between genetic variations with the specific phenotype in five genetic models were analyzed with the "SNPassoc" R package and rechecked with logistic regression analysis. Mediation models were conducted to explore whether the certain phenotype can mediate the association between SNPs and the risk of lean NAFLD. Results: Compared with lean non-NAFLD individuals, lean NAFLD patients had higher BMI, low-density lipoprotein and triglyceride, and lower HDL. The AMPK signaling pathway, which includes TBC1D1 and ADIPOQ genes, was the most significant (p < .001). The A allele frequency of rs2279028 in TBC1D1 (p = .006) and G allele frequency of rs17366568 in ADIPOQ (p = .038) were significantly lower in lean NAFLD. The association between rs2279028 and the risk of lean NAFLD was mediated by HDL (p = .014). No significant mediation effect was found between rs17366568 and the risk of lean NAFLD. Conclusion: This study, for the first time, indicated that rs2279028 of TBC1D1 may contribute to the progression of lean NAFLD through HDL. This finding provides more evidence for exploring the mechanism of lean NAFLD and suggests practical solutions for the treatment of lean NAFLD.
Collapse
Affiliation(s)
- Na Wu
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China,Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Xiangyu Zhai
- Graduate School of Sport Sciences, Waseda University, Saitama, Japan
| | - Fan Yuan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Li
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dong Li
- Zhangjiang Community Health Service Center of Pudong New District, Shanghai, China
| | - Jianying Wang
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lei Zhang
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yi Shi
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China,*Correspondence: Guang Ji, ; Guang He, ; Baocheng Liu, ,
| | - Guang He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China,*Correspondence: Guang Ji, ; Guang He, ; Baocheng Liu, ,
| | - Baocheng Liu
- Shanghai Innovation Center of Traditional Chinese Medicine Health Service, School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China,*Correspondence: Guang Ji, ; Guang He, ; Baocheng Liu, ,
| |
Collapse
|
|
16
|
Wang J, Qin T, Sun J, Li S, Cao L, Lu X. Non-invasive methods to evaluate liver fibrosis in patients with non-alcoholic fatty liver disease. Front Physiol 2022; 13:1046497. [PMID: 36589424 PMCID: PMC9794751 DOI: 10.3389/fphys.2022.1046497] [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: 09/16/2022] [Accepted: 11/15/2022] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic Fatty Liver Disease (NAFLD) is a chronic liver disease that is strongly related to insulin resistance and metabolic syndrome, and it has become the most common liver disorder in developed countries. NAFLD embraces the full pathological process of three conditions: steatosis, non-alcoholic steatohepatitis, and finally, cirrhosis. As NAFLD progresses, symptoms will become increasingly severe as fibrosis develops. Therefore, evaluating the fibrosis stage is crucial for patients with NAFLD. A liver biopsy is currently considered the gold standard for staging fibrosis. However, due to the limitations of liver biopsy, non-invasive alternatives were extensively studied and validated in patients with NAFLD. The advantages of non-invasive methods include their high safety and convenience compared with other invasive approaches. This review introduces the non-invasive methods, summarizes their benefits and limitations, and assesses their diagnostic performance for NAFLD-induced fibrosis.
Collapse
Affiliation(s)
- Jincheng Wang
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tao Qin
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jinyu Sun
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shiwu Li
- Liver Disease Center, Qinhuangdao Third Hospital, Qinhuangdao, China
| | - Lihua Cao
- Liver Disease Center, Qinhuangdao Third Hospital, Qinhuangdao, China,*Correspondence: Xiaojie Lu, ; Lihua Cao,
| | - Xiaojie Lu
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, China,*Correspondence: Xiaojie Lu, ; Lihua Cao,
| |
Collapse
|
|
17
|
Cavalcante LN, Porto J, Mazo D, Longatto-Filho A, Stefano JT, Lyra AC, Carrilho FJ, Reis RM, Alves VAF, Sanyal AJ, Oliveira CP. African genetic ancestry is associated with lower frequency of PNPLA3 G allele in non-alcoholic fatty liver in an admixed population. Ann Hepatol 2022; 27:100728. [PMID: 35710086 DOI: 10.1016/j.aohep.2022.100728] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/06/2022] [Accepted: 05/19/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES PNPLA3 (rs738409) and TM6SF2 (rs58542926) variants, interindividual and ethnic differences may be risk factors for non-alcoholic fatty liver disease (NAFLD). The PNPLA3 G allele is associated with worse NAFLD evolution in Hispanics and Caucasians. TM6SF2 is associated with hypertriglyceridemia, NAFLD, and cardiovascular disease. We aimed to evaluate the association between genetic ancestry by Ancestry Informative Markers (AIM), PNPLA3 and TM6SF2 polymorphisms in patients with biopsy-proven NAFLD in an admixed population. METHODS We included adults with biopsy-proven NAFLD and excluded patients with the presence of other chronic liver disease, alcohol intake >100g/week, HIV, drug-induced fatty liver disease, or liver transplantation. We classified NAFLD using the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH-CRN) histological scoring system. The PNPLA3 (rs738409 c.444C>G) and TM6SF2 (rs58542926 c.449C>T) genotyping were performed by RT-PCR. Genetic ancestry was determined using 46 insertion-deletion AIM; α<0.05 was considered significant. RESULTS A total of 248 patients with NAFLD were enrolled [34 with simple steatosis (NAFL); 214 with NASH]. Overall, we detected a greater European ancestry contribution (0.645), followed by African (0.173), Amerindian (0.095), and East Asian (0.087) ancestry contribution, without differences between NAFL and NASH patients. However, we found a higher African genetic ancestry contribution among patients with NAFL who had the PNPLA3 C/C genotype than those with the G allele (0.216 ± 0.205 versus 0.105 ± 0.101, respectively; p=0.047). Ancestry contributions did not differ among TM6SF2 genotypes. CONCLUSION Among NAFL patients, greater African genetic ancestry was associated to a lower frequency of the PNPLA3 G allele, demonstrating a possible NASH ancestry-related protective factor.
Collapse
Affiliation(s)
| | - Jun Porto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos-SP, Brazil
| | - Daniel Mazo
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Adhemar Longatto-Filho
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Department of Pathology (LIM-14), Faculty of Medicine, University of São Paulo, Brazil; Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - José Tadeu Stefano
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Andre Castro Lyra
- Federal University of Bahia, School of Medicine, Gastroenterology and Hepatology Services & Salvador-BA, Brazil
| | - Flair Jose Carrilho
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil; Department of Pathology (LIM-14), Faculty of Medicine, University of São Paulo, Brazil; Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal
| | - Venâncio A F Alves
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Department of Pathology (LIM-14), Faculty of Medicine, University of São Paulo, Brazil
| | - Arun J Sanyal
- Institute of Liver Disease and Metabolic Health; Interim Chair, Div. of Gastroenterology; Virginia Commonwealth University, USA
| | - Claudia P Oliveira
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| |
Collapse
|
|
18
|
Fernández-Ramos D, Lopitz-Otsoa F, Millet O, Alonso C, Lu SC, Mato JM. One Carbon Metabolism and S-Adenosylmethionine in Non-Alcoholic Fatty Liver Disease Pathogenesis and Subtypes. LIVERS 2022; 2:243-257. [PMID: 37123053 PMCID: PMC10137169 DOI: 10.3390/livers2040020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
One carbon metabolism (1CM) can be defined as the transfer of a carbon unit from one metabolite to another and its replenishment by different sources of labile methyl-group nutrients: primarily choline, methionine, betaine, and serine. This flow of carbon units allows the biosynthesis of nucleotides, amino acids, formylated methionyl-tRNA, polyamines, glutathione, phospholipids, detoxification reactions, maintenance of the redox status and the concentration of NAD, and methylation reactions including epigenetic modifications. That is, 1CM functions as a nutrient sensor and integrator of cellular metabolism. A critical process in 1CM is the synthesis of S-adenosylmethionine (SAMe), the source of essentially all the hundreds of millions of daily methyl transfer reactions in a cell. This versatility of SAMe imposes a tight control in its synthesis and catabolism. Much of our knowledge concerning 1CM has been gained from studies in the production and prevention of nonalcoholic fatty liver disease (NAFLD). Here, we discuss in detail the function of the most important enzymes for their quantitative contribution to maintaining the flux of carbon units through 1CM in the liver and discuss how alterations in their enzymatic activity contribute to the development of NAFLD. Next, we discuss NAFLD subtypes based on serum lipidomic profiles with different risk of cardiovascular disease. Among the latter, we highlight the so-called subtype A for its serum lipidomic profile phenocopying that of mice deficient in SAMe synthesis and because its high frequency (about 50% of the NAFLD patients).
Collapse
Affiliation(s)
- David Fernández-Ramos
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, BRTA, CIBERehd, Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain
| | - Fernando Lopitz-Otsoa
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, BRTA, CIBERehd, Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain
| | - Oscar Millet
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, BRTA, CIBERehd, Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain
| | - Cristina Alonso
- OWL Metabolomics, Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain
| | - Shelly C. Lu
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - José M. Mato
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, BRTA, CIBERehd, Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain
- Correspondence: ; Tel.: +34-944-061300; Fax: +34-944-0611301
| |
Collapse
|
|
19
|
Ivashkin VT, Maevskaya MV, Zharkova MS, Kotovskaya YV, Tkacheva ON, Troshina EA, Shestakova MV, Maev IV, Breder VV, Gheivandova NI, Doshchitsin VL, Dudinskaya EN, Ershova EV, Kodzoeva KB, Komshilova KA, Korochanskaya NV, Mayorov AY, Mishina EE, Nadinskaya MY, Nikitin IG, Pogosova NV, Tarzimanova AI, Shamkhalova MS. Clinical Practice Guidelines of the Russian Scientific Liver Society, Russian Gastroenterological Association, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians and National Society for Preventive Cardiology on Diagnosis and Treatment of Non-Alcoholic Liver Disease. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2022; 32:104-140. [DOI: 10.22416/1382-4376-2022-32-4-104-140] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Aim:present clinical guidelines, aimed at general practitioners, gastroenterologists, cardiologists, endocrinologists, comprise up-to-date methods of diagnosis and treatment of non-alcoholic fatty liver disease.Key points.Nonalcoholic fatty liver disease, the most wide-spread chronic liver disease, is characterized by accumulation of fat by more than 5 % of hepatocytes and presented by two histological forms: steatosis and nonalcoholic steatohepatitis. Clinical guidelines provide current views on pathogenesis of nonalcoholic fatty liver disease as a multisystem disease, methods of invasive and noninvasive diagnosis of steatosis and liver fibrosis, principles of nondrug treatment and pharmacotherapy of nonalcoholic fatty liver disease and associated conditions. Complications of nonalcoholic fatty liver disease include aggravation of cardiometabolic risks, development of hepatocellular cancer, progression of liver fibrosis to cirrhotic stage.Conclusion.Progression of liver disease can be avoided, cardiometabolic risks can be reduced and patients' prognosis — improved by the timely recognition of diagnosis of nonalcoholic fatty liver disease and associated comorbidities and competent multidisciplinary management of these patients.
Collapse
Affiliation(s)
| | | | | | - Yu. V. Kotovskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | - O. N. Tkacheva
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | | | | | - I. V. Maev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - V. V. Breder
- Blokhin National Medical Research Center of Oncology
| | | | | | - E. N. Dudinskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Bellini MI, Urciuoli I, Del Gaudio G, Polti G, Iannetti G, Gangitano E, Lori E, Lubrano C, Cantisani V, Sorrenti S, D’Andrea V. Nonalcoholic fatty liver disease and diabetes. World J Diabetes 2022; 13:668-682. [PMID: 36188142 PMCID: PMC9521438 DOI: 10.4239/wjd.v13.i9.668] [Citation(s) in RCA: 5] [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: 03/30/2022] [Revised: 05/03/2022] [Accepted: 08/05/2022] [Indexed: 02/05/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world and represents a clinical-histopathologic entity where the steatosis component may vary in degree and may or may not have fibrotic progression. The key concept of NAFLD pathogenesis is excessive triglyceride hepatic accumulation because of an imbalance between free fatty acid influx and efflux. Strong epidemiological, biochemical, and therapeutic evidence supports the premise that the primary pathophysiological derangement in most patients with NAFLD is insulin resistance; thus the association between diabetes and NAFLD is widely recognized in the literature. Since NAFLD is the hepatic manifestation of a metabolic disease, it is also associated with a higher cardio-vascular risk. Conventional B-mode ultrasound is widely adopted as a first-line imaging modality for hepatic steatosis, although magnetic resonance imaging represents the gold standard noninvasive modality for quantifying the amount of fat in these patients. Treatment of NAFLD patients depends on the disease severity, ranging from a more benign condition of nonalcoholic fatty liver to nonalcoholic steatohepatitis. Abstinence from alcohol, a Mediterranean diet, and modification of risk factors are recommended for patients suffering from NAFLD to avoid major cardiovascular events, as per all diabetic patients. In addition, weight loss induced by bariatric surgery seems to also be effective in improving liver features, together with the benefits for diabetes control or resolution, dyslipidemia, and hypertension. Finally, liver transplantation represents the ultimate treatment for severe nonalcoholic fatty liver disease and is growing rapidly as a main indication in Western countries. This review offers a comprehensive multidisciplinary approach to NAFLD, highlighting its connection with diabetes.
Collapse
Affiliation(s)
- Maria Irene Bellini
- Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
| | - Irene Urciuoli
- Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
| | - Giovanni Del Gaudio
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome 00161, Italy
| | - Giorgia Polti
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome 00161, Italy
| | - Giovanni Iannetti
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome 00161, Italy
| | - Elena Gangitano
- Department of Experimental Medicine, Section of Medical Physiopathology, Food Science and Endocrinology, Sapienza University of Rome, Rome 00161, Italy
| | - Eleonora Lori
- Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
| | - Carla Lubrano
- Department of Experimental Medicine, Section of Medical Physiopathology, Food Science and Endocrinology, Sapienza University of Rome, Rome 00161, Italy
| | - Vito Cantisani
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome 00161, Italy
| | - Salvatore Sorrenti
- Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
| | - Vito D’Andrea
- Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
| |
Collapse
|
|
21
|
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.
Collapse
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,
| |
Collapse
|
|
22
|
Muñoz A, Theusch E, Kuang YL, Nalula G, Peaslee C, Dorlhiac G, Landry MP, Streets A, Krauss RM, Iribarren C, Mattis AN, Medina MW. Undifferentiated Induced Pluripotent Stem Cells as a Genetic Model for Nonalcoholic Fatty Liver Disease. Cell Mol Gastroenterol Hepatol 2022; 14:1174-1176.e6. [PMID: 35863744 PMCID: PMC9608362 DOI: 10.1016/j.jcmgh.2022.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 01/31/2023]
Affiliation(s)
- Antonio Muñoz
- Department of Pediatrics, University of California San Francisco, San Francisco, California
| | - Elizabeth Theusch
- Department of Pediatrics, University of California San Francisco, San Francisco, California
| | - Yu-Lin Kuang
- Department of Pediatrics, University of California San Francisco, San Francisco, California
| | - Gilbert Nalula
- Department of Pediatrics, University of California San Francisco, San Francisco, California
| | - Caitlin Peaslee
- Department of Pathology, University of California San Francisco, San Francisco, California
| | - Gabriel Dorlhiac
- Biophysics Graduate Group, University of California Berkeley, Berkeley, California
| | - Markita P Landry
- Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, California; Chan Zuckerberg Biohub, San Francisco, California
| | - Aaron Streets
- Biophysics Graduate Group, University of California Berkeley, Berkeley, California; Chan Zuckerberg Biohub, San Francisco, California; Department of Bioengineering, University of California Berkeley, Berkeley, California
| | - Ronald M Krauss
- Department of Pediatrics, University of California San Francisco, San Francisco, California; Department of Medicine, University of California San Francisco, San Francisco, California
| | | | - Aras N Mattis
- Department of Pathology, University of California San Francisco, San Francisco, California; Liver Center, University of California San Francisco, San Francisco, California.
| | - Marisa W Medina
- Department of Pediatrics, University of California San Francisco, San Francisco, California.
| |
Collapse
|
|
23
|
Youssef SS, Abbas EAER, Youness RA, Elemeery MN, Nasr AS, Seif S. PNPLA3 and IL 28B signature for predicting susceptibility to chronic hepatitis C infection and fibrosis progression. Arch Physiol Biochem 2022; 128:483-489. [PMID: 31793339 DOI: 10.1080/13813455.2019.1694039] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Association studies identified genetic polymorphisms as predictive risk factors of rapid fibrosis progression in chronic hepatitis C (CHC). This study aims to assess the impact of IL28B rs8099917 polymorphism on CHC genotype 4 (G4) susceptibility and liver fibrosis progression individually; and in combination with PNPLA3 rs738409. PATIENTS AND METHODS IL28B rs8099917 and PNPLA3 rs738409 were genotyped in 150 Egyptian CHC patients and 175 healthy controls using real-time PCR. RESULTS IL28B rs8099917 genotype distribution significantly differs in healthy individuals versus CHC patients (p = .018); and in low versus advanced fibrosis IL28B (p = .013). The haplotype CC -GG (PNPLA3-IL28B) is considered a high-risk signature for susceptibility to CHC infection. Similarly, GG-GG (PNPLA3-IL28B) is considered a high-risk signature for higher degree of fibrosis. CONCLUSION IL28B rs8099917 and PNPLA3 rs738409 introduce genetic signature to identify patients at higher risk for CHC susceptibility and fibrosis progression in CHC G4.
Collapse
Affiliation(s)
- Samar Samir Youssef
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Egypt
| | - Eman Abd El Razek Abbas
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Egypt
| | - Rana Ahmed Youness
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Moustafa Nouh Elemeery
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Egypt
- Département de Neurosciences, CRCHUM, Université de Montréal, Montréal, Quebec, Canada
| | - Amal Soliman Nasr
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Sameh Seif
- National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| |
Collapse
|
|
24
|
Maevskaya M, Kotovskaya Y, Ivashkin V, Tkacheva O, Troshina E, Shestakova M, Breder V, Geyvandova N, Doschitsin V, Dudinskaya E, Ershova E, Kodzoeva K, Komshilova K, Korochanskaya N, Mayorov A, Mishina E, Nadinskaya M, Nikitin I, Pogosova N, Tarzimanova A, Shamkhalova M. The National Consensus statement on the management of adult patients with non-alcoholic fatty liver disease and main comorbidities. TERAPEVT ARKH 2022; 94:216-253. [PMID: 36286746 DOI: 10.26442/00403660.2022.02.201363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Indexed: 12/15/2022]
Abstract
The National Consensus was prepared with the participation of the National Medical Association for the Study of the Multimorbidity, Russian Scientific Liver Society, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians, National Society for Preventive Cardiology, Professional Foundation for the Promotion of Medicine Fund PROFMEDFORUM.
The aim of the multidisciplinary consensus is a detailed analysis of the course of non-alcoholic fatty liver disease (NAFLD) and the main associated conditions. The definition of NAFLD is given, its prevalence is described, methods for diagnosing its components such as steatosis, inflammation and fibrosis are described.
The association of NAFLD with a number of cardio-metabolic diseases (arterial hypertension, atherosclerosis, thrombotic complications, type 2 diabetes mellitus (T2DM), obesity, dyslipidemia, etc.), chronic kidney disease (CKD) and the risk of developing hepatocellular cancer (HCC) were analyzed. The review of non-drug methods of treatment of NAFLD and modern opportunities of pharmacotherapy are presented.
The possibilities of new molecules in the treatment of NAFLD are considered: agonists of nuclear receptors, antagonists of pro-inflammatory molecules, etc. The positive properties and disadvantages of currently used drugs (vitamin E, thiazolidinediones, etc.) are described. Special attention is paid to the multi-target ursodeoxycholic acid (UDCA) molecule in the complex treatment of NAFLD as a multifactorial disease. Its anti-inflammatory, anti-oxidant and cytoprotective properties, the ability to reduce steatosis an independent risk factor for the development of cardiovascular pathology, reduce inflammation and hepatic fibrosis through the modulation of autophagy are considered.
The ability of UDCA to influence glucose and lipid homeostasis and to have an anticarcinogenic effect has been demonstrated. The Consensus statement has advanced provisions for practitioners to optimize the diagnosis and treatment of NAFLD and related common pathogenetic links of cardio-metabolic diseases.
Collapse
|
|
25
|
Dalbeni A, Castelli M, Zoncapè M, Minuz P, Sacerdoti D. Platelets in Non-alcoholic Fatty Liver Disease. Front Pharmacol 2022; 13:842636. [PMID: 35250588 PMCID: PMC8895200 DOI: 10.3389/fphar.2022.842636] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/03/2022] [Indexed: 12/17/2022] Open
Abstract
Non alcoholic steatohepatitis (NASH) is the inflammatory reaction of the liver to excessive accumulation of lipids in the hepatocytes. NASH can progress to cirrhosis and hepatocellular carcinoma (HCC). Fatty liver is the hepatic manifestation of metabolic syndrome. A subclinical inflammatory state is present in patients with metabolic alterations like insulin resistance, type-2 diabetes, obesity, hyperlipidemia, and hypertension. Platelets participate in immune cells recruitment and cytokines-induced liver damage. It is hypothesized that lipid toxicity cause accumulation of platelets in the liver, platelet adhesion and activation, which primes the immunoinflammatory reaction and activation of stellate cells. Recent data suggest that antiplatelet drugs may interrupt this cascade and prevent/improve NASH. They may also improve some metabolic alterations. The pathophysiology of inflammatory liver disease and the implication of platelets are discussed in details.
Collapse
Affiliation(s)
- Andrea Dalbeni
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Marco Castelli
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Mirko Zoncapè
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Pietro Minuz
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
- *Correspondence: Pietro Minuz,
| | - David Sacerdoti
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| |
Collapse
|
|
26
|
Single Nucleotide Polymorphism of Genes Associated with Metabolic Fatty Liver Disease. JOURNAL OF ONCOLOGY 2022; 2022:9282557. [PMID: 35154322 PMCID: PMC8831055 DOI: 10.1155/2022/9282557] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/05/2022] [Accepted: 01/13/2022] [Indexed: 02/08/2023]
Abstract
Aims The present study aimed to reveal the relationship between single nucleotide polymorphism (SNP) of PNPLA3, TM6SF2, MBOAT7, GATAD2A, and STAT3 genes and metabolism-related fatty liver disease (MAFLD), so as to provide a research basis for further exploring the diagnosis and treatment of diseases at the molecular level. Methods A total of 564 patients were included in the physical examination center of Xinjiang Karamay People's Hospital. They were divided into an MAFLD case group and a healthy control group. The whole blood DNA of each sample was extracted by a whole blood genomic DNA extraction kit, and the genotypes of PNPLA3 rs738409, MBOAT7 rs64173, STAT3 rs744166, TM6SF2 rs58542926, and GATAD2A rs4808199 were performed; after adjusting for confounding factors, the additive model, dominant model, and recessive model of each gene were analyzed by multivariate logistic regression. Results The CC genotype of the PNPLA3 gene rs738409 and the TT genotype of the MBOAT7 gene rs64173 are risk factors in the occurrence of MAFLD. The AA genotype of the STAT3 gene rs744166 is a protective factor of MAFLD, while TM6SF2 rs58542926 and GATAD2A rs4808199 show no significant correlation with MAFLD.
Collapse
|
|
27
|
Valenti L, Pedica F, Colombo M. Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease. Dig Liver Dis 2022; 54:154-163. [PMID: 34294580 DOI: 10.1016/j.dld.2021.06.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 05/31/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is on the rise globally, causing more than 800 thousand deaths annually, with an estimated annual percent change of 0.51 for causes other than viral hepatitis, including nonalcoholic fatty liver disease (NAFLD). The incidence of NAFLD-related HCC is peaking in several Far East regions (6-12% vs. 2-3% in Western Europe and USA), HCC risk being mainly driven by the epidemic of obesity and diabetes, both favored by an unhealthy diet and sedentary lifestyle. Under inherited susceptibility outlined by such genetic markers as variants in PNPLA3, TM6SF2 and MBOAT7, neoplastic transformation of NAFLD is driven by sublethal lipotoxicity consequent to hepatocyte lipid overload, whereas a myriad of factors spanning from subverted circadian homeostasis and gut dysbiosis to alcohol abuse and tobacco may interact as risk modifiers. At variance with viral HCC, NAFLD-HCC shows a frequent association with cardiovascular co-morbidities, absence of cirrhosis in up to half of patients and an association with persistently normal transaminase values. All these misleading features of NAFLD-related HCC account for the low uptake of surveillance and linkage to curative treatments that has been reported in patients with this cancer, a downside that could be attenuated when scores for cost-effective risk stratification become available.
Collapse
Affiliation(s)
- Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy; Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Federica Pedica
- Department of Experimental Oncology, Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Massimo Colombo
- Liver Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| |
Collapse
|
|
28
|
Smirne C, Croce E, Di Benedetto D, Cantaluppi V, Comi C, Sainaghi PP, Minisini R, Grossini E, Pirisi M. Oxidative Stress in Non-Alcoholic Fatty Liver Disease. LIVERS 2022; 2:30-76. [DOI: 10.3390/livers2010003] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it still remains an orphan of adequate therapies. This review highlights the interaction between oxidative stress (OS) and disturbed lipid metabolism. Several reactive oxygen species generators, including those produced in the gastrointestinal tract, contribute to the lipotoxic hepatic (and extrahepatic) damage by fatty acids and a great variety of their biologically active metabolites in a “multiple parallel-hit model”. This leads to inflammation and fibrogenesis and contributes to NAFLD progression. The alterations of the oxidant/antioxidant balance affect also metabolism-related organelles, leading to lipid peroxidation, mitochondrial dysfunction, and endoplasmic reticulum stress. This OS-induced damage is at least partially counteracted by the physiological antioxidant response. Therefore, modulation of this defense system emerges as an interesting target to prevent NAFLD development and progression. For instance, probiotics, prebiotics, diet, and fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. The OS and its counter-regulation are under the influence of individual genetic and epigenetic factors as well. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors, coupled with new OS biomarkers, will likely assist in noninvasive diagnosis and monitoring of NAFLD progression and in further personalizing treatments.
Collapse
Affiliation(s)
- Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Eleonora Croce
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Davide Di Benedetto
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Vincenzo Cantaluppi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Cristoforo Comi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Pier Paolo Sainaghi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Elena Grossini
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| |
Collapse
|
|
29
|
Ramos MJ, Bandiera L, Menolascina F, Fallowfield JA. In vitro models for non-alcoholic fatty liver disease: Emerging platforms and their applications. iScience 2022; 25:103549. [PMID: 34977507 PMCID: PMC8689151 DOI: 10.1016/j.isci.2021.103549] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents a global healthcare challenge, affecting 1 in 4 adults, and death rates are predicted to rise inexorably. The progressive form of NAFLD, non-alcoholic steatohepatitis (NASH), can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. However, no medical treatments are licensed for NAFLD-NASH. Identifying efficacious therapies has been hindered by the complexity of disease pathogenesis, a paucity of predictive preclinical models and inadequate validation of pharmacological targets in humans. The development of clinically relevant in vitro models of the disease will pave the way to overcome these challenges. Currently, the combined application of emerging technologies (e.g., organ-on-a-chip/microphysiological systems) and control engineering approaches promises to unravel NAFLD biology and deliver tractable treatment candidates. In this review, we will describe advances in preclinical models for NAFLD-NASH, the recent introduction of novel technologies in this space, and their importance for drug discovery endeavors in the future.
Collapse
Affiliation(s)
- Maria Jimenez Ramos
- Centre for Inflammation Research, The University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK
| | - Lucia Bandiera
- Institute for Bioengineering, The University of Edinburgh, Edinburgh EH9 3BF, UK.,Synthsys - Centre for Synthetic and Systems Biology, The University of Edinburgh, Edinburgh EH9 3BF, UK
| | - Filippo Menolascina
- Institute for Bioengineering, The University of Edinburgh, Edinburgh EH9 3BF, UK.,Synthsys - Centre for Synthetic and Systems Biology, The University of Edinburgh, Edinburgh EH9 3BF, UK
| | - Jonathan Andrew Fallowfield
- Centre for Inflammation Research, The University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK
| |
Collapse
|
|
30
|
Ramos MJ, Bandiera L, Menolascina F, Fallowfield JA. In vitro models for non-alcoholic fatty liver disease: Emerging platforms and their applications. iScience 2022; 25:103549. [PMID: 34977507 DOI: 10.1016/j.isci] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents a global healthcare challenge, affecting 1 in 4 adults, and death rates are predicted to rise inexorably. The progressive form of NAFLD, non-alcoholic steatohepatitis (NASH), can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. However, no medical treatments are licensed for NAFLD-NASH. Identifying efficacious therapies has been hindered by the complexity of disease pathogenesis, a paucity of predictive preclinical models and inadequate validation of pharmacological targets in humans. The development of clinically relevant in vitro models of the disease will pave the way to overcome these challenges. Currently, the combined application of emerging technologies (e.g., organ-on-a-chip/microphysiological systems) and control engineering approaches promises to unravel NAFLD biology and deliver tractable treatment candidates. In this review, we will describe advances in preclinical models for NAFLD-NASH, the recent introduction of novel technologies in this space, and their importance for drug discovery endeavors in the future.
Collapse
Affiliation(s)
- Maria Jimenez Ramos
- Centre for Inflammation Research, The University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK
| | - Lucia Bandiera
- Institute for Bioengineering, The University of Edinburgh, Edinburgh EH9 3BF, UK
- Synthsys - Centre for Synthetic and Systems Biology, The University of Edinburgh, Edinburgh EH9 3BF, UK
| | - Filippo Menolascina
- Institute for Bioengineering, The University of Edinburgh, Edinburgh EH9 3BF, UK
- Synthsys - Centre for Synthetic and Systems Biology, The University of Edinburgh, Edinburgh EH9 3BF, UK
| | - Jonathan Andrew Fallowfield
- Centre for Inflammation Research, The University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK
| |
Collapse
|
|
31
|
Hussain F. Psychiatric Aspects of Obesity in Transplantation. TRANSPLANT PSYCHIATRY 2022:65-72. [DOI: 10.1007/978-3-031-15052-4_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
32
|
Balcar L, Semmler G, Oberkofler H, Zandanell S, Strasser M, Datz L, Niederseer D, Feldman A, Stickel F, Datz C, Paulweber B, Aigner E. PNPLA3 is the dominant SNP linked to liver disease severity at time of first referral to a tertiary center. Dig Liver Dis 2022; 54:84-90. [PMID: 34261618 DOI: 10.1016/j.dld.2021.06.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/26/2021] [Accepted: 06/14/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Single nucleotide polymorphisms (SNPs) in genes including PNPLA3, TM6SF2, HSD17B13 and SERPINA1 have been identified as risk modifiers of progression in chronic liver disease (CLD). However, it is unclear whether genotyping for these risk variants is useful in clinical routine. METHODS Liver disease severity was assessed by liver stiffness measurement (LSM) and by presence of clinical manifestations of advanced-chronic liver disease (ACLD) in 779 consecutive CLD patients at the time of referral to a tertiary center. The associations of risk variants with CLD severity were calculated individually and in a combined model using a polygenic risk-score. RESULTS Non-alcoholic fatty liver disease (NAFLD) was the most common etiology (n = 511, 65.6%), and ACLD was present in 217 (27.9%) patients. The PNPLA3-G-allele remained independently associated with higher LSM (adjusted-B: 2.508 [95%CI: 0.887-4.130], P = 0.002) or the presence of ACLD (aOR: 1.562 [95%CI: 1.097-2.226], P = 0.013). SERPINA1-Z-allele was also independently associated with LSM (adjusted-B: 4.558 [95%CI: 1.182-7.934], P = 0.008), while the other risk alleles did not attain statistical significance. Combining these risk alleles into a polygenic risk-score was significantly associated with LSM (adjusted-B: 0.948 [95%CI: 0.153-1.743], P = 0.020). CONCLUSION PNPLA3 risk-variants are linked to liver disease severity at the time of first referral to an outpatient hepatology clinic.
Collapse
Affiliation(s)
- Lorenz Balcar
- First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria; Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria; Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Hannes Oberkofler
- First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Stephan Zandanell
- First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Michael Strasser
- First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Leonora Datz
- Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria
| | - David Niederseer
- Department of Cardiology, University Hospital Zurich, Zurich, Switzerland
| | - Alexandra Feldman
- First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Christian Datz
- Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Bernhard Paulweber
- First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Elmar Aigner
- First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria.
| |
Collapse
|
|
33
|
TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models. Cell Mol Gastroenterol Hepatol 2021; 13:759-788. [PMID: 34823063 PMCID: PMC8783129 DOI: 10.1016/j.jcmgh.2021.11.007] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The I148M Patatin-like Phospholipase Domain-containing 3 (PNPLA3), the rs641738 in the Membrane bound O-acyltransferase domain containing 7-transmembrane channel-like 4 (MBOAT7-TMC4) locus, and the E167K Transmembrane 6 Superfamily Member 2 (TM6SF2) polymorphisms represent the main predisposing factors to nonalcoholic fatty liver disease (NAFLD) development and progression. We previously generated a full knockout of MBOAT7 in HepG2 cells (MBOAT7-/-), homozygous for I148M PNPLA3. Therefore, we aimed to investigate the synergic impact of the 3 at-risk variants on liver injury and hepatocellular carcinoma (HCC) in a large cohort of NAFLD patients, and create in vitro models of genetic NAFLD by silencing TM6SF2 in both HepG2 and MBOAT7-/- cells. METHODS NAFLD patients (n = 1380), of whom 121 had HCC, were stratified with a semiquantitative score ranging from 0 to 3 according to the number of PNPLA3, TM6SF2, and MBOAT7 at-risk variants. TM6SF2 was silenced in HepG2 (TM6SF2-/-) and MBOAT7-/- (MBOAT7-/-TM6SF2-/-) through Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9). RESULTS In NAFLD patients, the additive weight of these mutations was associated with liver disease severity and an increased risk of developing HCC. In HepG2 cells, TM6SF2 silencing altered lipid composition and induced the accumulation of microvesicular lipid droplets (LDs), whereas the MBOAT7-/-TM6SF2-/- cells showed a mixed microvesicular/macrovesicular pattern of LDs. TM6SF2 deletion strongly affected endoplasmic reticulum and mitochondria ultrastructures, thus increasing endoplasmic reticulum/oxidative stress. The mitochondrial number was increased in both TM6SF2-/- and MBOAT7-/-TM6SF2-/- models, suggesting an unbalancing in mitochondrial dynamics, and the silencing of both MBOAT7 and TM6SF2 impaired mitochondrial activity with a shift toward anaerobic glycolysis. MBOAT7-/-TM6SF2-/- cells also showed the highest proliferation rate. Finally, the re-overexpression of MBOAT7 and/or TM6SF2 reversed the metabolic and tumorigenic features observed in the compound knockout model. CONCLUSIONS The co-presence of the 3 at-risk variants impacts the NAFLD course in both patients and experimental models, affecting LD accumulation, mitochondrial functionality, and metabolic reprogramming toward HCC.
Collapse
|
|
34
|
Meroni M, Longo M, Tria G, Dongiovanni P. Genetics Is of the Essence to Face NAFLD. Biomedicines 2021; 9:1359. [PMID: 34680476 PMCID: PMC8533437 DOI: 10.3390/biomedicines9101359] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
Collapse
Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, 20122 Milano, Italy
| | - Giada Tria
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| |
Collapse
|
|
35
|
Epidemiology, risk factors, social determinants of health, and current management for non-alcoholic fatty liver disease in sub-Saharan Africa. Lancet Gastroenterol Hepatol 2021; 6:1036-1046. [PMID: 34508671 DOI: 10.1016/s2468-1253(21)00275-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/13/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease globally and is estimated to affect approximately 25% of the world's population. Data about the prevalence and incidence of NAFLD in Africa are scarce, but the prevalence is estimated to be 13·5% for the general population. This is likely to be an underestimate considering the increasing burden of non-communicable diseases, particularly the rising prevalence of obesity and type 2 diabetes, driven by the overlapping challenges of food insecurity, nutritional transition, and associated increased consumption of calorie-dense foods. Establishing the true prevalence of NAFLD, raising public awareness around the risk factors behind the increase in NAFLD, and proactively addressing all components of metabolic syndrome will be important to combat this silent epidemic, which will have long-term health-care costs and economic consequences for the region.
Collapse
|
|
36
|
Longo M, Meroni M, Paolini E, Macchi C, Dongiovanni P. Mitochondrial dynamics and nonalcoholic fatty liver disease (NAFLD): new perspectives for a fairy-tale ending? Metabolism 2021; 117:154708. [PMID: 33444607 DOI: 10.1016/j.metabol.2021.154708] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/05/2021] [Accepted: 01/07/2021] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver dysfunctions and it is predicted to become the primary cause of liver failure and hepatocellular carcinoma. Mitochondria are highly dynamic organelles involved in multiple metabolic/bioenergetic pathways in the liver. Emerging evidence outlined that hepatic mitochondria adapt in number and functionality in response to external cues, as high caloric intake and obesity, by modulating mitochondrial biogenesis, and maladaptive mitochondrial response has been described from the early stages of NAFLD. Indeed, mitochondrial plasticity is lost in progressive NAFLD and these organelles may assume an aberrant phenotype to drive or contribute to hepatocarcinogenesis. Severe alimentary regimen and physical exercise represent the cornerstone for NAFLD care, although the low patients' compliance is urging towards the discovery of novel pharmacological treatments. Mitochondrial-targeted drugs aimed to recover mitochondrial lifecycle and to modulate oxidative stress are becoming attractive molecules to be potentially introduced for NAFLD management. Although the path guiding the switch from bench to bedside remains tortuous, the study of mitochondrial dynamics is providing intriguing perspectives for future NAFLD healthcare.
Collapse
Affiliation(s)
- Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milano, Italy
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy
| | - Erika Paolini
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy; Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milano, Italy
| | - Chiara Macchi
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milano, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
| |
Collapse
|
|
37
|
Sangiovanni A, Colombo M. Surveillance for hepatocellular carcinoma in patients with advanced liver fibrosis. Saudi J Gastroenterol 2021; 27:64-72. [PMID: 33723094 PMCID: PMC8183361 DOI: 10.4103/sjg.sjg_636_20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Surveillance is the only pragmatic approach to improve treatment of hepatocellular carcinoma (HCC) owing to the fact that it allows detection of the tumor at an early and better curable stage. International liver societies recommend surveillance with biannual abdominal ultrasound (US) for patients with cirrhosis of any etiology because of their high risk of developing HCC. This strategy is considered cost-effective, as surveillance requires an articulated and costly set of interventions, including linkage to care of patients with an early detected tumor. However, as transition to HCC is increasingly being observed in noncirrhotic patients, the majority of which does not reach the threshold of cost effectiveness for screening. The European and Japanese liver societies elected to confine recommendations for HCC screening to noncirrhotic patients with advanced fibrosis due to hepatitis C or hepatitis B only. These latter recommendations, however, are challenged by the increasing number of patients with viral hepatitis in whom HCC risk has been attenuated but not eradicated by successful antiviral therapy. In this set of patients, entry criteria of surveillance need to be refined in the light of the suboptimal diagnostic accuracy of non invasive tests that are employed to identify the ideal candidates for surveillance.
Collapse
Affiliation(s)
- Angelo Sangiovanni
- IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC “A. M. and A. Migliavacca” Center for Liver Disease, Milan, Italy
| | - Massimo Colombo
- Liver Center, IRCCS San Raffaele Hospital, Milan, Italy,Address for correspondence: Prof. Massimo Colombo, Liver Center, IRCCS, Ospedale San Raffaele Hospital, Via Olgettina, 60 Milan, Italy. E-mail:
| |
Collapse
|
|
38
|
Sangiovanni A, Colombo M. Surveillance for hepatocellular carcinoma in patients with advanced liver fibrosis. Saudi J Gastroenterol 2021; 27:64-72. [PMID: 33723094 DOI: 10.4103/sjg.sjg-636-20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Surveillance is the only pragmatic approach to improve treatment of hepatocellular carcinoma (HCC) owing to the fact that it allows detection of the tumor at an early and better curable stage. International liver societies recommend surveillance with biannual abdominal ultrasound (US) for patients with cirrhosis of any etiology because of their high risk of developing HCC. This strategy is considered cost-effective, as surveillance requires an articulated and costly set of interventions, including linkage to care of patients with an early detected tumor. However, as transition to HCC is increasingly being observed in noncirrhotic patients, the majority of which does not reach the threshold of cost effectiveness for screening. The European and Japanese liver societies elected to confine recommendations for HCC screening to noncirrhotic patients with advanced fibrosis due to hepatitis C or hepatitis B only. These latter recommendations, however, are challenged by the increasing number of patients with viral hepatitis in whom HCC risk has been attenuated but not eradicated by successful antiviral therapy. In this set of patients, entry criteria of surveillance need to be refined in the light of the suboptimal diagnostic accuracy of non invasive tests that are employed to identify the ideal candidates for surveillance.
Collapse
Affiliation(s)
- Angelo Sangiovanni
- IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | | |
Collapse
|
|
39
|
Semmler G, Balcar L, Oberkofler H, Zandanell S, Strasser M, Niederseer D, Feldman A, Stickel F, Strnad P, Datz C, Paulweber B, Aigner E. PNPLA3 and SERPINA1 Variants Are Associated with Severity of Fatty Liver Disease at First Referral to a Tertiary Center. J Pers Med 2021; 11:jpm11030165. [PMID: 33804385 PMCID: PMC7999282 DOI: 10.3390/jpm11030165] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/15/2021] [Accepted: 02/20/2021] [Indexed: 12/18/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs), including PNPLA3 rs738409 and SERPINA1 rs17580, have been identified as risk modifiers in the progression fatty liver disease (alcoholic (ALD) or non-alcoholic (NAFLD)). While PNPLA3 has been studied in various settings, the value of both SNPs has so far not been addressed in a real-world cohort of subjects referred for a diagnostic work-up of liver disease. Thus, liver disease severity was assessed in 1257 consecutive patients with suspected ALD or NAFLD at the time of referral to a tertiary center. Advanced chronic liver disease (ACLD) was present in 309 (24.6%) patients and clinically significant portal hypertension (CSPH) was present in 185 (14.7%) patients. The PNPLA3 G-allele was independently associated with a higher liver stiffness measurement (LSM; adjusted B: 2.707 (1.435–3.979), p < 0.001), and higher odds of ACLD (adjusted odds ratio (aOR): 1.971 (1.448–2.681), p < 0.001) and CSPH (aOR: 1.685 (1.180–2.406), p = 0.004). While the SERPINA1 Z-allele was not associated with a higher LSM or the presence of ACLD, it was independently associated with higher odds of CSPH (aOR: 2.122 (1.067–4.218), p = 0.032). Associations of the PNPLA3 G-allele and the SERPINA1 Z-allele with CSPH were maintained independently of each other. The presence of both risk variants further increased the likelihood of ACLD and CSPH.
Collapse
Affiliation(s)
- Georg Semmler
- First Department of Medicine, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (G.S.); (L.B.); (S.Z.); (M.S.); (A.F.); (B.P.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
- Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, 5110 Oberndorf, Austria;
| | - Lorenz Balcar
- First Department of Medicine, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (G.S.); (L.B.); (S.Z.); (M.S.); (A.F.); (B.P.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | - Hannes Oberkofler
- Department of Laboratory Medicine, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria;
| | - Stephan Zandanell
- First Department of Medicine, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (G.S.); (L.B.); (S.Z.); (M.S.); (A.F.); (B.P.)
| | - Michael Strasser
- First Department of Medicine, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (G.S.); (L.B.); (S.Z.); (M.S.); (A.F.); (B.P.)
| | - David Niederseer
- Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, University of Zurich, 8006 Zurich, Switzerland;
| | - Alexandra Feldman
- First Department of Medicine, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (G.S.); (L.B.); (S.Z.); (M.S.); (A.F.); (B.P.)
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8006 Zurich, Switzerland;
| | - Pavel Strnad
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany;
| | - Christian Datz
- Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, 5110 Oberndorf, Austria;
| | - Bernhard Paulweber
- First Department of Medicine, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (G.S.); (L.B.); (S.Z.); (M.S.); (A.F.); (B.P.)
| | - Elmar Aigner
- First Department of Medicine, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; (G.S.); (L.B.); (S.Z.); (M.S.); (A.F.); (B.P.)
- Correspondence: ; Tel.: +43-(0)-57255-25400
| |
Collapse
|
|
40
|
Nimer N, Choucair I, Wang Z, Nemet I, Li L, Gukasyan J, Weeks TL, Alkhouri N, Zein N, Tang WHW, Fischbach MA, Brown JM, Allayee H, Dasarathy S, Gogonea V, Hazen SL. Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression. Metabolism 2021; 116:154457. [PMID: 33275980 PMCID: PMC7856026 DOI: 10.1016/j.metabol.2020.154457] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/18/2020] [Accepted: 11/26/2020] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Metabolomic studies suggest plasma levels of bile acids (BAs) are elevated amongst subjects with non-alcoholic fatty liver disease (NAFLD) compared to healthy controls. However, it remains unclear whether or not specific BAs are associated with the clinically relevant transition from nonalcoholic fatty liver (i.e. simple steatosis) to non-alcoholic steatohepatitis (NASH), or enhanced progression of hepatic fibrosis, or genetic determinants of NAFLD/NASH. METHODS Among sequential subjects (n=102) undergoing diagnostic liver biopsy, we examined the associations of a broad panel of BAs with distinct histopathological features of NAFLD, the presence of NASH, and their associations with genetic variants linked to NAFLD and NASH. RESULTS Plasma BA alterations were observed through the entire spectrum of NAFLD, with several glycine conjugated forms of the BAs demonstrating significant associations with higher grades of inflammation and fibrosis. Plasma 7-Keto-DCA levels showed the strongest associations with advanced stages of hepatic fibrosis [odds ratio(95% confidence interval)], 4.2(1.2-16.4), NASH 24.5(4.1-473), and ballooning 18.7(4.8-91.9). Plasma 7-Keto-LCA levels were associated with NASH 9.4(1.5-185) and ballooning 5.9(1.4-28.8). Genetic variants at several NAFLD/NASH loci were nominally associated with increased levels of 7-Keto- and glycine-conjugated forms of BAs, and the NAFLD risk allele at the TRIB1 locus showed strong tendency toward increased plasma levels of GCA (p=0.02) and GUDCA (p=0.009). CONCLUSIONS Circulating bile acid levels are associated with histopathological and genetic determinants of the transition from simple hepatic steatosis into NASH. Further studies exploring the potential involvement of bile acid metabolism in the development and/or progression of distinct histopathological features of NASH are warranted.
Collapse
Affiliation(s)
- Nisreen Nimer
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA
| | - Ibrahim Choucair
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Zeneng Wang
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Ina Nemet
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Lin Li
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Janet Gukasyan
- Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Taylor L Weeks
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Naim Alkhouri
- Texas Liver Institute and University of Texas Health, San Antonio, TX 78215, USA
| | - Nizar Zein
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA
| | - W H Wilson Tang
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Michael A Fischbach
- Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA
| | - J Mark Brown
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Hooman Allayee
- Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Srinivasan Dasarathy
- Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Valentin Gogonea
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
| | - Stanley L Hazen
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
| |
Collapse
|
|
41
|
Sun Y, Tan Z, Jiang Z, Li M, Wang W, Huang Y, Sun J. Comparative efficacy and safety of traditional Chinese patent medicine for NAFLD in childhood or adolescence: A protocol for a Bayesian network meta analysis. Medicine (Baltimore) 2021; 100:e24277. [PMID: 33546051 PMCID: PMC7837984 DOI: 10.1097/md.0000000000024277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease is a common reason for chronic liver disease in children and adults. The increasing incidence of the disease has become one of the most critical public health problems in the 21st century, closely related to genetic and environmental factors. So far, apart from changing lifestyle and diet, modern medicine still lacks effective treatment measures. Chinese patent medicine has the advantages of apparent curative effect, overall regulation and fewer side effects. However, there is a lack of research on the simultaneous comparison of various Chinese patent medicines. Therefore, we used a reticular meta-analysis to indirectly compare the efficacy and safety of different oral Chinese patent medicines through standard reference. METHOD We will conduct a comprehensive and systematic search of Chinese and English databases from the beginning to December 2020. All randomized controlled trials (RCTs) of oral Chinese patent medicine for NAFLD in children will be searched. The 2 researchers then independently filter the retrieved literature, extract the data according to the data extraction table and assess the risk of bias. We will perform a pair of meta-analyses and a Bayesian network meta-analysis. STATA and Win BUGS software will be used for data analysis. RESULTS This study will thoroughly compare and analyze the differences in the efficacy of all kinds of TCPM in NAFLD treatment in childhood or adolescence. CONCLUSION This study will provide reference and evidence support for clinical drug selection optimization. ETHICS AND DISSEMINATION This study does not require ethical approval. INPLASY REGISTRATION NUMBER 2020120068.
Collapse
Affiliation(s)
- Yuli Sun
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Zhaofeng Tan
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Zhenyuan Jiang
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine
| | - Min Li
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Weiqin Wang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Yaoyao Huang
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine
| | - Jianguang Sun
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine
| |
Collapse
|
|
42
|
Nahon P, Allaire M, Nault JC, Paradis V. Characterizing the mechanism behind the progression of NAFLD to hepatocellular carcinoma. Hepat Oncol 2020; 7:HEP36. [PMID: 33680428 PMCID: PMC7907968 DOI: 10.2217/hep-2020-0017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 09/11/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) developed in non-alcoholic fatty liver disease (NAFLD) individuals presents substantial clinical and biological characteristics, which remain to be elucidated. Its occurrence in noncirrhotic patients raises issues regarding surveillance strategies, which cannot be considered as cost-effective given the high prevalence of obesity and metabolic syndrome, and furthermore delineates specific oncogenic process that could be targeted in the setting of primary or secondary prevention. In this context, the identification of a genetic heterogeneity modulating HCC risk as well as specific biological pathways have been made possible through genome-wide association studies, development of animal models and in-depth analyses of human samples at the pathological and genomic levels. These advances must be confirmed and pursued to pave the way for personalized management of NAFLD-related HCC.
Collapse
Affiliation(s)
- Pierre Nahon
- APHP, Service d’Hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Bondy
- Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie, Paris, France
- Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France
| | - Manon Allaire
- APHP, Service d’Hépatologie, GH Pitié-Salpêtrière, Paris, France
- Université de Paris, Centre de recherche sur l’inflammation, Inserm-UMR1149, 75018 Paris, France
| | - Jean-Charles Nault
- APHP, Service d’Hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Bondy
- Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie, Paris, France
- Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France
| | - Valérie Paradis
- APHP, Service d’Anatomopathologie, Hôpital Beaujon, Clichy, France
- Université de Paris, CNRS, Centre de Recherche sur l’Inflammation (CRI), Paris F-75890, France
| |
Collapse
|
|
43
|
Lee GH, Phyo WW, Loo WM, Kwok R, Ahmed T, Shabbir A, So J, Koh CJ, Hartono JL, Muthiah M, Lim K, Tan PS, Lee YM, Lim SG, Dan YY. Validation of genetic variants associated with metabolic dysfunction-associated fatty liver disease in an ethnic Chinese population. World J Hepatol 2020; 12:1228-1238. [PMID: 33442450 PMCID: PMC7772735 DOI: 10.4254/wjh.v12.i12.1228] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/28/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Genetic factors play an important role in the pathogenesis and development of metabolic dysfunction-associated fatty liver disease (MAFLD).
AIM To study the association of single nucleotide polymorphisms (SNPs), previously identified in Western populations, with the risk of MAFLD in a Singapore Chinese population and their interactions with environmental and medical risk factors.
METHODS A retrospective case-control study was conducted with 72 MAFLD cases and 72 controls with no hepatic steatosis on computed tomography, magnetic resonance imaging, or controlled attenuation parameter score. Subjects were recruited from two tertiary hospitals. Genetic alleles such as NCAN, GCKR, LYPLAL1, PNPLA3, PPP1R3B, FDFT1, COL13A1, EFCAB4B, PZP, and TM6SF2 were genotyped using the TaqMan® Predesigned SNP Genotyping Assay.
RESULTS Weight and body mass index (BMI) were 1.2-times higher in patients (70.6 kg, 95% confidence interval [CI]: 57.1-84.1 vs 60.8 kg, 95%CI: 48.5-73.1, P < 0.001 and 26.9 kg, 95%CI: 23-40.8 vs 23.3 kg 95%CI: 19-27.6, P < 0.001 respectively). The prevalence of diabetes mellitus in patients was 40.3% and 20.8% in controls (P = 0.011). Patients had higher mean triglycerides than controls (P < 0.001). PNPLA3 GG was more likely to be associated with MAFLD (43.4% CC vs 69.7% GG, P = 0.017, and 44.8% CG vs 69.7% GG, P = 0.022). In multivariable analysis, hypertriglyceridemia (odds ratio [OR]: 2.04 95%CI: 1.3-3.1, P = 0.001), BMI (OR: 1.2 95%CI: 1.1-1.4, P < 0.001) and PNPLA3 GG (OR: 3.4 95%CI: 1.3-9.2, P = 0.014) were associated with MAFLD (area under the receiver operating characteristic curve of 0.823).
CONCLUSION Among the Chinese population of Singapore, PNPLA3 homozygous GG allele is a strong predictor of MAFLD, whereas LYPLAL1, GCKR, FDFT1, COL13A1, PZP, and TM6SF2 are not significantly associated. Hypertriglyceridemia, high BMI, and PNPLA3 GG are independent predictors of MAFLD.
Collapse
Affiliation(s)
- Guan Huei Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Wah Wah Phyo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Wai Mun Loo
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Raymond Kwok
- Department of Medicine, Khoo Teck Puat Hospital, Singapore 768828, Singapore
| | - Taufique Ahmed
- Department of Medicine, Khoo Teck Puat Hospital, Singapore 768828, Singapore
| | - Asim Shabbir
- Department of Surgery, National University Health System, Singapore 119228, Singapore
| | - Jimmy So
- Department of Surgery, National University Health System, Singapore 119228, Singapore
| | - Calvin Jianyi Koh
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Juanda Leo Hartono
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Kieron Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Poh Seng Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Yin Mei Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Yock Young Dan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| |
Collapse
|
|
44
|
Pang Q, Sun Z, Shao C, Cai H, Bao Z, Wang L, Li L, Jing L, Zhang L, Wang Z. CML/RAGE Signal Bridges a Common Pathogenesis Between Atherosclerosis and Non-alcoholic Fatty Liver. Front Med (Lausanne) 2020; 7:583943. [PMID: 33240906 PMCID: PMC7677500 DOI: 10.3389/fmed.2020.583943] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/07/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become a common chronic disease in the world. NAFLD is not only a simple intrahepatic lesion, but also affects the occurrence of a variety of extrahepatic complications. In particular, cardiovascular complications are particularly serious, which is the main cause of death in patients with NAFLD. To study the relationship between NAFLD and AS may be a new way to improve the quality of life in patients with NAFLD. As we all known, inflammatory response plays an important role in the occurrence and development of NAFLD and AS. In this study, we found that the accumulation of Nε-carboxymethyllysine (CML) in the liver leads to hepatic steatosis. CML can induce the expression of interleukin (IL-1β), interleukin (IL-6), tumor necrosis factor (TNF-α), C-reactionprotein (CRP) by binding with advanced glycosylation end-product receptor (RAGE) and accelerate the development of AS. After silencing RAGE expression, the expression of pro-inflammatory cytokines was inhibited and liver and aorta pathological changes were relieved. In conclusion, CML/RAGE signal promotes the progression of non-alcoholic fatty liver disease and atherosclerosis. We hope to provide new ideas for the study of liver vascular dialogue in multi organ communication.
Collapse
Affiliation(s)
- Qiwen Pang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhen Sun
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Chen Shao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Honghua Cai
- Department of Burn Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhengyang Bao
- Department of Internal Medicine, Affiliated Hospital of Wuxi Maternity and Child Health of Nanjing Medical University, Wuxi, China
| | - Lin Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lihua Li
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lele Jing
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lili Zhang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.,Department of Burn Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China.,Department of Internal Medicine, Affiliated Hospital of Wuxi Maternity and Child Health of Nanjing Medical University, Wuxi, China.,Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| |
Collapse
|
|
45
|
Lisboa QC, Nardelli MJ, Pereira PDA, Miranda DM, Ribeiro SN, Costa RSN, Versiani CA, Vidigal PVT, Ferrari TCDA, Couto CA. PNPLA3 and TM6SF2 polymorphisms in Brazilian patients with nonalcoholic fatty liver disease. World J Hepatol 2020; 12:792-806. [PMID: 33200017 PMCID: PMC7643213 DOI: 10.4254/wjh.v12.i10.792] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/28/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide, with significant morbidity associated with nonalcoholic steatohepatitis (NASH). Genome-wide association studies demonstrated that the variants rs738409 C/G in the PNPLA3 and rs58542926 C/T in the TM6SF2 genes are determinants of inter-individual and ethnicity-related differences in hepatic fat content and NAFLD progression.
AIM To investigate PNPLA3 and TM6SF2 genotype frequency and their association with NAFLD development and progression in Brazilian patients.
METHODS This cross-sectional case-control study enrolled 285 individuals from the Gastroenterology and Hepatology clinics at a university hospital in Brazil. The case patients (n = 148) were confirmed to have NAFLD by the identification of hepatic steatosis on ultrasonography and exclusion of other causes of liver disease. According to the clinical protocol, patients underwent liver biopsy when at high risk for NASH and/or advanced fibrosis (n = 65). Steatohepatitis was confirmed in 54 patients. Individuals who did not have biopsy indication or NASH on histology were considered to have simple steatosis (n = 94). The control group (n = 137) was selected among patients that attended the Intestinal Disease clinic and was composed of subjects without abnormalities on abdominal ultrasonography and normal liver biochemical tests. All individuals underwent PNPLA3 and TM6SF2 genotype analysis.
RESULTS PNPLA3 CC, CG and GG genotype frequencies were 37%, 44% and 19%, respectively, in NAFLD patients and were 58%, 31% and 10% in controls (P < 0.001). In a model adjusted for gender, age, body mass index and type 2 diabetes mellitus, the G allele increased the chance of NAFLD (OR = 1.69, 95%CI: 1.21-2.36, P = 0.002) and NASH (OR = 3.50, 95%CI: 1.84-6.64, P < 0.001). The chance of NASH was even higher with GG homozygosis (OR = 5.53, 95%CI: 2.04-14.92, P = 0.001). No association was found between G allele and the features of metabolic syndrome. In histological assessment, PNPLA3 genotype was not associated with steatosis grade, although GG homozygosis increased the chance of significant NASH activity (OR = 17.11, 95%CI: 1.87-156.25, P = 0.01) and fibrosis (OR = 7.42, 95%CI: 1.55-34.47, P = 0.01) in the same adjusted model. TM6SF2 CC, CT and TT genotype frequencies were 83%, 15% and 0.7%, respectively, in NAFLD patients and were 84%, 16% and 0.7% in controls (P = 0.78). The T allele presence was not associated with NAFLD or NASH, and was not associated with histological features.
CONCLUSION PNPLA3 may be involved in susceptibility and progression of NAFLD and NASH in the Brazilian population. More advanced histological liver disease was associated with the G allele. The TM6SF2 genetic variants were not associated with NAFLD susceptibility and progressive histological forms in the population studied, but further studies are required to confirm these findings.
Collapse
Affiliation(s)
- Quelson Coelho Lisboa
- Departament de Clínica Médica, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil
| | - Mateus Jorge Nardelli
- Departament de Clínica Médica, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil
| | - Patrícia de Araújo Pereira
- Departament de Clínica Médica, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil
| | - Débora Marques Miranda
- Departament de Clínica Médica, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil
| | - Stephanie Nunes Ribeiro
- Departament de Clínica Médica, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil
| | - Raissa Soares Neves Costa
- Departament de Clínica Médica, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil
| | - Camila Azevedo Versiani
- Departament de Clínica Médica, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil
| | - Paula Vieira Teixeira Vidigal
- Departament de Clínica Médica, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil
| | | | - Claudia Alves Couto
- Departament de Clínica Médica, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil
| |
Collapse
|
|
46
|
Castaldo L, Laguzzi F, Strawbridge RJ, Baldassarre D, Veglia F, Vigo L, Tremoli E, de Faire U, Eriksson P, Smit AJ, Aubrecht J, Leander K, Pirro M, Giral P, Ritieni A, Di Minno G, Mälarstig A, Gigante B. Genetic Variants Associated with Non-Alcoholic Fatty Liver Disease Do Not Associate with Measures of Sub-Clinical Atherosclerosis: Results from the IMPROVE Study. Genes (Basel) 2020; 11:genes11111243. [PMID: 33105679 PMCID: PMC7690395 DOI: 10.3390/genes11111243] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 10/16/2020] [Accepted: 10/21/2020] [Indexed: 01/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis-related cardiovascular diseases (CVD) share common metabolic pathways. We explored the association between three NAFLD-associated single nucleotide polymorphisms (SNPs) rs738409, rs10401969, and rs1260326 with sub-clinical atherosclerosis estimated by the carotid intima-media thickness (c-IMT) and the inter-adventitia common carotid artery diameter (ICCAD) in patients free from clinically overt NAFLD and CVD. The study population is the IMPROVE, a multicenter European study (n = 3711). C-IMT measures and ICCAD were recorded using a standardized protocol. Linear regression with an additive genetic model was used to test for association of the three SNPs with c-IMT and ICCAD. In secondary analyses, the association of the three SNPs with c-IMT and ICCAD was tested after stratification by alanine aminotransferase levels (ALT). No associations were found between rs738409, rs1260326, rs10401969, and c-IMT or ICCAD. Rs738409-G and rs10401969-C were associated with ALT levels (p < 0.001). In patients with ALT levels above 28 U/L (highest quartile), we observed an association between rs10401969-C and c-IMT measures of c-IMTmax and c-IMTmean-max (p = 0.018 and 0.021, respectively). In conclusion, NAFLD-associated SNPs do not associate with sub-clinical atherosclerosis measures. However, our results suggest a possible mediating function of impaired liver function on atherosclerosis development.
Collapse
Affiliation(s)
- Luigi Castaldo
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80138 Naples, Italy;
- Department of Pharmacy, University of Naples “Federico II”, 80138 Naples, Italy;
- Correspondence: ; Tel.: +39-081-678116
| | - Federica Laguzzi
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden; (F.L.); (U.d.F.); (K.L.)
| | - Rona J. Strawbridge
- Mental Health and Wellbeing, Institute of Health and Wellbeing, University of Glasgow, Glasgow G12-8QQ, UK;
- Health Data Research University of Glasgow, College of Medicine, Veterinarian and Life Sciences, Glasgow G12-8RZ, UK
- Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden; (P.E.); (A.M.); (B.G.)
| | - Damiano Baldassarre
- Centro Cardiologico Monzino, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Parea 4, 20138 Milan, Italy; (D.B.); (F.V.); (L.V.); (E.T.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milano MI, Italy
| | - Fabrizio Veglia
- Centro Cardiologico Monzino, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Parea 4, 20138 Milan, Italy; (D.B.); (F.V.); (L.V.); (E.T.)
| | - Lorenzo Vigo
- Centro Cardiologico Monzino, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Parea 4, 20138 Milan, Italy; (D.B.); (F.V.); (L.V.); (E.T.)
| | - Elena Tremoli
- Centro Cardiologico Monzino, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Parea 4, 20138 Milan, Italy; (D.B.); (F.V.); (L.V.); (E.T.)
| | - Ulf de Faire
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden; (F.L.); (U.d.F.); (K.L.)
| | - Per Eriksson
- Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden; (P.E.); (A.M.); (B.G.)
| | - Andries J. Smit
- Department of Medicine, Division of vascular medicine University Medical Center Groningen, 9713 GZ Groningen, The Netherlands;
| | - Jiri Aubrecht
- Takeda Pharmaceuticals International Co., Cambridge, 02139 MA, USA;
| | - Karin Leander
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden; (F.L.); (U.d.F.); (K.L.)
| | - Matteo Pirro
- Unit of Internal Medicine, Department of Medicine, University of Perugia, 06123 Perugia PG, Italy;
| | - Philippe Giral
- Assistance Publique—Hopitaux de Paris; Service Endocrinologie-Metabolisme, Groupe Hôpitalier Pitie-Salpetriere, Unités de Prévention Cardiovasculaire, 75013 Paris, France;
| | - Alberto Ritieni
- Department of Pharmacy, University of Naples “Federico II”, 80138 Naples, Italy;
| | - Giovanni Di Minno
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80138 Naples, Italy;
| | - Anders Mälarstig
- Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden; (P.E.); (A.M.); (B.G.)
| | - Bruna Gigante
- Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden; (P.E.); (A.M.); (B.G.)
| |
Collapse
|
|
47
|
Robinson KE, Shah VH. Pathogenesis and pathways: nonalcoholic fatty liver disease & alcoholic liver disease. Transl Gastroenterol Hepatol 2020; 5:49. [PMID: 33073044 DOI: 10.21037/tgh.2019.12.05] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 11/29/2019] [Indexed: 12/16/2022] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) account for the majority of hepatic morbidity and deaths due to cirrhosis in the United States. ALD is an umbrella term for a number of conditions linked to excessive alcohol consumption including simple steatosis, cirrhosis, acute alcoholic hepatitis (AH) with or without cirrhosis, and hepatocellular carcinoma (HCC) as a complication of cirrhosis. Although it presents with histological features resembling alcohol-induced liver injury, NAFLD occurs in patients with little or no history of alcohol consumption. NAFLD is a broad-spectrum term used to describe anything from fat accumulation in hepatocytes without inflammation or fibrosis (simple hepatic steatosis) to hepatic steatosis with a necroinflammatory component (steatohepatitis) with or without associated fibrosis. The pathogenesis is not fully understood for either disease. Development of severe liver disease is highly variable amongst chronic abusers of alcohol. Sex, age, genetics, host microbiome, and behavior are all factors linked to the development of ALD. These factors also contribute to NAFLD, but by contrast, insulin resistance is widely believed to be the main driver of nonalcoholic hepatic steatosis. The mechanism behind the transition from nonalcoholic steatosis to steatohepatitis remains a matter of debate with insulin resistance, oxidative injury, hepatic iron, gut hormones, antioxidant deficiency, and host microbiome all suspected to play part of the role.
Collapse
Affiliation(s)
- Kyle E Robinson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
|
48
|
Meroni M, Longo M, Dongiovanni P. Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver disease. EXPLORATION OF MEDICINE 2020; 1:218-243. [DOI: 10.37349/emed.2020.00015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 06/20/2020] [Indexed: 01/04/2025] Open
Abstract
The prevalence of nonalcoholic or more recently re-defined metabolic associated fatty liver disease (MAFLD) is rapidly growing worldwide. It is characterized by hepatic fat accumulation exceeding 5% of liver weight not attributable to alcohol consumption. MAFLD refers to an umbrella of conditions ranging from simple steatosis to nonalcoholic steatohepatitis which may finally progress to cirrhosis and hepatocellular carcinoma. MAFLD is closely related to components of the metabolic syndrome and to environmental factors. In addition to the latter, genetic predisposition plays a key role in MAFLD pathogenesis and strictly contributes to its progressive forms. The candidate genes which have been related to MAFLD hereditability are mainly involved in lipids remodeling, lipid droplets assembly, lipoprotein packaging and secretion, de novo lipogenesis, and mitochondrial redox status. In the recent years, it has emerged the opportunity to translate the genetics into clinics by aggregating the genetic variants mostly associated with MAFLD in polygenic risk scores. These scores might be used in combination with metabolic factors to identify those patients at higher risk to develop more severe liver disease and to schedule an individual therapeutic approach.
Collapse
Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milano, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy
| |
Collapse
|
|
49
|
Meroni M, Longo M, Fracanzani AL, Dongiovanni P. MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD. EBioMedicine 2020; 57:102866. [PMID: 32629394 PMCID: PMC7339032 DOI: 10.1016/j.ebiom.2020.102866] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/12/2020] [Accepted: 06/16/2020] [Indexed: 12/11/2022] Open
Abstract
Metabolic associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, which include steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, that is a critical risk factor for hepatocellular carcinoma (HCC) development. Its pathogenesis is intertwined with obesity and type 2 diabetes (T2D). However, the predisposition to develop MAFLD is severely influenced by environmental and inherited cues. The rs641738 variant close to MBOAT7 gene has been identified by a genome-wide association screening in heavy drinkers. Although this variant has been associated with the entire spectrum of MAFLD, these results have not been completely replicated and the debate is still opened. Thus, functional studies that unravel the biological mechanisms underlying the genetic association with fatty liver are required. This review aims to summarize the clinical and experimental findings regarding the rs641738 variation and MBOAT7 function, with the purpose to shed light to its role as novel player in MAFLD pathophysiology.
Collapse
Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Anna L Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy.
| |
Collapse
|
|
50
|
Tong M, Wang F. APOC3
rs2854116
,
PNPLA3
rs738409,
and
TM6SF2
rs58542926
polymorphisms might influence predisposition of
NAFLD
: A meta‐analysis. IUBMB Life 2020; 72:1757-1764. [PMID: 32525256 DOI: 10.1002/iub.2302] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 04/17/2020] [Accepted: 04/22/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Mingjiong Tong
- Department of Infection and HepatologyAffiliated Hospital of Shaoxing University Shaoxing China
| | - Fengyong Wang
- Department of General SurgeryTongde Hospital of Zhejiang Province Hangzhou China
| |
Collapse
|