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Villagrán-Silva F, Loren P, Sandoval C, Lanas F, Salazar LA. Circulating microRNAs as Potential Biomarkers of Overweight and Obesity in Adults: A Narrative Review. Genes (Basel) 2025; 16:349. [PMID: 40149500 PMCID: PMC11942292 DOI: 10.3390/genes16030349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 03/29/2025] Open
Abstract
In an obesogenic environment, such as the one we have been experiencing in recent decades, epigenetics provides answers to the relationship between hereditary and environmentally acquired patterns that have significantly contributed to the global rise in obesity prevalence. MicroRNA (miRNA) constitutes a diminutive non-coding small RNA molecule, 20 to 24 nucleotides in length, that functions as a regulator of gene regulation at the post-translational level. Circulating miRNAs (c-miRNAs) have been detected in multiple body fluids, including blood, plasma, serum, saliva, milk from breastfeeding mothers, and urine. These molecules hold significant therapeutic value and serve as extracellular biomarkers in metabolic diseases. They aid in the diagnosis and tracking of therapy responses, as well as dietary and physical habit modifications. Researchers have studied c-miRNAs as potential biomarkers for diagnosing and characterizing systemic diseases in people of all ages and backgrounds since then. These conditions encompass dyslipidemia, type 2 diabetes mellitus (T2DM), cardiovascular risk, metabolic syndrome, cardiovascular diseases, and obesity. This review therefore analyzes the usefulness of c-miRNAs as therapeutic markers over the past decades. It also provides an update on c-miRNAs associated with general obesity and overweight, as well as with the most prevalent pathologies in the adult population. It also examines the effect of different nutritional approaches and physical activity regarding the activity of miRNAs in circulation in adults with overweight or general obesity. All of this is done with the aim of evaluating their potential use as biomarkers in various research contexts related to overweight and obesity in adults.
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Affiliation(s)
- Francisca Villagrán-Silva
- Doctoral Program in Morphological Sciences, Faculty of Medicine, Universidad de la Frontera, Temuco 4811230, Chile;
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (P.L.); (F.L.)
| | - Pía Loren
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (P.L.); (F.L.)
| | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras 753, Osorno 5310431, Chile;
- Department of Internal Medicine, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile
| | - Fernando Lanas
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (P.L.); (F.L.)
- Department of Internal Medicine, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile
| | - Luis A. Salazar
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (P.L.); (F.L.)
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Liu MH, Xia X, Wang YL, Wang DY, Wang SW, Chen YZ, Sun ML, Xing JX, Xuan JF, Yao J. Current progress and future perspectives in personal identification of monozygotic twins in forensic medicine. Forensic Sci Int Genet 2025; 76:103231. [PMID: 39883969 DOI: 10.1016/j.fsigen.2025.103231] [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: 10/17/2024] [Revised: 01/24/2025] [Accepted: 01/25/2025] [Indexed: 02/01/2025]
Abstract
The personal identification of monozygotic (MZ) twins is of great importance in forensic medicine. Due to the extreme similarity in genetic between MZ twins, it is challenging to differentiate them using autosomal STR genotyping. Forensic experts are striving to explore available genetic markers that can differentiate between MZ twins. With the advent of next-generation sequence (NGS), an increasing number of genetic markers have been demonstrated to effectively differentiate between MZ twins. Here, we summarized for the relevant studies on MZ twins' differentiation and discussed the limitations of the underlying markers. In details, single-nucleotide variants (SNVs), copy number variation (CNV), mitochondrial DNA (mtDNA), DNA methylation, and non-coding RNA have been demonstrated considerable value. Furthermore, the utilization of proteomics, metabolomics, and microbiomics has shed light on MZ twin differentiation. Additionally, we introduce the methodologies for MZ differentiation based on external morphological variations observed in the human body. Looking to the future, the process of aging may represent a novel avenue for the differentiation of MZ twins.
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Affiliation(s)
- Ming-Hui Liu
- School of Forensic Medicine, China Medical University, Shenyang, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, Liaoning Province PR China; China Medical University Center of Forensic Investigation, Shenyang, PR China.
| | - Xi Xia
- School of Forensic Medicine, China Medical University, Shenyang, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, Liaoning Province PR China; China Medical University Center of Forensic Investigation, Shenyang, PR China.
| | - Yi-Long Wang
- Department of Radiotherapy, The First Hospital of China Medical University, Shenyang, PR China.
| | - Dan-Yang Wang
- School of Forensic Medicine, China Medical University, Shenyang, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, Liaoning Province PR China; China Medical University Center of Forensic Investigation, Shenyang, PR China.
| | - Si-Wen Wang
- School of Forensic Medicine, China Medical University, Shenyang, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, Liaoning Province PR China; China Medical University Center of Forensic Investigation, Shenyang, PR China.
| | - Yun-Zhou Chen
- School of Forensic Medicine, China Medical University, Shenyang, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, Liaoning Province PR China; China Medical University Center of Forensic Investigation, Shenyang, PR China.
| | - Mao-Ling Sun
- School of Forensic Medicine, China Medical University, Shenyang, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, Liaoning Province PR China; China Medical University Center of Forensic Investigation, Shenyang, PR China.
| | - Jia-Xin Xing
- School of Forensic Medicine, China Medical University, Shenyang, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, Liaoning Province PR China; China Medical University Center of Forensic Investigation, Shenyang, PR China.
| | - Jin-Feng Xuan
- School of Forensic Medicine, China Medical University, Shenyang, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, Liaoning Province PR China; China Medical University Center of Forensic Investigation, Shenyang, PR China.
| | - Jun Yao
- School of Forensic Medicine, China Medical University, Shenyang, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, Liaoning Province PR China; China Medical University Center of Forensic Investigation, Shenyang, PR China; Shanghai Key Laboratory of Forensic Medicine and Key Laboratory of Forensic Science, Ministry of Justice, PR China.
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Xu WM, Zhang HF, Feng YH, Li SJ, Xie BY. Genetically predicted fatty liver disease and risk of psychiatric disorders: A mendelian randomization study. World J Clin Cases 2024; 12:2359-2369. [PMID: 38765736 PMCID: PMC11099412 DOI: 10.12998/wjcc.v12.i14.2359] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/18/2024] [Accepted: 04/02/2024] [Indexed: 04/29/2024] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ArLD) constitute the primary forms of chronic liver disease, and their incidence is progressively increasing with changes in lifestyle habits. Earlier studies have documented a correlation between the occurrence and development of prevalent mental disorders and fatty liver. AIM To investigate the correlation between fatty liver and mental disorders, thus necessitating the implementation of a mendelian randomization (MR) study to elucidate this association. METHODS Data on NAFLD and ArLD were retrieved from the genome-wide association studies catalog, while information on mental disorders, including Alzheimer's disease, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, multiple personality disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and schizophrenia was acquired from the psychiatric genomics consortium. A two-sample MR method was applied to investigate mediators in significant associations. RESULTS After excluding weak instrumental variables, a causal relationship was identified between fatty liver disease and the occurrence and development of some psychiatric disorders. Specifically, the findings indicated that ArLD was associated with a significantly elevated risk of developing ADHD (OR: 5.81, 95%CI: 5.59-6.03, P < 0.01), bipolar disorder (OR: 5.73, 95%CI: 5.42-6.05, P = 0.03), OCD (OR: 6.42, 95%CI: 5.60-7.36, P < 0.01), and PTSD (OR: 5.66, 95%CI: 5.33-6.01, P < 0.01). Meanwhile, NAFLD significantly increased the risk of developing bipolar disorder (OR: 55.08, 95%CI: 3.59-845.51, P < 0.01), OCD (OR: 61.50, 95%CI: 6.69-565.45, P < 0.01), and PTSD (OR: 52.09, 95%CI: 4.24-639.32, P < 0.01). CONCLUSION Associations were found between genetic predisposition to fatty liver disease and an increased risk of a broad range of psychiatric disorders, namely bipolar disorder, OCD, and PTSD, highlighting the significance of preventive measures against psychiatric disorders in patients with fatty liver disease.
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Affiliation(s)
- Wei-Ming Xu
- Department of Medicine, The First People's Hospital of Fuyang, Hangzhou 311400, Zhejiang Province, China
| | - Hai-Fu Zhang
- Department of Internal Medicine, The First People's Hospital of Fuyang, Hangzhou 311400, Zhejiang Province, China
| | - Yong-Hang Feng
- Department of Internal Medicine, The First People's Hospital of Fuyang, Hangzhou 311400, Zhejiang Province, China
| | - Shuo-Jun Li
- Department of Internal Medicine, The First People's Hospital of Fuyang, Hangzhou 311400, Zhejiang Province, China
| | - Bi-Yun Xie
- Department of Internal Medicine, The First People's Hospital of Fuyang, Hangzhou 311400, Zhejiang Province, China
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Samy AM, Kandeil MA, Sabry D, Abdel-Ghany A, Mahmoud MO. From NAFLD to NASH: Understanding the spectrum of non-alcoholic liver diseases and their consequences. Heliyon 2024; 10:e30387. [PMID: 38737288 PMCID: PMC11088336 DOI: 10.1016/j.heliyon.2024.e30387] [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: 08/23/2023] [Revised: 04/04/2024] [Accepted: 04/25/2024] [Indexed: 05/14/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become one of the most frequent chronic liver diseases worldwide in recent decades. Metabolic diseases like excessive blood glucose, central obesity, dyslipidemia, hypertension, and liver function abnormalities cause NAFLD. NAFLD significantly increases the likelihood of liver cancer, heart disease, and mortality, making it a leading cause of liver transplants. Non-alcoholic steatohepatitis (NASH) is a more advanced form of the disease that causes scarring and inflammation of the liver over time and can ultimately result in cirrhosis and hepatocellular carcinoma. In this review, we briefly discuss NAFLD's pathogenic mechanisms, their progression into NASH and afterward to NASH-related cirrhosis. It also covers disease epidemiology, metabolic mechanisms, glucose and lipid metabolism in the liver, macrophage dysfunction, bile acid toxicity, and liver stellate cell stimulation. Additionally, we consider the contribution of intestinal microbiota, genetics, epigenetics, and ecological factors to fibrosis progression and hepatocellular carcinoma risk in NAFLD and NASH patients.
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Affiliation(s)
- Ahmed M. Samy
- Department of Biochemistry, Faculty of Pharmacy, Nahda University, Beni-Suef 62513, Egypt
| | - Mohamed A. Kandeil
- Department of Biochemistry, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62511, Egypt
| | - Dina Sabry
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Badr University in Cairo, Cairo 11829, Egypt
| | - A.A. Abdel-Ghany
- Department of Biochemistry, Faculty of Pharmacy, Nahda University, Beni-Suef 62513, Egypt
- Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Assuit Branch, Egypt
| | - Mohamed O. Mahmoud
- Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
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Cernea S. NAFLD Fibrosis Progression and Type 2 Diabetes: The Hepatic-Metabolic Interplay. Life (Basel) 2024; 14:272. [PMID: 38398781 PMCID: PMC10890557 DOI: 10.3390/life14020272] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/13/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024] Open
Abstract
The bidirectional relationship between type 2 diabetes and (non-alcoholic fatty liver disease) NAFLD is indicated by the higher prevalence and worse disease course of one condition in the presence of the other, but also by apparent beneficial effects observed in one, when the other is improved. This is partly explained by their belonging to a multisystemic disease that includes components of the metabolic syndrome and shared pathogenetic mechanisms. Throughout the progression of NAFLD to more advanced stages, complex systemic and local metabolic derangements are involved. During fibrogenesis, a significant metabolic reprogramming occurs in the hepatic stellate cells, hepatocytes, and immune cells, engaging carbohydrate and lipid pathways to support the high-energy-requiring processes. The natural history of NAFLD evolves in a variable and dynamic manner, probably due to the interaction of a variable number of modifiable (diet, physical exercise, microbiota composition, etc.) and non-modifiable (genetics, age, ethnicity, etc.) risk factors that may intervene concomitantly, or subsequently/intermittently in time. This may influence the risk (and rate) of fibrosis progression/regression. The recognition and control of the factors that determine a rapid progression of fibrosis (or its regression) are critical, as the fibrosis stages are associated with the risk of liver-related and all-cause mortality.
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Affiliation(s)
- Simona Cernea
- Department M3, Internal Medicine I, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, 540142 Târgu Mureş, Romania; or
- Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, 540136 Târgu Mureş, Romania
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Wang S, Friedman SL. Found in translation-Fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). Sci Transl Med 2023; 15:eadi0759. [PMID: 37792957 PMCID: PMC10671253 DOI: 10.1126/scitranslmed.adi0759] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 09/15/2023] [Indexed: 10/06/2023]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of liver disease that poses a global health threat because of its potential to progress to advanced fibrosis, leading to cirrhosis and liver cancer. Recent advances in single-cell methodologies, refined disease models, and genetic and epigenetic insights have provided a nuanced understanding of MASH fibrogenesis, with substantial cellular heterogeneity in MASH livers providing potentially targetable cell-cell interactions and behavior. Unlike fibrogenesis, mechanisms underlying fibrosis regression in MASH are still inadequately understood, although antifibrotic targets have been recently identified. A refined antifibrotic treatment framework could lead to noninvasive assessment and targeted therapies that preserve hepatocellular function and restore the liver's architectural integrity.
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Affiliation(s)
- Shuang Wang
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Frías M, Corona-Mata D, Moyano JM, Camacho-Espejo A, López-López P, Caballero-Gómez J, Ruiz-Cáceres I, Casares-Jiménez M, Pérez-Valero I, Rivero-Juárez A, Rivero A. Lack of associations of microRNAs with severe NAFLD in people living with HIV: discovery case-control study. Front Endocrinol (Lausanne) 2023; 14:1230046. [PMID: 37810880 PMCID: PMC10556652 DOI: 10.3389/fendo.2023.1230046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 08/28/2023] [Indexed: 10/10/2023] Open
Abstract
Background & objective Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in people living with HIV (PLWH) and the expression of some microRNAs could be useful as biomarkers for the diagnosis of NAFLD. The aim of this study was to identify patterns of differential expression of microRNAs in PLWH and assess their diagnostic value for NALFD. Methods A discovery case-control study with PLWH was carried out. The expression of miRNAs was determined using HTG EdgeSeq technology. Cases were defined as patients with severe NAFLD and controls as patients without NAFLD, characterized using the controlled attenuation parameter (CAP). Cases and controls were matched 1:1 for age, sex, BMI, CD4+ lymphocyte count, active HCV infection, and ART regimen. Results Serum 2,083 simultaneous microRNA transcripts were analyzed using HTG technology and compared between cases and controls. Forty-five patients, 23 cases, and 22 controls were included in the study. In the analysis of the expression pattern of the 2,083 microRNAs, no differential expression patterns were found between both groups of patients included in the study. Conclusion Analysis of the microRNA transcriptome profile of nonobese PLWH with severe NAFLD did not appear to differ from that of patients without NAFLD. Thus, microRNA might not serve as a proper biomarker for predicting severe NALFD in this population.
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Affiliation(s)
- Mario Frías
- Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Clinical Virology and Zoonoses, Maimonides Biomedical Research Institute of Cordoba, University of Córdoba, Córdoba, Spain
- CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III (CIBERINFEC, ISCIII), Madrid, Spain
- Animal Health Department, Animal Health and Zoonoses Research Group (GISAZ), University of Córdoba, Córdoba, Spain
| | - Diana Corona-Mata
- Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Clinical Virology and Zoonoses, Maimonides Biomedical Research Institute of Cordoba, University of Córdoba, Córdoba, Spain
| | - Jose M. Moyano
- Department of Computer Science and Artificial Intelligence, Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI), University of Granada, Granada, Spain
| | - Angela Camacho-Espejo
- Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Clinical Virology and Zoonoses, Maimonides Biomedical Research Institute of Cordoba, University of Córdoba, Córdoba, Spain
- CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III (CIBERINFEC, ISCIII), Madrid, Spain
| | - Pedro López-López
- Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Clinical Virology and Zoonoses, Maimonides Biomedical Research Institute of Cordoba, University of Córdoba, Córdoba, Spain
- CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III (CIBERINFEC, ISCIII), Madrid, Spain
| | - Javier Caballero-Gómez
- Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Clinical Virology and Zoonoses, Maimonides Biomedical Research Institute of Cordoba, University of Córdoba, Córdoba, Spain
- CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III (CIBERINFEC, ISCIII), Madrid, Spain
- Animal Health Department, Animal Health and Zoonoses Research Group (GISAZ), University of Córdoba, Córdoba, Spain
| | - Inmaculada Ruiz-Cáceres
- Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Clinical Virology and Zoonoses, Maimonides Biomedical Research Institute of Cordoba, University of Córdoba, Córdoba, Spain
| | - María Casares-Jiménez
- Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Clinical Virology and Zoonoses, Maimonides Biomedical Research Institute of Cordoba, University of Córdoba, Córdoba, Spain
| | - Ignacio Pérez-Valero
- Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Clinical Virology and Zoonoses, Maimonides Biomedical Research Institute of Cordoba, University of Córdoba, Córdoba, Spain
- CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III (CIBERINFEC, ISCIII), Madrid, Spain
| | - Antonio Rivero-Juárez
- Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Clinical Virology and Zoonoses, Maimonides Biomedical Research Institute of Cordoba, University of Córdoba, Córdoba, Spain
- CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III (CIBERINFEC, ISCIII), Madrid, Spain
| | - Antonio Rivero
- Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Clinical Virology and Zoonoses, Maimonides Biomedical Research Institute of Cordoba, University of Córdoba, Córdoba, Spain
- CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III (CIBERINFEC, ISCIII), Madrid, Spain
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Bartiromo M, Nardolillo M, Ferrara S, Russo G, Miraglia Del Giudice E, Di Sessa A. The challenging role of micro-RNAs in non-alcoholic fatty liver disease in children with obesity: is it time for a new era? Expert Rev Gastroenterol Hepatol 2023; 17:817-824. [PMID: 37497846 DOI: 10.1080/17474124.2023.2242245] [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: 11/19/2022] [Revised: 07/04/2023] [Accepted: 07/26/2023] [Indexed: 07/28/2023]
Abstract
INTRODUCTION As the pediatric obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in childhood. Pediatric NAFLD pathophysiology is tangled and still unclear, but insulin resistance (IR), genetics, epigenetics, oxidative stress, and inflammation act as key players. Due to the increased cardiometabolic risk of these patients, several biomarkers have been proposed for early NAFLD identification, but their clinical utility is poor. Recently, hepatic dysregulation of microRNAs (miRNAs) has been linked to metabolic dysfunction, which in turn implied in NAFLD development. Evidence on the intriguing role of miRNAs in NAFLD pathogenesis has emerging especially in at-risk children such as those with obesity. However, pediatric evidence supporting their potential use as early noninvasive NAFLD tools is still limited but promising. AREAS COVERED We provided an overview on the emerging role of miRNAs in pediatric NAFLD by addressing some issues regarding their pathophysiological link with the metabolic milieu and their role as reliable NAFLD markers in children with obesity. EXPERT OPINION Strong evidence supports a potential role of miRNAs as early biomarkers of NAFLD in children with obesity. They might represent a valid diagnostic and targeted therapeutic tool due to its close pathogenic link with the metabolic milieu.
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Affiliation(s)
- Mario Bartiromo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Michele Nardolillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Serena Ferrara
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppina Russo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Emanuele Miraglia Del Giudice
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Anna Di Sessa
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
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Rana M, Saini M, Das R, Gupta S, Joshi T, Mehta DK. Circulating MicroRNAs: Diagnostic Value as Biomarkers in the Detection of Non-alcoholic Fatty Liver Diseases and Hepatocellular Carcinoma. Microrna 2023; 12:99-113. [PMID: 37005546 DOI: 10.2174/2211536612666230330083146] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 01/09/2023] [Accepted: 01/20/2023] [Indexed: 04/04/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), a metabolic-related disorder, is the most common cause of chronic liver disease which, if left untreated, can progress from simple steatosis to advanced fibrosis and eventually cirrhosis or hepatocellular carcinoma, which is the leading cause of hepatic damage globally. Currently available diagnostic modalities for NAFLD and hepatocellular carcinoma are mostly invasive and of limited precision. A liver biopsy is the most widely used diagnostic tool for hepatic disease. But due to its invasive procedure, it is not practicable for mass screening. Thus, noninvasive biomarkers are needed to diagnose NAFLD and HCC, monitor disease progression, and determine treatment response. Various studies indicated that serum miRNAs could serve as noninvasive biomarkers for both NAFLD and HCC diagnosis because of their association with different histological features of the disease. Although microRNAs are promising and clinically useful biomarkers for hepatic diseases, larger standardization procedures and studies are still required.
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Affiliation(s)
- Minakshi Rana
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Manisha Saini
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Rina Das
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Sumeet Gupta
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Tanishq Joshi
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Dinesh Kumar Mehta
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
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Yang Y, Li X, Liu Z, Ruan X, Wang H, Zhang Q, Cao L, Song L, Chen Y, Sun Y. Moderate Treadmill Exercise Alleviates NAFLD by Regulating the Biogenesis and Autophagy of Lipid Droplet. Nutrients 2022; 14:nu14224910. [PMID: 36432597 PMCID: PMC9697757 DOI: 10.3390/nu14224910] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/13/2022] [Accepted: 11/17/2022] [Indexed: 11/22/2022] Open
Abstract
Lipid droplet is a dynamic organelle that undergoes periods of biogenesis and degradation under environmental stimuli. The excessive accumulation of lipid droplets is the major characteristic of non-alcoholic fatty liver disease (NAFLD). Moderate aerobic exercise is a powerful intervention protecting against the progress of NAFLD. However, its impact on lipid droplet dynamics remains ambiguous. Mice were fed with 15 weeks of high-fat diet in order to induce NAFLD. Meanwhile, the mice performed 15 weeks of treadmill exercise. Our results showed that 15 weeks of regular moderate treadmill exercise alleviated obesity, insulin intolerance, hyperlipidemia, and hyperglycemia induced by HFD. Importantly, exercise improved histological phenotypes of NAFLD, including hepatic steatosis, inflammation, and locular ballooning, as well as prevented liver fat deposition and liver injury induced by HFD. Exercise reduced hepatic lipid droplet size, and moreover, it reduced PLIN2 protein level and increased PLIN3 protein level in the liver of HFD mice. Interestingly, our results showed that exercise did not significantly affect the gene expressions of DGAT1, DGAT2, or SEIPIN, which were involved in TG synthesis. However, it did reduce the expressions of FITM2, CIDEA, and FSP27, which were major involved in lipid droplet growth and budding, and lipid droplet expansion. In addition, exercise reduced ATGL protein level in HFD mice, and regulated lipophagy-related markers, including increasing ATG5, LAMP1, LAMP2, LAL, and CTSD, decreasing LC3II/I and p62, and promoting colocalization of LAMP1 with LDs. In summary, our data suggested that 15 weeks of moderate treadmill exercise was beneficial for regulating liver lipid droplet dynamics in HFD mice by inhibiting abnormal lipid droplets expansion and enhancing clearance of lipid droplets by lysosomes during the lipophagic process, which might provide highly flexible turnover for lipid mobilization and metabolism. Abbreviations: β-actin: actin beta; ATG5: autophagy related 5; LAMP2: lysosomal-associated membrane protein 2; LAMP1: lysosomal-associated membrane protein 1; SQSTM1/p62: sequestosome 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ATGL: adipose triglyceride lipase; CSTD: cathepsin D; LAL: lysosomal acid lipase; DGAT1: diacylglycerol-o-acyltransferase 1; DGAT2: diacylglycerol-o-acyltransferase 2; CIDEA: cell death inducing dffa-like effector a; CIDEC/FSP27: cell death inducing dffa-like effector c; FITM2: fat storage-inducing transmembrane protein 2; PLIN2: adipose differentiation related protein; PLN3: tail-interacting protein 47; HSP90: heat shock protein 90; SREBP1c: sterol regulatory element binding protein-1c; chREBP: carbohydrate response element binding protein.
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Affiliation(s)
- Yangjun Yang
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China
| | - Xi Li
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China
| | - Zonghan Liu
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China
| | - Xinyu Ruan
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China
| | - Huihui Wang
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China
| | - Qiang Zhang
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China
| | - Lu Cao
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China
| | - Luchen Song
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China
| | - Yinghong Chen
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China
| | - Yi Sun
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China
- Correspondence: ; Tel.: +86-021-54341197
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11
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Gangopadhyay A, Ibrahim R, Theberge K, May M, Houseknecht KL. Non-alcoholic fatty liver disease (NAFLD) and mental illness: Mechanisms linking mood, metabolism and medicines. Front Neurosci 2022; 16:1042442. [PMID: 36458039 PMCID: PMC9707801 DOI: 10.3389/fnins.2022.1042442] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/21/2022] [Indexed: 09/26/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world and one of the leading indications for liver transplantation. It is one of the many manifestations of insulin resistance and metabolic syndrome as well as an independent risk factor for cardiovascular disease. There is growing evidence linking the incidence of NAFLD with psychiatric illnesses such as schizophrenia, bipolar disorder and depression mechanistically via genetic, metabolic, inflammatory and environmental factors including smoking and psychiatric medications. Indeed, patients prescribed antipsychotic medications, regardless of diagnosis, have higher incidence of NAFLD than population norms. The mechanistic pharmacology of antipsychotic-associated NAFLD is beginning to emerge. In this review, we aim to discuss the pathophysiology of NAFLD including its risk factors, insulin resistance and systemic inflammation as well as its intersection with psychiatric illnesses.
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Affiliation(s)
| | | | | | | | - Karen L. Houseknecht
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, ME, United States
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12
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Carratto TMT, Moraes VMS, Recalde TSF, Oliveira MLGD, Teixeira Mendes-Junior C. Applications of massively parallel sequencing in forensic genetics. Genet Mol Biol 2022; 45:e20220077. [PMID: 36121926 PMCID: PMC9514793 DOI: 10.1590/1678-4685-gmb-2022-0077] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 07/15/2022] [Indexed: 11/22/2022] Open
Abstract
Massively parallel sequencing, also referred to as next-generation sequencing, has positively changed DNA analysis, allowing further advances in genetics. Its capability of dealing with low quantity/damaged samples makes it an interesting instrument for forensics. The main advantage of MPS is the possibility of analyzing simultaneously thousands of genetic markers, generating high-resolution data. Its detailed sequence information allowed the discovery of variations in core forensic short tandem repeat loci, as well as the identification of previous unknown polymorphisms. Furthermore, different types of markers can be sequenced in a single run, enabling the emergence of DIP-STRs, SNP-STR haplotypes, and microhaplotypes, which can be very useful in mixture deconvolution cases. In addition, the multiplex analysis of different single nucleotide polymorphisms can provide valuable information about identity, biogeographic ancestry, paternity, or phenotype. DNA methylation patterns, mitochondrial DNA, mRNA, and microRNA profiling can also be analyzed for different purposes, such as age inference, maternal lineage analysis, body-fluid identification, and monozygotic twin discrimination. MPS technology also empowers the study of metagenomics, which analyzes genetic material from a microbial community to obtain information about individual identification, post-mortem interval estimation, geolocation inference, and substrate analysis. This review aims to discuss the main applications of MPS in forensic genetics.
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Affiliation(s)
- Thássia Mayra Telles Carratto
- Universidade de São Paulo, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Departamento de Química, Laboratório de Pesquisas Forenses e Genômicas, Ribeirão Preto, SP, Brazil
| | - Vitor Matheus Soares Moraes
- Universidade de São Paulo, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Departamento de Química, Laboratório de Pesquisas Forenses e Genômicas, Ribeirão Preto, SP, Brazil
| | | | | | - Celso Teixeira Mendes-Junior
- Universidade de São Paulo, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Departamento de Química, Laboratório de Pesquisas Forenses e Genômicas, Ribeirão Preto, SP, Brazil
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13
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Wajsbrot NB, Leite NC, Salles GF, Villela-Nogueira CA. Non-alcoholic fatty liver disease and the impact of genetic, epigenetic and environmental factors in the offspring. World J Gastroenterol 2022; 28:2890-2899. [PMID: 35978876 PMCID: PMC9280730 DOI: 10.3748/wjg.v28.i25.2890] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/20/2022] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is strongly associated with metabolic deregulation. More recently, a significant impact of parental NAFLD in the offspring was demonstrated and has been widely discussed. However, pathogenetic pathways implicated in the inheritance by the offspring and relatives are still under debate. Probably, multiple mechanisms are involved as well as in NAFLD pathogenesis itself. Among the multifactorial involved mechanisms, genetic, epigenetic and environmental backgrounds are strongly related to NAFLD development in the offspring. Thus, based on recent evidence from the available literature concerning genetic, epigenetic and environmental disease modifiers, this review aimed to discuss the relationship between parental NAFLD and its impact on the offspring.
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Affiliation(s)
- Natalia Balassiano Wajsbrot
- Division of Hepatology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 20941-913, Brazil
| | - Nathalie Carvalho Leite
- Division of Hepatology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 20941-913, Brazil
| | - Gil F Salles
- Department of Internal Medicine, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro 22750-240, Brazil
| | - Cristiane A Villela-Nogueira
- Department of Internal Medicine, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro 22750-240, Brazil
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14
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Czaja AJ. Epigenetic Aspects and Prospects in Autoimmune Hepatitis. Front Immunol 2022; 13:921765. [PMID: 35844554 PMCID: PMC9281562 DOI: 10.3389/fimmu.2022.921765] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/12/2022] [Indexed: 12/12/2022] Open
Abstract
The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4+ and CD19+ T lymphocytes of patients with autoimmune hepatitis, and the circulating micro-ribonucleic acids, miR-21 and miR-122, have correlated with laboratory and histological features of liver inflammation. Both epigenetic agents have also correlated inversely with the stage of liver fibrosis. The reduced hepatic concentration of miR-122 in cirrhosis suggests that its deficiency may de-repress the pro-fibrotic prolyl-4-hydroxylase subunit alpha-1 gene. Conversely, miR-155 is over-expressed in the liver tissue of patients with autoimmune hepatitis, and it may signify active immune-mediated liver injury. Different epigenetic findings have been described in diverse autoimmune and non-autoimmune liver diseases, and these changes may have disease-specificity. They may also be responses to environmental cues or heritable adaptations that distinguish the diseases. Advances in epigenetic editing and methods for blocking micro-ribonucleic acids have improved opportunities to prove causality and develop site-specific, therapeutic interventions. In conclusion, the role of epigenetics in affecting the risk, clinical phenotype, and outcome of autoimmune hepatitis is under-evaluated. Full definition of the epigenome of autoimmune hepatitis promises to enhance understanding of pathogenic mechanisms and satisfy the unmet clinical need to improve therapy for refractory disease.
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Affiliation(s)
- Albert J. Czaja
- *Correspondence: Albert J. Czaja, ; orcid.org/0000-0002-5024-3065
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15
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Dietary Improvement during Lactation Normalizes miR-26a, miR-222 and miR-484 Levels in the Mammary Gland, but Not in Milk, of Diet-Induced Obese Rats. Biomedicines 2022; 10:biomedicines10061292. [PMID: 35740314 PMCID: PMC9219892 DOI: 10.3390/biomedicines10061292] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 05/24/2022] [Accepted: 05/24/2022] [Indexed: 02/01/2023] Open
Abstract
We aimed to evaluate in rats whether the levels of specific miRNA are altered in the mammary gland (MG) and milk of diet-induced obese dams, and whether improving maternal nutrition during lactation attenuates such alterations. Dams fed with a standard diet (SD) (control group), with a Western diet (WD) prior to and during gestation and lactation (WD group), or with WD prior to and during gestation but moved to SD during lactation (Rev group) were followed. The WD group showed higher miR-26a, miR-222 and miR-484 levels than the controls in the MG, but the miRNA profile in Rev animals was not different from those of the controls. The WD group also displayed higher miR-125a levels than the Rev group. Dams of the WD group, but not the Rev group, displayed lower mRNA expression levels of Rb1 (miR-26a’s target) and Elovl6 (miR-125a’s target) than the controls in the MG. The WD group also presented lower expression of Insig1 (miR-26a’s target) and Cxcr4 (miR-222’s target) than the Rev group. However, both WD and Rev animals displayed lower expression of Vegfa (miR-484’s target) than the controls. WD animals also showed greater miR-26a, miR-125a and miR-222 levels in the milk than the controls, but no differences were found between the WD and Rev groups. Thus, implementation of a healthy diet during lactation normalizes the expression levels of specific miRNAs and some target genes in the MG of diet-induced obese dams but not in milk.
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16
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Advances of microRNAs in regulating mitochondrial function: new potential application in NAFLD treatment. Mol Biol Rep 2022; 49:9841-9853. [PMID: 35612781 DOI: 10.1007/s11033-022-07503-0] [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: 01/17/2022] [Accepted: 04/22/2022] [Indexed: 11/09/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common metabolic diseases and closely associated with lipid disorder. Mitochondrion has been recognized to play a key role in lipid metabolism as the main site of energy metabolism in cells, and its dysfunction is involved in the progression of NAFLD. MicroRNAs (miRNAs), one of regulators in the pathogenesis of NAFLD, are discovered to modulate mitochondrial function by targeting mitochondrial proteins or mitochondrial-related factors, thereby improving or deteriorating NAFLD-associated pathologies. This review summarizes the differentially expressed miRNAs from clinical and experimental models of NAFLD with abilities in regulating mitochondrial function, expounds their underlying molecular mechanism and discusses their prospect and future research direction.
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17
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Bardhi E, McDaniels J, Rousselle T, Maluf DG, Mas VR. Nucleic acid biomarkers to assess graft injury after liver transplantation. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100439. [PMID: 35243279 PMCID: PMC8856989 DOI: 10.1016/j.jhepr.2022.100439] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/13/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023]
Abstract
Many risk factors and complications impact the success of liver transplantation, such as ischaemia-reperfusion injury, acute rejection, and primary graft dysfunction. Molecular biomarkers have the potential to accurately diagnose, predict, and monitor injury progression or organ failure. There is a critical opportunity for reliable and non-invasive biomarkers to reduce the organ shortage by enabling i) the assessment of donor organ quality, ii) the monitoring of short- and long-term graft function, and iii) the prediction of acute and chronic disease development. To date, no established molecular biomarkers have been used to guide clinical decision-making in transplantation. In this review, we outline the recent advances in cell-free nucleic acid biomarkers for monitoring graft injury in liver transplant recipients. Prior work in this area can be divided into two categories: biomarker discovery and validation studies. Circulating nucleic acids (CNAs) can be found in the extracellular environment pertaining to different biological fluids such as bile, blood, urine, and perfusate. CNAs that are packaged into extracellular vesicles may facilitate intercellular and interorgan communication. Thus, decoding their biological function, cellular origins and molecular composition is imperative for diagnosing causes of graft injury, guiding immunosuppression and improving overall patient survival. Herein, we discuss the most promising molecular biomarkers, their state of development, and the critical aspects of study design in biomarker research for early detection of post-transplant liver injury. Future advances in biomarker studies are expected to personalise post-transplant therapy, leading to improved patient care and outcomes.
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18
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Abstract
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease, worldwide. The molecular pathogenesis of NAFLD is complex, involving numerous signalling molecules including microRNAs (miRNAs). Dysregulation of miRNA expression is associated with hepatic inflammation, fibrosis and hepatocellular carcinoma. Although miRNAs are also critical to the cellular response to vitamin D, mediating regulation of the vitamin D receptor (VDR) and vitamin D’s anticancer effects, a role for vitamin D regulated miRNAs in NAFLD pathogenesis has been relatively unexplored. Therefore, this review aimed to critically assess the evidence for a potential subset of miRNAs that are both dysregulated in NAFLD and modulated by vitamin D. Comprehensive review of 89 human studies identified 25 miRNAs found dysregulated in more than one NAFLD study. In contrast, only 17 studies, including a protocol for a trial in NAFLD, had examined miRNAs in relation to vitamin D status, response to supplementation, or vitamin D in the context of the liver. This paper summarises these data and reviews the biological roles of six miRNAs (miR-21, miR-30, miR-34, miR-122, miR-146, miR-200) found dysregulated in multiple independent NAFLD studies. While modulation of miRNAs by vitamin D has been understudied, integrating the data suggests seven vitamin D modulated miRNAs (miR-27, miR-125, miR-155, miR-192, miR-223, miR-375, miR-378) potentially relevant to NAFLD pathogenesis. Our summary tables provide a significant resource to underpin future hypothesis-driven research, and we conclude that the measurement of serum and hepatic miRNAs in response to vitamin D supplementation in larger trials is warranted.
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19
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Heritability analysis of liver stiffness detected by ultrasound shear wave elastography: a twin study. Eur J Gastroenterol Hepatol 2021; 33:e766-e770. [PMID: 34284414 DOI: 10.1097/meg.0000000000002246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES OF THE STUDY Nonalcoholic fatty liver disease (NAFLD) is a common condition with a subset of individuals developing liver fibrosis as a major risk factor for advanced liver disease. The contribution of genetic factors to this progression remains incompletely understood. Our aim was to analyze heritability in the development of liver fibrosis estimated by ultrasound shear wave elastography (SWE) in an asymptomatic adult twin cohort. METHODS In total 172 adult Hungarian twins (51 monozygotic and 36 dizygotic pairs; 63% women; mean age 54.9 ± 15.1 years) underwent B-mode ultrasonography to assess steatosis and SWE to determine Young's modulus as a noninvasive marker or liver fibrosis. RESULTS We identified 99 subjects with steatosis, which was mild in 46 subjects (46%), moderate in 52 subjects (52%) and severe in a single subject (1%). Mean Young's modulus was 7.58 ± 3.53 kPa in this slightly overweight study cohort (BMI: 25.7 ± 4.6 kg/m2). Univariate analysis adjusted for age, sex and BMI indicated no discernible role for genetic components in the presence of liver stiffness, whereas shared and unshared environmental effects accounted for 38.3% (95% confidence interval (CI), 17-56.1%) and 61.7% (95% CI, 43.9-83%). CONCLUSIONS Our findings do not support the heritability of liver stiffness in an asymptomatic, twin cohort with slight overweight and variable degree of steatosis, underscoring the importance of environmental factors in the development of NAFLD and liver fibrosis.
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20
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Wu C, Zhou Y, Wang M, Dai G, Liu X, Lai L, Tang S. Bioinformatics Analysis Explores Potential Hub Genes in Nonalcoholic Fatty Liver Disease. Front Genet 2021; 12:772487. [PMID: 34777484 PMCID: PMC8586215 DOI: 10.3389/fgene.2021.772487] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 10/18/2021] [Indexed: 01/14/2023] Open
Abstract
Background: Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most prevalent chronic liver disease worldwide. However, the dysregulated gene expression for NAFLD is still poorly understood. Material and methods: We analyzed two public datasets (GSE48452 and GSE89632) to identify differentially expressed genes (DEGs) in NAFLD. Then, we performed a series of bioinformatics analyses to explore potential hub genes in NAFLD. Results: This study included 26 simple steatosis (SS), 34 nonalcoholic steatohepatitis (NASH), and 13 healthy controls (HC). We observed 6 up- and 19 down-regulated genes in SS, and 13 up- and 19 down-regulated genes in NASH compared with HC. Meanwhile, the overlapping pathways between SS and NASH were PI3K-Akt signaling pathway and pathways in cancer. Then, we screened out 10 hub genes by weighted Gene Co-Expression Network Analysis (WGCNA) and protein-protein interaction (PPI) networks. Eventually, we found that CYP7A1/GINS2/PDLIM3 were associated with the prognosis of hepatocellular carcinoma (HCC) in the TCGA database. Conclusion: Although further validation is still needed, we provide useful and novel information to explore the potential candidate genes for NAFLD prognosis and therapeutic options.
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Affiliation(s)
- Chutian Wu
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Yun Zhou
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China.,Department of Gastroenterology, The First Affiliated Hospital, Gannan Medical University, Ganzhou, China
| | - Min Wang
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Guolin Dai
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Xiongxiu Liu
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Leizhen Lai
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Shaohui Tang
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
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21
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Merve Bayram H, Eren F, Esra Gunes F. The relationship between polyphenols and miRNAs: A novel therapeutic strategy for metabolic associated fatty liver disease. HEPATOLOGY FORUM 2021; 2:128-136. [PMID: 35784906 PMCID: PMC9138948 DOI: 10.14744/hf.2021.2021.0037] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 09/10/2021] [Indexed: 06/15/2023]
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a public health problem that is increasingly recognized, currently affecting up to a quarter of the world's adult population. Although a biopsy is the current gold standard to diagnose MAFLD, there are potentially serious complications, making it inadequate. Thus far, noninvasive methods have not been able to determine the stage and the subtype of MAFLD. The development and prognosis of MAFLD are modulated by epigenetic factors, including microRNAs (miRNAs), which may be potential biomarkers for MAFLD. Polyphenols, found in many fruits and vegetables, may be useful, as they alter gene expression with epigenetic factors, such as miRNAs. This review presents an overview of the relationship between polyphenols and miRNAs in MAFLD. The literature suggests that miRNAs could be used as a diagnostic method for MAFLD, especially miRNA-122 and miRNA-34a. However, though it has been demonstrated that polyphenols may contribute to improving MAFLD, to our knowledge, no study to date has shown the relationship between polyphenols and miRNAs in MAFLD. The exact mechanisms of polyphenols on miRNAs in MAFLD remain unclear. Future studies may provide hope for diet therapy for MAFLD patients as well as the development of polyphenol-related foods or drugs that target miRNAs to treat MAFLD.
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Affiliation(s)
- Hatice Merve Bayram
- Department of Nutrition and Dietetics, Istanbul Gelisim University Faculty of Health Sciences, Istanbul, Turkey
| | - Fatih Eren
- Institute of Gastroenterology, Marmara University, Istanbul, Turkey
- Department of Medical Biology, Marmara University School of Medicine, Istanbul, Turkey
| | - Fatma Esra Gunes
- Department of Nutrition and Dietetics, Marmara University Faculty of Health Sciences, Istanbul, Turkey
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22
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Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 2021; 184:2537-2564. [PMID: 33989548 PMCID: PMC12168897 DOI: 10.1016/j.cell.2021.04.015] [Citation(s) in RCA: 1145] [Impact Index Per Article: 286.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/21/2021] [Accepted: 04/09/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Its more advanced subtype, nonalcoholic steatohepatitis (NASH), connotes progressive liver injury that can lead to cirrhosis and hepatocellular carcinoma. Here we provide an in-depth discussion of the underlying pathogenetic mechanisms that lead to progressive liver injury, including the metabolic origins of NAFLD, the effect of NAFLD on hepatic glucose and lipid metabolism, bile acid toxicity, macrophage dysfunction, and hepatic stellate cell activation, and consider the role of genetic, epigenetic, and environmental factors that promote fibrosis progression and risk of hepatocellular carcinoma in NASH.
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Affiliation(s)
- Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Gerald I Shulman
- Departments of Internal Medicine and Cellular & Molecular Physiology, Yale Diabetes Research Center, Yale School of Medicine, New Haven, CT 06520, USA.
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23
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Zhang X, Asllanaj E, Amiri M, Portilla-Fernandez E, Bramer WM, Nano J, Voortman T, Pan Q, Ghanbari M. Deciphering the role of epigenetic modifications in fatty liver disease: A systematic review. Eur J Clin Invest 2021; 51:e13479. [PMID: 33350463 PMCID: PMC8243926 DOI: 10.1111/eci.13479] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 12/17/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Fatty liver disease (FLD), primarily nonalcoholic fatty liver disease (NAFLD), is the most common liver disorder that affects a quarter of the global population. NAFLD is a spectrum of disease ranging from simple steatosis to nonalcoholic steatohepatitis, which is associated with increased risk of developing liver cancer. Given that the pathogenic mechanisms of fatty liver remain largely elusive, it is important to further investigate potential underlying mechanisms including epigenetic modifications. Here, we performed a systematic review of human epigenetic studies on FLD presence. METHODS Five bibliographic databases were screened until 28 August 2020. We included cross-sectional, case-control and cohort studies in humans that examined the association of epigenetic modifications including global, candidate or epigenome-wide methylation of DNA, noncoding RNAs and histone modifications with FLD. RESULTS In total 36 articles, based on 33 unique studies, consisting of 12 112 participants met the inclusion criteria. Among these, two recent epigenome-wide association studies conducted among large population-based cohorts have reported the association between cg06690548 (SLC7A11) and FLD. Moreover, several studies have demonstrated the association between microRNAs (miRNAs) and FLD, in which miR-122, miR-34a and miR-192 were recognized as the most relevant miRNAs as biomarkers for FLD. We did not find any studies examining histone modifications in relation to FLD. CONCLUSIONS Cumulative evidence suggests a link between epigenetic mechanisms, specifically DNA methylation and miRNAs, and FLD. Further efforts should investigate the molecular pathways by which these epigenetic markers may regulate FLD and also the potential role of histone modifications in FLD.
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Affiliation(s)
- Xiaofang Zhang
- Department of Epidemiology, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Eralda Asllanaj
- Department of Epidemiology, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands.,Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Masoud Amiri
- Department of Epidemiology, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Eliana Portilla-Fernandez
- Department of Epidemiology, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Wichor M Bramer
- Medical Library, Erasmus MC, Erasmus University Medical Centre, Rotterdam, the Netherlands
| | - Jana Nano
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.,German Diabetes Center, München-Neuherberg, Germany
| | - Trudy Voortman
- Department of Epidemiology, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Mohsen Ghanbari
- Department of Epidemiology, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
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24
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Geh D, Anstee QM, Reeves HL. NAFLD-Associated HCC: Progress and Opportunities. J Hepatocell Carcinoma 2021; 8:223-239. [PMID: 33854987 PMCID: PMC8041650 DOI: 10.2147/jhc.s272213] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 03/08/2021] [Indexed: 12/13/2022] Open
Abstract
Due to an increase in the obesity-associated metabolic syndrome of epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of hepatocellular carcinoma (HCC) in western countries. This presents added challenges, as NAFLD-associated HCC tends to present at an advanced stage in older patients with co-morbidities. Their prognosis is generally poor with the benefits of standard therapies less certain. The pathogenesis of NAFLD-associated HCC is multifactorial and not well understood, although the risk of HCC developing undoubtedly increases as NAFLD progresses to steatohepatitis and cirrhosis. Recent advances in our understanding of the drivers of NAFLD and HCC will hopefully lead to the development of clinically relevant biomarkers, tools and strategies to aid the identification of high-risk patients, inform preventive measures, and introduction of better tolerated targeted therapies. Lifestyle modification and chemoprevention with drugs such as anti-platelets, statins and anti-diabetics are being evaluated for HCC prevention. The landmark IMBrave150 study introducing the combination of atezolizumab and bevacizumab has recently transformed the landscape of systemic therapies in HCC, with follow-up analyses and real-world data for patients with NAFLD-associated HCC eagerly anticipated. While responses may vary in ways not yet appreciated, the rate of discovery and progress suggests imminent change and opportunities.
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Affiliation(s)
- Daniel Geh
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Quentin M Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.,The Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.,The Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.,Hepatopancreatobiliary Multidisciplinary Team, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
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25
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Zhang X, Mens MMJ, Abozaid YJ, Bos D, Darwish Murad S, de Knegt RJ, Ikram MA, Pan Q, Ghanbari M. Circulatory microRNAs as potential biomarkers for fatty liver disease: the Rotterdam study. Aliment Pharmacol Ther 2021; 53:432-442. [PMID: 33244812 PMCID: PMC7839694 DOI: 10.1111/apt.16177] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/12/2020] [Accepted: 11/05/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Fatty liver disease (FLD) is the most common cause of liver dysfunction in developed countries. There is great interest in developing clinically valid and minimally invasive biomarkers to enhance early diagnosis of FLD. AIM To investigate the potential of circulatory microRNAs (miRNAs) as biomarkers of FLD at the population level. METHODS Plasma levels of 2083 miRNAs were measured by RNA sequencing in 1999 participants from the prospective population-based Rotterdam Study cohort. The Hounsfield Unit (HU) attenuation of liver was measured using non-enhanced computed tomography (CT) scan. Logistic and linear regression models adjusting for potential confounders were used to examine the association of circulatory miRNAs with liver enzymes (n = 1991) and CT-based FLD (n = 954). Moreover, the association of miRNAs with hepatic steatosis and liver fibrosis was assessed longitudinally in individuals who underwent abdominal ultrasound (n = 1211) and transient elastography (n = 777) after a median follow-up of >6 years. RESULTS Cross-sectional analysis showed 61 miRNAs significantly associated with serum gamma-glutamyl transferase and/or alkaline phosphatase levels (Bonferroni-corrected P < 8.46 × 10-5 ). Moreover, 17 miRNAs were significantly associated with CT-based FLD (P < 8.46 × 10-5 ); 14 were among miRNAs associated with liver enzymes. Longitudinal analysis showed that 4 of these 14 miRNAs (miR-193a-5p, miR-122-5p, miR-378d and miR-187-3p) were significantly associated with hepatic steatosis (P < 3.57 × 10-3 ) and three (miR-193a-5p, miR-122-5p and miR-193b-3p) were nominally associated with liver fibrosis (P < 0.05). Nine of the 14 identified miRNAs were involved in pathways underlying liver diseases. CONCLUSIONS Plasma levels of several miRNAs can be used as biomarkers of FLD, laying the groundwork for future clinical applications.
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Affiliation(s)
- Xiaofang Zhang
- Department of EpidemiologyErasmus University Medical CenterRotterdamthe Netherlands
| | - Michelle M. J. Mens
- Department of EpidemiologyErasmus University Medical CenterRotterdamthe Netherlands
| | - Yasir J. Abozaid
- Department of EpidemiologyErasmus University Medical CenterRotterdamthe Netherlands
| | - Daniel Bos
- Department of EpidemiologyErasmus University Medical CenterRotterdamthe Netherlands,Department of Radiology and Nuclear MedicineErasmus University Medical CenterRotterdamthe Netherlands
| | - Sarwa Darwish Murad
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamthe Netherlands
| | - Robert J. de Knegt
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamthe Netherlands
| | - M. Arfan Ikram
- Department of EpidemiologyErasmus University Medical CenterRotterdamthe Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamthe Netherlands
| | - Mohsen Ghanbari
- Department of EpidemiologyErasmus University Medical CenterRotterdamthe Netherlands
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26
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MicroRNAs: An Update of Applications in Forensic Science. Diagnostics (Basel) 2020; 11:diagnostics11010032. [PMID: 33375374 PMCID: PMC7823886 DOI: 10.3390/diagnostics11010032] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/17/2020] [Accepted: 12/23/2020] [Indexed: 12/25/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of non-coding RNAs containing 18–24 nucleotides that are involved in the regulation of many biochemical mechanisms in the human body. The level of miRNAs in body fluids and tissues increases because of altered pathophysiological mechanisms, thus they are employed as biomarkers for various diseases and conditions. In recent years, miRNAs obtained a great interest in many fields of forensic medicine given their stability and specificity. Several specific miRNAs have been studied in body fluid identification, in wound vitality in time of death determination, in drowning, in the anti-doping field, and other forensic fields. However, the major problems are (1) lack of universal protocols for diagnostic expression testing and (2) low reproducibility of independent studies. This review is an update on the application of these molecular markers in forensic biology.
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27
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Liu Q, Lei C. Neuroprotective effects of miR-331-3p through improved cell viability and inflammatory marker expression: Correlation of serum miR-331-3p levels with diagnosis and severity of Alzheimer's disease. Exp Gerontol 2020; 144:111187. [PMID: 33279668 DOI: 10.1016/j.exger.2020.111187] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 11/09/2020] [Accepted: 11/26/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Alzheimer's disease (AD) is a common neurodegenerative disease with an increasing incidence rate. Numerous microRNAs (miRNAs) have been found to be involved in AD progression. This study aimed to investigate the expression and diagnostic value of microRNA-331-3p (miR-331-3p) in AD patients and to explore the effects of miR-331-3p on neuronal viability and neuroinflammation. METHODS This study recruited AD patients and used Aβ1-40 treated SH-SY5Y cells mimicking AD characteristics. The expression of miR-331-3p was estimated using reverse transcription quantitative PCR. A receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic value of miR-331-3p, and the correlation of miR-331-3p with patients' Mini-Mental State Examination (MMSE) scores and serum proinflammatory cytokines were analyzed. The effects of miR-331-3p on neuronal viability and inflammatory response were explored in SH-SY5Y cells by in vitro analysis. RESULTS In AD patients and Aβ1-40 treated SH-SY5Y cells, the expression of miR-331-3p was significantly downregulated. Serum miR-331-3p had certain diagnostic potential and was correlated with the MMSE scores and serum proinflammatory cytokine levels of AD patients. In Aβ1-40-treated SH-SY5Y cells, the overexpression of miR-331-3p enhanced cell viability and inhibited inflammatory responses. CONCLUSION The data of this study indicated that serum expression of miR-331-3p is decreased in AD patients, and is correlated with the MMSE scores and proinflammatory cytokine levels of AD patients. In addition, miR-331-3p can regulate the cell viability and the expression of pro-inflammatory cytokines of Aβ1-40 treated SH-SY5Y cells, indicating the potential neuroprotective role of miR-331-3p.
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Affiliation(s)
- Qingling Liu
- Department of Clinical Laboratory, Zibo Maternal and Child Health Hospital, No. 11 Xing Yuan Dong Road, Zibo 255000, China
| | - Chengbin Lei
- Department of Clinical Laboratory, Zibo Central Hospital, Gongqingtuan West Road, Zibo 255036, China.
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28
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A Universal Gut-Microbiome-Derived Signature Predicts Cirrhosis. Cell Metab 2020; 32:878-888.e6. [PMID: 32610095 PMCID: PMC7822714 DOI: 10.1016/j.cmet.2020.06.005] [Citation(s) in RCA: 193] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/20/2020] [Accepted: 06/08/2020] [Indexed: 12/18/2022]
Abstract
Dysregulation of the gut microbiome has been implicated in the progression of non-alcoholic fatty liver disease (NAFLD) to advanced fibrosis and cirrhosis. To determine the diagnostic capacity of this association, we compared stool microbiomes across 163 well-characterized participants encompassing non-NAFLD controls, NAFLD-cirrhosis patients, and their first-degree relatives. Interrogation of shotgun metagenomic and untargeted metabolomic profiles by using the random forest machine learning algorithm and differential abundance analysis identified discrete metagenomic and metabolomic signatures that were similarly effective in detecting cirrhosis (diagnostic accuracy 0.91, area under curve [AUC]). Combining the metagenomic signature with age and serum albumin levels accurately distinguished cirrhosis in etiologically and genetically distinct cohorts from geographically separated regions. Additional inclusion of serum aspartate aminotransferase levels, which are increased in cirrhosis patients, enabled discrimination of cirrhosis from earlier stages of fibrosis. These findings demonstrate that a core set of gut microbiome species might offer universal utility as a non-invasive diagnostic test for cirrhosis.
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29
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Mandala A, Janssen RC, Palle S, Short KR, Friedman JE. Pediatric Non-Alcoholic Fatty Liver Disease: Nutritional Origins and Potential Molecular Mechanisms. Nutrients 2020; 12:E3166. [PMID: 33081177 PMCID: PMC7602751 DOI: 10.3390/nu12103166] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the number one chronic liver disease worldwide and is estimated to affect nearly 40% of obese youth and up to 10% of the general pediatric population without any obvious signs or symptoms. Although the early stages of NAFLD are reversible with diet and lifestyle modifications, detecting such stages is hindered by a lack of non-invasive methods of risk assessment and diagnosis. This absence of non-invasive means of diagnosis is directly related to the scarcity of long-term prospective studies of pediatric NAFLD in children and adolescents. In the majority of pediatric NAFLD cases, the mechanisms driving the origin and rapid progression of NAFLD remain unknown. The progression from NAFLD to non-alcoholic steatohepatitis (NASH) in youth is associated with unique histological features and possible immune processes and metabolic pathways that may reflect different mechanisms compared with adults. Recent data suggest that circulating microRNAs (miRNAs) are important new biomarkers underlying pathways of liver injury. Several factors may contribute to pediatric NAFLD development, including high-sugar diets, in utero exposures via epigenetic alterations, changes in the neonatal microbiome, and altered immune system development and mitochondrial function. This review focuses on the unique aspects of pediatric NAFLD and how nutritional exposures impact the immune system, mitochondria, and liver/gastrointestinal metabolic health. These factors highlight the need for answers to how NAFLD develops in children and for early stage-specific interventions.
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Affiliation(s)
- Ashok Mandala
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (K.R.S.)
| | - Rachel C. Janssen
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (K.R.S.)
| | - Sirish Palle
- Department of Pediatrics, Section of Gastroenterology, Hepatology & Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Kevin R. Short
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (K.R.S.)
- Department of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Jacob E. Friedman
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (A.M.); (R.C.J.); (K.R.S.)
- Department of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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30
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Soto-Angona Ó, Anmella G, Valdés-Florido MJ, De Uribe-Viloria N, Carvalho AF, Penninx BWJH, Berk M. Non-alcoholic fatty liver disease (NAFLD) as a neglected metabolic companion of psychiatric disorders: common pathways and future approaches. BMC Med 2020; 18:261. [PMID: 32998725 PMCID: PMC7528270 DOI: 10.1186/s12916-020-01713-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 07/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in over 5% of the parenchyma in the absence of excessive alcohol consumption. It is more prevalent in patients with diverse mental disorders, being part of the comorbidity driving loss of life expectancy and quality of life, yet remains a neglected entity. NAFLD can progress to non-alcoholic steatohepatitis (NASH) and increases the risk for cirrhosis and hepatic carcinoma. Both NAFLD and mental disorders share pathophysiological pathways, and also present a complex, bidirectional relationship with the metabolic syndrome (MetS) and related cardiometabolic diseases. MAIN TEXT This review compares the demographic data on NAFLD and NASH among the global population and the psychiatric population, finding differences that suggest a higher incidence of this disease among the latter. It also analyzes the link between NAFLD and psychiatric disorders, looking into common pathophysiological pathways, such as metabolic, genetic, and lifestyle factors. Finally, possible treatments, tailored approaches, and future research directions are suggested. CONCLUSION NAFLD is part of a complex system of mental and non-communicable somatic disorders with a common pathogenesis, based on shared lifestyle and environmental risks, mediated by dysregulation of inflammation, oxidative stress pathways, and mitochondrial function. The recognition of the prevalent comorbidity between NAFLD and mental disorders is required to inform clinical practice and develop novel interventions to prevent and treat these complex and interacting disorders.
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Affiliation(s)
- Óscar Soto-Angona
- Department of Psychiatry, Vall d'Hebron University Hospital, Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Catalonia, Spain.
- Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia.
| | - Gerard Anmella
- Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
- Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0, 08036, Barcelona, Catalonia, Spain
| | | | - Nieves De Uribe-Viloria
- Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
- Department of Psychiatry, Hospital Clínico Universitario de Valladolid, Castilla y León, Spain
| | - Andre F Carvalho
- Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
- Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
| | - Brenda W J H Penninx
- Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam University Medical Center/Vrije Universiteit & GGZinGeest, Amsterdam, the Netherlands
| | - Michael Berk
- Deakin University, IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
- Orygen, The National Centre of Excellence in Youth Mental Health, the Department of Psychiatry, and the Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia
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31
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Lonardo A, Mantovani A, Lugari S, Targher G. Epidemiology and pathophysiology of the association between NAFLD and metabolically healthy or metabolically unhealthy obesity. Ann Hepatol 2020; 19:359-366. [PMID: 32349939 DOI: 10.1016/j.aohep.2020.03.001] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 03/02/2020] [Accepted: 03/02/2020] [Indexed: 02/06/2023]
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is continuing to rise in many countries, paralleling the epidemic of obesity worldwide. In the last years, the concept of metabolically healthy obesity [MHO, generally defined as obesity without metabolic syndrome (MetS)] has raised considerable scientific interest. MHO is a complex phenotype with risks intermediate between metabolically healthy individuals with normal-weight (NWMH) and patients who are obese and metabolically unhealthy (MUO, i.e. obesity with MetS). In this review we aimed to examine the association and pathophysiological link of NAFLD with MHO and MUO. Compared to NWMH individuals, patients with obesity, regardless of the presence of MetS features, are at higher risk of all-cause mortality and cardiovascular events. Moreover, MHO patients have a greater risk of NAFLD development and progression compared to NWMH individuals. However, this risk is generally lower than that of MUO patients, suggesting a stronger adverse effect of coexisting MetS disorders than obesity per se on the severity of NAFLD. Nevertheless, since MHO is a dynamic state (with a significant proportion of MHO subjects progressing to MUO over time) and NAFLD itself may predict the transition from MHO to MUO, we believe that any effort should be made to identify NAFLD in all obese individuals, although they appear to be "metabolically healthy". Future research is needed to better understand the role of NAFLD and other pathogenic factors potentially involved in the transition from MHO to MUO and to elucidate how this transition may affect the presence and severity of NAFLD.
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Affiliation(s)
- Amedeo Lonardo
- Operating Unit of Metabolic Syndrome, Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, Modena, Italy.
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, University of Verona, Verona, Italy
| | | | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, University of Verona, Verona, Italy
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32
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Liu X, Chen S, Zhang L. Downregulated microRNA-130b-5p prevents lipid accumulation and insulin resistance in a murine model of nonalcoholic fatty liver disease. Am J Physiol Endocrinol Metab 2020; 319:E34-E42. [PMID: 32228319 DOI: 10.1152/ajpendo.00528.2019] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) amplifies the risk of various liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis, and ultimately hepatocellular carcinoma. Accumulating evidence suggests the involvement of aberrant microRNAs (miRNAs or miRs) in the activation of cellular stress, inflammation, and fibrogenesis in hepatic cells at different stages of NAFLD and liver fibrosis. Here, we explored the potential role of miR-130b-5p in the pathogenesis of NAFLD, including lipid accumulation and insulin resistance, as well as the underlying mechanism. Initially, the expression of miR-130b-5p and insulin-like growth factor binding protein 2 (IGFBP2) was examined in the established high-fat diet-induced NAFLD mouse models. Then, the interaction between miR-130b-5p and IGFBP2 was validated using dual luciferase reporter assay. The effects of miR-130b-5p and IGFBP2 on lipid accumulation and insulin resistance, as well as the AKT pathway-related proteins, were evaluated using gain or loss-of-function approaches. miR-130b-5p was upregulated, and IGFBP2 was downregulated in liver tissues of NAFLD mice. miR-130b-5p targeted IGFBP2 and downregulated its expression. MiR-130b-5p inhibition or IGFBP2 overexpression reduced the expression of SREBP-1, LXRα, ChREBP, stearoyl CoA desaturase 1, acetyl CoA carboxylase 1, and fatty acid synthase, and levels of fasting blood glucose, fasting insulin, and homeostasis model assessment-insulin resistance, while increasing the ratio of p-AKT/AKT in NAFLD mice. Overall, downregulation of miR-130b-5p can prevent hepatic lipid accumulation and insulin resistance in NAFLD by activating IGFBP2-dependent AKT pathway, highlighting the potential use of anti-miR-130b-5p as therapeutic approaches for the prevention and treatment of NAFLD.
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Affiliation(s)
- Xiaonan Liu
- Department of Endocrinology, Linyi People's Hospital, Linyi, Shandong, People's Republic of China
| | - Shuhong Chen
- Department of Endocrinology, Linyi People's Hospital, Linyi, Shandong, People's Republic of China
| | - Lanju Zhang
- Department of Endocrinology, Linyi People's Hospital, Linyi, Shandong, People's Republic of China
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Bisaccia G, Ricci F, Mantini C, Tana C, Romani GL, Schiavone C, Gallina S. Nonalcoholic fatty liver disease and cardiovascular disease phenotypes. SAGE Open Med 2020; 8:2050312120933804. [PMID: 32612827 PMCID: PMC7307287 DOI: 10.1177/2050312120933804] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 05/21/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease is increasingly recognized as a major global health problem. Intertwined with diabetes, metabolic syndrome, and obesity, nonalcoholic fatty liver disease embraces a spectrum of liver conditions spanning from steatosis to inflammation, fibrosis, and liver failure. Compared with the general population, the prevalence of cardiovascular disease is higher among nonalcoholic fatty liver disease patients, in whom comprehensive cardiovascular risk assessment is highly desirable. Preclinical effects of nonalcoholic fatty liver disease on the heart include both metabolic and structural changes eventually preceding overt myocardial dysfunction. Particularly, nonalcoholic fatty liver disease is associated with enhanced atherosclerosis, heart muscle disease, valvular heart disease, and arrhythmias, with endothelial dysfunction, inflammation, metabolic dysregulation, and oxidative stress playing in the background. In this topical review, we aimed to summarize current evidence on the epidemiology of nonalcoholic fatty liver disease, discuss the pathophysiological links between nonalcoholic fatty liver disease and cardiovascular disease, illustrate nonalcoholic fatty liver disease-related cardiovascular phenotypes, and finally provide a glimpse on the relationship between nonalcoholic fatty liver disease and cardiac steatosis, mitochondrial (dys)function, and cardiovascular autonomic dysfunction.
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Affiliation(s)
- Giandomenico Bisaccia
- Department of Neuroscience, Imaging and Clinical Sciences, Institute for Advanced Biomedical Technologies, "G. d'Annunzio" University of Chieti and Pescara, Chieti, Italy
| | - Fabrizio Ricci
- Department of Neuroscience, Imaging and Clinical Sciences, Institute for Advanced Biomedical Technologies, "G. d'Annunzio" University of Chieti and Pescara, Chieti, Italy.,Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Cesare Mantini
- Department of Neuroscience, Imaging and Clinical Sciences, Institute for Advanced Biomedical Technologies, "G. d'Annunzio" University of Chieti and Pescara, Chieti, Italy
| | - Claudio Tana
- Internal Medicine and Critical Subacute Care Unit, Medicine Geriatric-Rehabilitation Department, and Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy
| | - Gian Luca Romani
- Department of Neuroscience, Imaging and Clinical Sciences, Institute for Advanced Biomedical Technologies, "G. d'Annunzio" University of Chieti and Pescara, Chieti, Italy
| | - Cosima Schiavone
- Department of Internistic Ultrasound, "G. d'Annunzio" University of Chieti and Pescara, Chieti, Italy
| | - Sabina Gallina
- Department of Neuroscience, Imaging and Clinical Sciences, Institute for Advanced Biomedical Technologies, "G. d'Annunzio" University of Chieti and Pescara, Chieti, Italy
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Valenti L, Pelusi S. The Natural History of NAFLD: Environmental vs. Genetic Risk Factors. NON-ALCOHOLIC FATTY LIVER DISEASE 2020:129-145. [DOI: 10.1007/978-3-319-95828-6_7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Ajmera VH, Cachay E, Ramers C, Vodkin I, Bassirian S, Singh S, Mangla N, Bettencourt R, Aldous JL, Park D, Lee D, Blanchard J, Mamidipalli A, Boehringer A, Aslam S, Leinhard OD, Richards L, Sirlin C, Loomba R. MRI Assessment of Treatment Response in HIV-associated NAFLD: A Randomized Trial of a Stearoyl-Coenzyme-A-Desaturase-1 Inhibitor (ARRIVE Trial). Hepatology 2019; 70:1531-1545. [PMID: 31013363 PMCID: PMC7164416 DOI: 10.1002/hep.30674] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/01/2019] [Indexed: 12/12/2022]
Abstract
Aramchol, an oral stearoyl-coenzyme-A-desaturase-1 inhibitor, has been shown to reduce hepatic fat content in patients with primary nonalcoholic fatty liver disease (NAFLD); however, its effect in patients with human immunodeficiency virus (HIV)-associated NAFLD is unknown. The aramchol for HIV-associated NAFLD and lipodystrophy (ARRIVE) trial was a double-blind, randomized, investigator-initiated, placebo-controlled trial to test the efficacy of 12 weeks of treatment with aramchol versus placebo in HIV-associated NAFLD. Fifty patients with HIV-associated NAFLD, defined by magnetic resonance imaging (MRI)-proton density fat fraction (PDFF) ≥5%, were randomized to receive either aramchol 600 mg daily (n = 25) or placebo (n = 25) for 12 weeks. The primary endpoint was a change in hepatic fat as measured by MRI-PDFF in colocalized regions of interest. Secondary endpoints included changes in liver stiffness using magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE), and exploratory endpoints included changes in total-body fat and muscle depots on dual-energy X-ray absorptiometry (DXA), whole-body MRI, and cardiac MRI. The mean (± standard deviation) of age and body mass index were 48.2 ± 10.3 years and 30.7 ± 4.6 kg/m2 , respectively. There was no difference in the reduction in mean MRI-PDFF between the aramchol group at -1.3% (baseline MRI-PDFF 15.6% versus end-of-treatment MRI-PDFF 14.4%, P = 0.24) and the placebo group at -1.4% (baseline MRI-PDFF 13.3% versus end-of-treatment MRI-PDFF 11.9%, P = 0.26). There was no difference in the relative decline in mean MRI-PDFF between the aramchol and placebo groups (6.8% versus 1.1%, P = 0.68). There were no differences in MRE-derived and VCTE-derived liver stiffness and whole-body (fat and muscle) composition analysis by MRI or DXA. Compared to baseline, end-of-treatment aminotransferases were lower in the aramchol group but not in the placebo arm. There were no significant adverse events. Conclusion: Aramchol, over a 12-week period, did not reduce hepatic fat or change body fat and muscle composition by using MRI-based assessment in patients with HIV-associated NAFLD (clinicaltrials.gov ID:NCT02684591).
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Affiliation(s)
- Veeral H. Ajmera
- NAFLD Research Center, Department of Medicine, La Jolla, California,Division of Gastroenterology, Department of Medicine, La Jolla, California
| | - Edward Cachay
- Division of Infectious Diseases, Owen Clinic, University of California San Diego, San Diego, California
| | | | - Irine Vodkin
- Division of Gastroenterology, Department of Medicine, La Jolla, California
| | - Shirin Bassirian
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Seema Singh
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Neeraj Mangla
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | | | | | | | - Daniel Lee
- Division of Infectious Diseases, Owen Clinic, University of California San Diego, San Diego, California
| | - Jennifer Blanchard
- Division of Infectious Diseases, Owen Clinic, University of California San Diego, San Diego, California
| | - Adrija Mamidipalli
- Liver Imaging Group, University of California, San Diego, La Jolla, California
| | - Andrew Boehringer
- Liver Imaging Group, University of California, San Diego, La Jolla, California
| | - Saima Aslam
- Division of Infectious Diseases and Global Public Health, University of California, San Diego, San Diego California
| | - Olof Dahlqvist Leinhard
- AMRA Medical AB, Linkoping Sweden,Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Lisa Richards
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Claude Sirlin
- Liver Imaging Group, University of California, San Diego, La Jolla, California
| | - Rohit Loomba
- NAFLD Research Center, Department of Medicine, La Jolla, California,Division of Gastroenterology, Department of Medicine, La Jolla, California,Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California
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Caussy C, Ajmera VH, Puri P, Li-Shin Hsu C, Bassirian S, Mgdsyan M, Singh S, Faulkner C, Valasek MA, Rizo E, Richards L, Brenner DA, Sirlin CB, Sanyal AJ, Loomba R. Serum metabolites detect the presence of advanced fibrosis in derivation and validation cohorts of patients with non-alcoholic fatty liver disease. Gut 2019; 68:1884-1892. [PMID: 30567742 PMCID: PMC8328048 DOI: 10.1136/gutjnl-2018-317584] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/22/2018] [Accepted: 11/29/2018] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Non-invasive and accurate diagnostic tests for the screening of disease severity in non-alcoholic fatty liver disease (NAFLD) remain a major unmet need. Therefore, we aimed to examine if a combination of serum metabolites can accurately predict the presence of advanced fibrosis. DESIGN This is a cross-sectional analysis of a prospective derivation cohort including 156 well-characterised patients with biopsy-proven NAFLD and two validation cohorts, including (1) 142 patients assessed using MRI elastography (MRE) and(2) 59 patients with biopsy-proven NAFLD with untargeted serum metabolome profiling. RESULTS In the derivation cohort, 23 participants (15%) had advanced fibrosis and 32 of 652 analysed metabolites were significantly associated with advanced fibrosis after false-discovery rate adjustment. Among the top 10 metabolites, 8 lipids (5alpha-androstan-3beta monosulfate, pregnanediol-3-glucuronide, androsterone sulfate, epiandrosterone sulfate, palmitoleate, dehydroisoandrosterone sulfate, 5alpha-androstan-3beta disulfate, glycocholate), one amino acid (taurine) and one carbohydrate (fucose) were identified. The combined area under the receiver operating characteristic curve (AUROC) of the top 10 metabolite panel was higher than FIB--4 and NAFLD Fibrosis Score (NFS) for the detection of advanced fibrosis: 0.94 (95% CI 0.897 to 0.982) versus 0.78 (95% CI0.674 to 0.891), p=0.002 and versus 0.84 (95% CI 0.724 to 0.929), p=0.017, respectively. The AUROC of the top 10 metabolite panel remained excellent in the independent validation cohorts assessed by MRE or liver biopsy: c-statistic of 0.94 and 0.84, respectively. CONCLUSION A combination of 10 serum metabolites demonstrated excellent discriminatory ability for the detection of advanced fibrosis in an derivation and two independent validation cohorts with greater diagnostic accuracy than the FIB-4-index and NFS. This proof-of-concept study demonstrates that a non-invasive blood-based diagnostic test can provide excellent performance characteristics for the detection of advanced fibrosis.
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Affiliation(s)
- Cyrielle Caussy
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA,Université Lyon 1, Hospices Civils de Lyon, Lyon, California, France
| | - Veeral H Ajmera
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Puneet Puri
- Virginia Commonwealth University, Richmond, Virginia, USA
| | | | - Shirin Bassirian
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Mania Mgdsyan
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Seema Singh
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Claire Faulkner
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Mark A Valasek
- Department of Pathology, University of California at San Diego, La Jolla, California, USA
| | - Emily Rizo
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Lisa Richards
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - David A Brenner
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA,Division of Gastroenterology, Department of Medicine, La Jolla, California, USA
| | - Claude B Sirlin
- Liver Imaging Group, Department of Radiology, University of California, San Diego, La Jolla, California, USA
| | - Arun J Sanyal
- Virginia Commonwealth University, Richmond, Virginia, USA
| | - Rohit Loomba
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA,Division of Gastroenterology, Department of Medicine, La Jolla, California, USA,Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California, USA
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Cai C, Lin Y, Yu C. Circulating miRNAs as Novel Diagnostic Biomarkers in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Can J Gastroenterol Hepatol 2019; 2019:2096161. [PMID: 31531307 PMCID: PMC6720843 DOI: 10.1155/2019/2096161] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 07/14/2019] [Accepted: 07/21/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND AND AIMS Recent studies have indicated that circulating miRNAs could serve as accurate biomarkers for diagnosing nonalcoholic fatty liver disease (NAFLD). We aimed to assess the evidence on the probability of circulating miRNAs as new diagnostic biomarkers in patients with NAFLD. METHODS We comprehensively retrieved relevant English literature from the databases of PubMed, Embase, and the Cochrane Library from 2000 to 1 January 2019. The diagnostic accuracy of circulating miRNAs as markers for NAFLD was analyzed. Moreover, we evaluated the methodological quality of the included article. STATA was applied to perform statistical analyses. RESULTS In this meta-analysis, 17 studies that enrolled 1408 patients of NAFLD and 926 healthy people from 6 articles were analyzed. We constructed a summary receiver-operating characteristic (SROC) curve of all circulating miRNAs, and the area under the curve (AUC) was 0.83, with the pooled sensitivity (SEN) 0.70 and the pooled specificity (SPE) 0.82 in distinguishing patients with NAFLD from healthy controls. Among them, miR-122 showed high diagnostic accuracy, with the diagnostic index of pooled SEN, SPE, and AUC being 0.88, 0.66, and 0.86, respectively. We then performed subgroup analyses based on the mode of miRNA regulation, countries, miRNA profiling, sample size, and male proportion. We then did a regression analysis and found the cause of heterogeneity might be miRNA profiling. Finally, publication bias was not found, and Fagan's nomogram showed valuable clinical utility. CONCLUSION Circulating miRNAs, especially miR-122, might be promising diagnostic biomarkers for NAFLD with high-accuracy, and more large-sample studies are required to support the above findings in the future.
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Affiliation(s)
- Changzhou Cai
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yiming Lin
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, China
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Caussy C, Bhargava M, Villesen IF, Gudmann NS, Leeming DJ, Karsdal MA, Faulkner C, Bao D, Liu A, Lo MT, Bettencourt R, Bassirian S, Richards L, Brenner DA, Chen CH, Sirlin CB, Loomba R. Collagen Formation Assessed by N-Terminal Propeptide of Type 3 Procollagen Is a Heritable Trait and Is Associated With Liver Fibrosis Assessed by Magnetic Resonance Elastography. Hepatology 2019; 70:127-141. [PMID: 30859582 PMCID: PMC6984974 DOI: 10.1002/hep.30610] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 03/03/2019] [Indexed: 12/18/2022]
Abstract
N-terminal propeptide of type 3 procollagen (PRO-C3) is a biomarker of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). This study examines the association between PRO-C3 concentration and liver fibrosis assessed by magnetic resonance elastography (MRE)-measured stiffness (MRE-stiffness) and the heritability of PRO-C3 concentration in a cohort of twins and families with and without NAFLD. We performed a cross-sectional analysis of a well-characterized prospective cohort of 306 participants, including 44 probands with NAFLD-cirrhosis and their 72 first-degree relatives, 24 probands with NAFLD without advanced fibrosis and their 24 first-degree relatives, and 72 controls without NAFLD and their 72 first-degree relatives. Liver steatosis was assessed by magnetic resonance imaging proton density fat fraction, and liver fibrosis was assessed by MRE-stiffness. Serum PRO-C3 was assessed by competitive, enzyme-linked immunosorbent assay. We assessed the familial correlation of PRO-C3 concentration, the shared gene effects between PRO-C3 concentration and liver steatosis and fibrosis, and the association between PRO-C3 concentration and genetic variants in the patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing (MBOAT), and glucokinase regulator (CGKR) genes. In multivariable-adjusted models including age, sex, body mass index, and ethnicity, serum PRO-C3 correlated strongly with liver fibrosis (r2 = 0.50, P < 0.001) and demonstrated robust heritability (h2 , 0.36; 95% confidence interval [CI], 0.07, 0.59; P = 0.016). PRO-C3 concentration and steatosis had a strong genetic correlation (shared genetic determination: 0.62; 95% CI, 0.236, 1.001; P = 0.002), whereas PRO-C3 concentration and fibrosis had a strong environmental correlation (shared environmental determination: 0.55; 95% CI, 0.317, 0.717; P < 0.001). PRO-C3 concentrations were higher in carriers of the TM6SF2 rs58542926-T allele compared with noncarriers: 15.7 (± 10.5) versus 10.8 (± 5.7) ng/L (P = 0.047). Conclusion: Serum PRO-C3 correlates with MRE-assessed fibrosis, is heritable, shares genetic correlation with liver steatosis and shares environmental correlation with liver fibrosis. PRO-C3 concentration appears to be linked to both fibrosis and steatosis and increased in carriers of the TM6SF2 rs58542926 risk allele.
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Affiliation(s)
- Cyrielle Caussy
- NAFLD Research Center, Department of Medicine, La Jolla, California,Université Lyon 1, Hospices Civils de Lyon, Lyon, France
| | - Meera Bhargava
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | | | | | | | | | - Claire Faulkner
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Denny Bao
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Amy Liu
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Min-Tzu Lo
- Department of Radiology, University of California at San Diego, La Jolla, California
| | - Ricki Bettencourt
- NAFLD Research Center, Department of Medicine, La Jolla, California,Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California
| | - Shirin Bassirian
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Lisa Richards
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - David A. Brenner
- NAFLD Research Center, Department of Medicine, La Jolla, California,Division of Gastroenterology, Department of Medicine, La Jolla, California
| | - Chi-Hua Chen
- Department of Radiology, University of California at San Diego, La Jolla, California
| | - Claude B. Sirlin
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, California
| | - Rohit Loomba
- NAFLD Research Center, Department of Medicine, La Jolla, California,Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California,Division of Gastroenterology, Department of Medicine, La Jolla, California
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Xiao C, Pan C, Liu E, He H, Liu C, Huang Y, Yi S, Huang D. Differences of microRNA expression profiles between monozygotic twins' blood samples. Forensic Sci Int Genet 2019; 41:152-158. [PMID: 31132533 DOI: 10.1016/j.fsigen.2019.05.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 05/14/2019] [Accepted: 05/16/2019] [Indexed: 12/14/2022]
Abstract
Monozygotic (MZ) twins are widely regarded as genetically identical, and traditional DNA typing methods are insufficient in identifying MZ twins. So the discrimination of MZ twins become a forensic problem. MicroRNAs (miRNAs) are a class of small, endogenous, non-protein-coding RNA molecules of approximately 22 nucleotides in length, and exist extensively in a variety of eukaryotic cells. MiRNAs regulate gene expression and play fundamental roles in multiple biological processes, including cell differentiation, proliferation and apoptosis as well as aging and disease processes. The goal of this study is to explore the differential expression of miRNAs within MZ twin pairs, and aimed to find new biomarkers for distinguishing MZ twins. Thus, the miRNA expression profiles of seven pairs of healthy MZ twins of different sex and age were analyzed by miRNA microarray. A total of 545 miRNAs were found to be differentially expressed in these MZ twin pairs, and 2, 5, 22, 53 and 132 differentially expressed miRNAs were shared across six, five, four, three and two pairs of MZ twins respectively. These findings had been confirmed by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assays on select miRNAs, including miR-151a-3p, miR-3653-3p, miR-142-3p, miR-4325, miR-16-5p, let-7i-5p, miR-222-3p, miR-550b-3p, miR-4791 and miR-27a-3p. The results demonstrated that there are differences in the expression of miRNAs within MZ twin pairs, suggesting a role of miRNAs in identifying MZ twins.
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Affiliation(s)
- Chao Xiao
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Chao Pan
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Erliang Liu
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; Tianjin Municipal Public Security Bureau Wuqing Branch, Tianjin, PR China
| | - Huayu He
- Xiaogan Municipal Public Security Bureau, Xiaogan, PR China
| | - Chunfeng Liu
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Yujie Huang
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Shaohua Yi
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Daixin Huang
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
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Kim NH, Ahn J, Choi YM, Son HJ, Choi WH, Cho HJ, Yu JH, Seo JA, Jang YJ, Jung CH, Ha TY. Differential circulating and visceral fat microRNA expression of non-obese and obese subjects. Clin Nutr 2019; 39:910-916. [PMID: 31003790 DOI: 10.1016/j.clnu.2019.03.033] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 02/25/2019] [Accepted: 03/26/2019] [Indexed: 10/27/2022]
Abstract
BACKGROUND & AIMS Altered microRNA (miRNA) expression is associated with the pathophysiology of obesity; however, little is known about the miRNAs commonly dysregulated in the blood and visceral fat tissue of obese patients. This study compared the circulating and visceral fat miRNA expression in subjects with and without obesity. METHODS For the circulating miRNA study, 20 healthy control and 30 obese subjects were recruited. For the tissue miRNA expression study, omental fat tissue was collected in ten female subjects each in the control and obese groups. MiRNA expression was measured by TaqMan low-density arrays. Metabolic risk factors were measured. Target genes for selected miRNAs were analyzed using informatics tools and a functional network map was constructed. RESULTS 11 miRNAs were down-regulated (miR-133a, -139-5p, -15b, -26a, -301, -30b, -30c, -374, -451, -570, and -636), and one was up-regulated (miR-155) in both depots in obese subjects. These miRNAs had significant associations with BMI, waist circumference, and fat mass. Among them, miR-15b, miR-26a, miR-301, miR-30b, and miR-30c had more predicted obesity-related target genes than other miRNAs. In particular, miR-15b had numerous target genes associated with adipogenesis, mammalian target of rapamycin (mTOR) signaling, diabetes and insulin resistance, and mitochondrial function. CONCLUSIONS It is suggested that the miRNA alteration in the serum and visceral fat has pathophysiological implications for obesity. Our study identified dysregulated miRNAs that may be novel therapeutic targets to combat obesity.
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Affiliation(s)
- Nan Hee Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Jiyun Ahn
- Nutrition and Metabolism Research Division, Korea Food Research Institute, Wanju-gun, Republic of Korea; Department of Food Biotechnology, University of Science and Technology, Daejeon, Republic of Korea
| | - Yong Min Choi
- Nutrition and Metabolism Research Division, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Hyo Jung Son
- Nutrition and Metabolism Research Division, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Won Hee Choi
- Nutrition and Metabolism Research Division, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Hyun Joo Cho
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Ji Hee Yu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Ji A Seo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Young Jin Jang
- Nutrition and Metabolism Research Division, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Chang Hwa Jung
- Nutrition and Metabolism Research Division, Korea Food Research Institute, Wanju-gun, Republic of Korea; Department of Food Biotechnology, University of Science and Technology, Daejeon, Republic of Korea
| | - Tae Youl Ha
- Nutrition and Metabolism Research Division, Korea Food Research Institute, Wanju-gun, Republic of Korea; Department of Food Biotechnology, University of Science and Technology, Daejeon, Republic of Korea.
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A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun 2019; 10:1406. [PMID: 30926798 PMCID: PMC6440960 DOI: 10.1038/s41467-019-09455-9] [Citation(s) in RCA: 235] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 02/22/2019] [Indexed: 02/06/2023] Open
Abstract
The presence of cirrhosis in nonalcoholic-fatty-liver-disease (NAFLD) is the most important predictor of liver-related mortality. Limited data exist concerning the diagnostic accuracy of gut-microbiome-derived signatures for detecting NAFLD-cirrhosis. Here we report 16S gut-microbiome compositions of 203 uniquely well-characterized participants from a prospective twin and family cohort, including 98 probands encompassing the entire spectrum of NAFLD and 105 of their first-degree relatives, assessed by advanced magnetic-resonance-imaging. We show strong familial correlation of gut-microbiome profiles, driven by shared housing. We report a panel of 30 features, including 27 bacterial features with discriminatory ability to detect NAFLD-cirrhosis using a Random Forest classifier model. In a derivation cohort of probands, the model has a robust diagnostic accuracy (AUROC of 0.92) for detecting NAFLD-cirrhosis, confirmed in a validation cohort of relatives of proband with NAFLD-cirrhosis (AUROC of 0.87). This study provides evidence for a fecal-microbiome-derived signature to detect NAFLD-cirrhosis. Development of cirrhosis in individuals with non-alcoholic fatty liver disease can predict mortality. Here the authors used a unique twin and family cohort to identify a gut microbiome-derived 16sRNA signature that can detect cirrhosis in individuals with non-alcoholic fatty liver disease.
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Heo MJ, Yun J, Kim SG. Role of non-coding RNAs in liver disease progression to hepatocellular carcinoma. Arch Pharm Res 2019; 42:48-62. [PMID: 30610616 DOI: 10.1007/s12272-018-01104-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 12/23/2018] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is a tumor with poor prognosis and frequently aggressive. The development of HCC is associated with fibrosis and cirrhosis, which mainly results from nonalcoholic fatty liver disease, excessive alcohol consumption, and viral infections. Non-coding RNAs (ncRNAs) are RNAs transcribed from the genome, but are not translated into proteins. Recently, ncRNAs emerged as key contributors to tumor development and progression because of their abilities to regulate various targets and modulate cell proliferation, differentiation, apoptosis, and development. In this review, we summarize the frequently activated pathways in HCC and discuss the pathological implications of ncRNAs in the context of human liver disease progression, in particular HCC development and progression. This review aims to summarize the role of ncRNA dysregulation in the diseases and discuss the diagnostic and therapeutic potentials of ncRNAs.
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Affiliation(s)
- Mi Jeong Heo
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanakro, Seoul, 08826, South Korea
| | - Jessica Yun
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanakro, Seoul, 08826, South Korea
| | - Sang Geon Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanakro, Seoul, 08826, South Korea.
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43
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Caussy C, Hsu C, Singh S, Bassirian S, Kolar J, Faulkner C, Sinha N, Bettencourt R, Gara N, Valasek MA, Schnabl B, Richards L, Brenner DA, Hofmann AF, Loomba R. Serum bile acid patterns are associated with the presence of NAFLD in twins, and dose-dependent changes with increase in fibrosis stage in patients with biopsy-proven NAFLD. Aliment Pharmacol Ther 2019; 49:183-193. [PMID: 30506692 PMCID: PMC6319963 DOI: 10.1111/apt.15035] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 08/16/2018] [Accepted: 10/05/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND The fasting-state serum bile acid profile in nonalcoholic fatty liver disease (NAFLD) has been reported to differ when nonalcoholic steatohepatitis is compared to nonalcoholic fatty liver. However, there are few data comparing changes in NAFLD vs non-NAFLD, or whether the bile acid profile differs according to the degree of fibrosis. AIM To examine the serum bile acid profile across the entire spectrum of NAFLD. METHODS We performed a cross-sectional analysis of two complementary cohorts: a Twin and Family cohort of 156 participants, and a biopsy-proven-NAFLD cohort of 156 participants with fasting bile acid profiling using liquid chromatography/mass spectrometry. RESULTS In the Twin and Family cohort (mean age 46.3 years and body mass index (BMI) 26.6 kg/m2 ), 36 (23%) participants had NAFLD (magnetic resonance imaging proton density fat fraction ≥ 5%). Higher chenodeoxycholyl conjugates (9.0% vs 6.5%, P = 0.019) and lower glycohyocholate (1.2% vs 3.6%, P < 0.001) were observed in NAFLD compared to non-NAFLD-controls. In the biopsy-proven-NAFLD cohort (mean age 49.8 years, BMI 32.0 kg/m2 ), no differences in total bile acid were seen between nonalcoholic fatty liver vs nonalcoholic steatohepatitis. The total unconjugated bile acid significantly decreased across nonalcoholic steatohepatitis categories (P = 0.044). The distribution of stage of fibrosis was F0: 42.3%, F1: 32.7%, F2: 10.3%, F3: 8.3% and F4: 6.4%. The total serum bile acid increased with increase in fibrosis stage (P < 0.001). The primary conjugated bile acid proportion increased (P < 0.001) whereas unconjugated bile acid (P = 0.006), unconjugated cholyl (P < 0.001) and chenodeoxycholyl conjugates (P < 0.002) significantly decreased with increase in liver fibrosis stage. CONCLUSIONS Fasting-state serum bile acid profile alterations are seen across the entire spectrum of NAFLD. The total serum bile acids did not differ significantly between NAFLD vs non-NAFLD and nonalcoholic fatty liver vs nonalcoholic steatohepatitis, but were significantly perturbed progressively as liver fibrosis increases.
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Affiliation(s)
- Cyrielle Caussy
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, California,Université Lyon 1, Hospices Civils de Lyon, Lyon, France
| | - Cynthia Hsu
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, California
| | - Seema Singh
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, California
| | - Shirin Bassirian
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, California
| | - James Kolar
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, California
| | - Claire Faulkner
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, California
| | - Nikhil Sinha
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, California
| | - Ricki Bettencourt
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, California,Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, La Jolla, California
| | - Naveen Gara
- Department of Pathology, University of California at San Diego, La Jolla, California
| | - Mark A. Valasek
- Division of Gastroenterology, Department of Medicine, La Jolla, California
| | - Bernd Schnabl
- Division of Gastroenterology, Department of Medicine, La Jolla, California
| | - Lisa Richards
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, California
| | - David A. Brenner
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, California,Division of Gastroenterology, Department of Medicine, La Jolla, California
| | - Alan F. Hofmann
- Division of Gastroenterology, Department of Medicine, La Jolla, California
| | - Rohit Loomba
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, California,Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, La Jolla, California,Division of Gastroenterology, Department of Medicine, La Jolla, California
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44
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Dongiovanni P, Meroni M, Longo M, Fargion S, Fracanzani AL. miRNA Signature in NAFLD: A Turning Point for a Non-Invasive Diagnosis. Int J Mol Sci 2018; 19:E3966. [PMID: 30544653 PMCID: PMC6320931 DOI: 10.3390/ijms19123966] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 12/03/2018] [Accepted: 12/06/2018] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) defines a wide pathological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may predispose to liver cirrhosis and hepatocellular carcinoma. It represents the leading cause of hepatic damage worldwide. Diagnosis of NASH still requires liver biopsy but due to the high prevalence of NAFLD, this procedure, which is invasive, is not practicable for mass screening. Thus, it is crucial to non-invasively identify NAFLD patients at higher risk of progression to NASH and fibrosis. It has been demonstrated that hepatic fat content and progressive liver damage have a strong heritable component. Therefore, genetic variants associated with NAFLD have been proposed as non-invasive markers to be used in clinical practice. However, genetic variability is not completely explained by these common variants and it is possible that many of the phenotypic differences result from gene-environment interactions. Indeed, NAFLD development and progression is also modulated by epigenetic factors, in particular microRNAs (miRNAs), which control at post-transcriptional level many complementary target mRNAs and whose dysregulation has been shown to have high prognostic and predictive value in NAFLD. The premise of the current review is to discuss the role of miRNAs as pathogenic factors, risk predictors and therapeutic targets in NAFLD.
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Affiliation(s)
- Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
| | - Silvia Fargion
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano 20122, Italy.
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano 20122, Italy.
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Liu CH, Ampuero J, Gil-Gómez A, Montero-Vallejo R, Rojas Á, Muñoz-Hernández R, Gallego-Durán R, Romero-Gómez M. miRNAs in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Hepatol 2018; 69:1335-1348. [PMID: 30142428 DOI: 10.1016/j.jhep.2018.08.008] [Citation(s) in RCA: 121] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 07/21/2018] [Accepted: 08/07/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS microRNAs (miRNAs) are deregulated in non-alcoholic fatty liver disease (NAFLD) and have been proposed as useful markers for the diagnosis and stratification of disease severity. We conducted a meta-analysis to identify the potential usefulness of miRNA biomarkers in the diagnosis and stratification of NAFLD severity. METHODS After a systematic review, circulating miRNA expression consistency and mean fold-changes were analysed using a vote-counting strategy. The sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio and area under the curve (AUC) for the diagnosis of NAFLD or non-alcoholic steatohepatitis (NASH) were pooled using a bivariate meta-analysis. Deeks' funnel plot was used to assess the publication bias. RESULTS Thirty-seven studies of miRNA expression profiles and six studies of diagnostic accuracy were ultimately included in the quantitative analysis. miRNA-122 and miRNA-192 showed consistent upregulation. miRNA-122 was upregulated in every scenario used to distinguish NAFLD severity. The miRNA expression correlation between the serum and liver tissue was inconsistent across studies. miRNA-122 distinguished NAFLD from healthy controls with an AUC of 0.82 (95% CI 0.75-0.89), and miRNA-34a distinguished non-alcoholic steatohepatitis (NASH) from non-alcoholic fatty liver (NAFL) with an AUC of 0.78 (95% CI 0.67-0.88). CONCLUSION miRNA-34a, miRNA-122 and miRNA-192 were identified as potential diagnostic markers to segregate NAFL from NASH. Both miRNA-122, in distinguishing NAFLD from healthy controls, and miRNA-34a, in distinguishing NASH from NAFL, showed moderate diagnostic accuracy. miRNA-122 was upregulated in every scenario of NAFL, NASH and fibrosis. LAY SUMMARY: microRNAs are deregulated in non-alcoholic fatty liver disease. The microRNAs, miRNA-34a, miRNA-122 and miRNA-192, were identified as potential biomarkers of non-alcoholic fatty liver and non-alcoholic steatohepatitis, at different stages of disease severity. The correlation between miRNA expression in the serum and in liver tissue was inconsistent, or even inverse.
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Affiliation(s)
- Chang-Hai Liu
- Institute of Biomedicine of Seville, Sevilla, Spain; University of Seville, Seville, Spain
| | - Javier Ampuero
- Institute of Biomedicine of Seville, Sevilla, Spain; Unit of Digestive Diseases and Ciberehd, University Hospital Virgen del Rocío, Seville, Spain; University of Seville, Seville, Spain
| | - Antonio Gil-Gómez
- Institute of Biomedicine of Seville, Sevilla, Spain; University of Seville, Seville, Spain
| | - Rocío Montero-Vallejo
- Institute of Biomedicine of Seville, Sevilla, Spain; University of Seville, Seville, Spain
| | - Ángela Rojas
- Institute of Biomedicine of Seville, Sevilla, Spain
| | | | | | - Manuel Romero-Gómez
- Institute of Biomedicine of Seville, Sevilla, Spain; Unit of Digestive Diseases and Ciberehd, University Hospital Virgen del Rocío, Seville, Spain; University of Seville, Seville, Spain.
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46
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Fang C, Zhao J, Liu X, Zhang J, Cao Y, Yang Y, Yu C, Zhang X, Qian J, Liu W, Wu H, Yan J. MicroRNA profile analysis for discrimination of monozygotic twins using massively parallel sequencing and real-time PCR. Forensic Sci Int Genet 2018; 38:23-31. [PMID: 30321748 DOI: 10.1016/j.fsigen.2018.09.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 07/22/2018] [Accepted: 09/28/2018] [Indexed: 12/12/2022]
Abstract
In general, it is extremely problematic to discriminate between monozygotic twins (MZTs), who share the same genomic DNA sequence, using traditional DNA-based identification methods such as short tandem repeat profiling. MicroRNAs (miRNAs) have shown potential in forensic applications owing to their low molecular weight, abundant and tissue-specific expression. In this study, we utilized massively parallel sequencing technology to perform genome-wide profiling of miRNAs in the blood from four pairs of healthy MZTs. On average, 158 miRNAs were detected in each individual and 14% of which were differentially expressed within each pair of MZTs. The miRNAs with the most significant differences in expression between the twins were confirmed using real-time polymerase chain reaction. Our results demonstrated that miRNAs have potential for use as molecular markers in MZTs discrimination.
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Affiliation(s)
- Chen Fang
- Beijing Center for Physical and Chemical Analysis, Beijing 100094, PR China; Beijing Engineering Technology Research Centre of Gene Sequencing and Gene Function Analysis, Beijing 100094, PR China
| | - Jing Zhao
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100010, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Xu Liu
- Beijing Center for Physical and Chemical Analysis, Beijing 100094, PR China; Beijing Engineering Technology Research Centre of Gene Sequencing and Gene Function Analysis, Beijing 100094, PR China
| | - Jingjing Zhang
- Beijing Huayan Judicial Authentication Institute, Beijing 100192, PR China
| | - Yunwang Cao
- School of Forensic Medicine, Shanxi Medical University, Taiyuan 030001, PR China
| | - Yaran Yang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100010, PR China
| | - Chunrui Yu
- Beijing Center for Physical and Chemical Analysis, Beijing 100094, PR China; Beijing Engineering Technology Research Centre of Gene Sequencing and Gene Function Analysis, Beijing 100094, PR China
| | - Xiaoli Zhang
- Beijing Center for Physical and Chemical Analysis, Beijing 100094, PR China; Beijing Engineering Technology Research Centre of Gene Sequencing and Gene Function Analysis, Beijing 100094, PR China
| | - Jialin Qian
- Beijing Center for Physical and Chemical Analysis, Beijing 100094, PR China; Beijing Engineering Technology Research Centre of Gene Sequencing and Gene Function Analysis, Beijing 100094, PR China
| | - Wenli Liu
- Beijing Center for Physical and Chemical Analysis, Beijing 100094, PR China; Beijing Engineering Technology Research Centre of Gene Sequencing and Gene Function Analysis, Beijing 100094, PR China
| | - Huijuan Wu
- Beijing Center for Physical and Chemical Analysis, Beijing 100094, PR China; Beijing Engineering Technology Research Centre of Gene Sequencing and Gene Function Analysis, Beijing 100094, PR China; Beijing Gene Medical Laboratory Co., Ltd., Beijing 100094, PR China.
| | - Jiangwei Yan
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100010, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China; School of Forensic Medicine, Shanxi Medical University, Taiyuan 030001, PR China.
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47
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Torres JL, Novo-Veleiro I, Manzanedo L, Alvela-Suárez L, Macías R, Laso FJ, Marcos M. Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease. World J Gastroenterol 2018; 24:4104-4118. [PMID: 30271077 PMCID: PMC6158486 DOI: 10.3748/wjg.v24.i36.4104] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 06/25/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate multiple physiological and pathological functions through the modulation of gene expression at the post-transcriptional level. Accumulating evidence has established a role for miRNAs in the development and pathogenesis of liver disease. Specifically, a large number of studies have assessed the role of miRNAs in alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), two diseases that share common underlying mechanisms and pathological characteristics. The purpose of the current review is to summarize and update the body of literature investigating the role of miRNAs in liver disease. In addition, the potential use of miRNAs as biomarkers and/or therapeutic targets is discussed. Among all miRNAs analyzed, miR-34a, miR-122 and miR-155 are most involved in the pathogenesis of NAFLD. Of note, these three miRNAs have also been implicated in ALD, reinforcing a common disease mechanism between these two entities and the pleiotropic effects of specific miRNAs. Currently, no single miRNA or panel of miRNAs has been identified for the detection of, or staging of ALD or NAFLD. While promising results have been shown in murine models, no therapeutic based-miRNA agents have been developed for use in humans with liver disease.
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Affiliation(s)
- Jorge-Luis Torres
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
- Spanish Working Group on Alcohol and Alcoholism, Spanish Society of Internal Medicine, Madrid 28016, Spain
| | - Ignacio Novo-Veleiro
- Department of Internal Medicine, University Hospital of Santiago de Compostela, A Coruña 15706, Spain
- Spanish Working Group on Alcohol and Alcoholism, Spanish Society of Internal Medicine, Madrid 28016, Spain
| | - Laura Manzanedo
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
| | - Lucía Alvela-Suárez
- Department of Internal Medicine, HM Rosaleda Hospital, Santiago de Compostela, A Coruña 15701, Spain
| | - Ronald Macías
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
| | - Francisco-Javier Laso
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
- Department of Medicine, Faculty of Medicine, University of Salamanca, Salamanca 37007, Spain
- Spanish Working Group on Alcohol and Alcoholism, Spanish Society of Internal Medicine, Madrid 28016, Spain
| | - Miguel Marcos
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
- Department of Medicine, Faculty of Medicine, University of Salamanca, Salamanca 37007, Spain
- Spanish Working Group on Alcohol and Alcoholism, Spanish Society of Internal Medicine, Madrid 28016, Spain
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48
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Caussy C, Hsu C, Lo MT, Liu A, Bettencourt R, Ajmera VH, Bassirian S, Hooker J, Sy E, Richards L, Schork N, Schnabl B, Brenner DA, Sirlin CB, Chen CH, Loomba R, for the Genetics of NAFLD in Twins Consortium. Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. Hepatology 2018; 68:918-932. [PMID: 29572891 PMCID: PMC6151296 DOI: 10.1002/hep.29892] [Citation(s) in RCA: 151] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 02/21/2018] [Accepted: 03/20/2018] [Indexed: 12/21/2022]
Abstract
Previous studies have shown that gut-microbiome is associated with nonalcoholic fatty liver disease (NAFLD). We aimed to examine if serum metabolites, especially those derived from the gut-microbiome, have a shared gene-effect with hepatic steatosis and fibrosis. This is a cross-sectional analysis of a prospective discovery cohort including 156 well-characterized twins and families with untargeted metabolome profiling assessment. Hepatic steatosis was assessed using magnetic-resonance-imaging proton-density-fat-fraction (MRI-PDFF) and fibrosis using MR-elastography (MRE). A twin additive genetics and unique environment effects (AE) model was used to estimate the shared gene-effect between metabolites and hepatic steatosis and fibrosis. The findings were validated in an independent prospective validation cohort of 156 participants with biopsy-proven NAFLD including shotgun metagenomics sequencing assessment in a subgroup of the cohort. In the discovery cohort, 56 metabolites including 6 microbial metabolites had a significant shared gene-effect with both hepatic steatosis and fibrosis after adjustment for age, sex and ethnicity. In the validation cohort, 6 metabolites were associated with advanced fibrosis. Among them, only one microbial metabolite, 3-(4-hydroxyphenyl)lactate, remained consistent and statistically significantly associated with liver fibrosis in the discovery and validation cohort (fold-change of higher-MRE versus lower-MRE: 1.78, P < 0.001 and of advanced versus no advanced fibrosis: 1.26, P = 0.037, respectively). The share genetic determination of 3-(4-hydroxyphenyl)lactate with hepatic steatosis was RG :0.57,95%CI:0.27-0.80, P < 0.001 and with fibrosis was RG :0.54,95%CI:0.036-1, P = 0.036. Pathway reconstruction linked 3-(4-hydroxyphenyl)lactate to several human gut-microbiome species. In the validation cohort, 3-(4-hydroxyphenyl)lactate was significantly correlated with the abundance of several gut-microbiome species, belonging only to Firmicutes, Bacteroidetes and Proteobacteria phyla, previously reported as associated with advanced fibrosis. Conclusion: This proof of concept study provides evidence of a link between the gut-microbiome and 3-(4-hydroxyphenyl)lactate that shares gene-effect with hepatic steatosis and fibrosis. (Hepatology 2018).
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Affiliation(s)
- Cyrielle Caussy
- NAFLD Research Center, Department of Medicine, La Jolla, California
- Université Lyon 1, Hospices Civils de Lyon, Lyon, France
| | - Cynthia Hsu
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Min-Tzu Lo
- Department of Radiology, University of California at San Diego, La Jolla, California
| | - Amy Liu
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | | | - Veeral H. Ajmera
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Shirin Bassirian
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Jonathan Hooker
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, California
| | - Ethan Sy
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, California
| | - Lisa Richards
- NAFLD Research Center, Department of Medicine, La Jolla, California
| | - Nicholas Schork
- Human Biology, J. Craig Venter Institute, La Jolla, California
| | - Bernd Schnabl
- NAFLD Research Center, Department of Medicine, La Jolla, California
- Division of Gastroenterology, Department of Medicine, La Jolla, California
| | - David A. Brenner
- NAFLD Research Center, Department of Medicine, La Jolla, California
- Division of Gastroenterology, Department of Medicine, La Jolla, California
| | - Claude B. Sirlin
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, California
| | - Chi-Hua Chen
- Department of Radiology, University of California at San Diego, La Jolla, California
| | - Rohit Loomba
- NAFLD Research Center, Department of Medicine, La Jolla, California
- Division of Gastroenterology, Department of Medicine, La Jolla, California
- Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California
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López-Riera M, Conde I, Quintas G, Pedrola L, Zaragoza Á, Perez-Rojas J, Salcedo M, Benlloch S, Castell JV, Jover R. Non-invasive prediction of NAFLD severity: a comprehensive, independent validation of previously postulated serum microRNA biomarkers. Sci Rep 2018; 8:10606. [PMID: 30006517 PMCID: PMC6045608 DOI: 10.1038/s41598-018-28854-4] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 06/29/2018] [Indexed: 12/22/2022] Open
Abstract
Liver biopsy is currently the only reliable method to establish nonalcoholic fatty liver disease (NAFLD) severity. However, this technique is invasive and occasionally associated with severe complications. Thus, non-invasive diagnostic markers for NAFLD are needed. Former studies have postulated 18 different serum microRNA biomarkers with altered levels in NAFLD patients. In the present study, we have re-examined the predictive value of these serum microRNAs and found that 9 of them (miR-34a, -192, -27b, -122, -22, -21, -197, -30c and -16) associated to NAFLD severity in our independent cohort. Moreover, miR-192, -27b, -22, -197 and -30c appeared specific for NAFLD, when compared with patients with drug-induced liver injury. Preliminary serum RNAseq analysis allowed identifying novel potential miRNA biomarkers for nonalcoholic steatohepatitis (NASH). The classification performance of validated miRNAs (and their ratios) for NASH was better than that reached by AST, whereas for advanced fibrosis prediction miRNAs did not perform better than the FIB-4 algorithm. Cross-validated models combining both clinical and miRNA variables showed enhanced predictivity. In conclusion, the circulating microRNAs validated demonstrate a better diagnostic potential than conventional serum markers to identify NASH patients and could complement and improve current fibrosis prediction algorithms. The research in this field is still open.
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Affiliation(s)
| | - Isabel Conde
- Hepatología Experimental, IIS Hospital La Fe, Valencia, Spain.,Medicina Digestiva, Sección Hepatología, Hospital La Fe, Valencia, Spain
| | - Guillermo Quintas
- Hepatología Experimental, IIS Hospital La Fe, Valencia, Spain.,Health and Biomedicine, Leitat Technological Center, Barcelona, Spain
| | - Laia Pedrola
- Unidad de Genómica, Servicio de Secuenciación, IIS Hospital La Fe, Valencia, Spain
| | - Ángela Zaragoza
- Medicina Digestiva, Sección Hepatología, Hospital La Fe, Valencia, Spain
| | - Judith Perez-Rojas
- Anatomía Patológica, Sección Hepatología, Hospital La Fe, Valencia, Spain
| | | | - Salvador Benlloch
- Medicina Digestiva, Sección Hepatología, Hospital La Fe, Valencia, Spain
| | - José V Castell
- Hepatología Experimental, IIS Hospital La Fe, Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Ramiro Jover
- Hepatología Experimental, IIS Hospital La Fe, Valencia, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain. .,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
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50
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Younossi ZM, Loomba R, Anstee QM, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, Serfaty L, Negro F, Caldwell SH, Ratziu V, Corey KE, Friedman SL, Abdelmalek MF, Harrison SA, Sanyal AJ, Lavine JE, Mathurin P, Charlton MR, Goodman ZD, Chalasani NP, Kowdley KV, George J, Lindor K. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis. Hepatology 2018. [PMID: 29222917 DOI: 10.1002/hep.29721 10.1002/hep.29721] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a spectrum comprised of isolated steatosis, nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis. The majority of NAFLD subjects do not have NASH and do not carry a significant risk for liver-related adverse outcomes (cirrhosis and mortality). Globally, the prevalence of NAFLD is approximately 25%. In Asia, a gradient of high to low prevalence rates is noted from urban to rural areas. Given the prevalence of NAFLD, the clinical and economic burden of NAFLD and NASH can be substantial. With increasing recognition of NASH as an important liver disease, the diagnosis of NASH still requires a liver biopsy that is suboptimal. Although liver biopsy is the most accurate modality to diagnose and stage the severity of NASH, this method suffers from being invasive, costly, associated with potential complications, and plagued with interobserver variability of individual pathological features. A number of noninvasive modalities to diagnose NASH and stage liver fibrosis are being developed. These modalities include predictive models (NAFLD fibrosis score) and serum biomarkers such as enhanced liver fibrosis (ELF). Other tests are based on radiological techniques, such as transient elastography (TE) or magnetic resonance elastography (MRE), which are used to estimate liver stiffness as a potential surrogate of hepatic fibrosis. Although a dynamic field of research, most of these diagnostic modalities have area under the curve ranging between 0.76 and 0.90%, with MRE having the best predictive performance. In summary, developing safe and easily accessible noninvasive modalities to accurately diagnose and monitor NASH and associated fibrosis is of utmost importance in clinical practice and clinical research. These tests are not only important to risk stratify subjects at the greatest risk for progressive liver disease, but also to serve as appropriate surrogate endpoints for therapeutic clinical trials of NASH. (Hepatology 2018;68:349-360).
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Affiliation(s)
- Zobair M Younossi
- Department of Medicine and Betty and Guy Beatty Center for Integrated Research, Claude Moore, Inova Health Systems, Falls Church, VA
| | - Rohit Loomba
- NAFLD Research Center, University of California at San Diego, La Jolla, CA
| | - Quentin M Anstee
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Mary E Rinella
- University of Torino, Department of Medical Sciences, Torino, Italy
| | | | - Giulio Marchesini
- Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO
| | | | | | - Francesco Negro
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA
| | - Stephen H Caldwell
- Institute of Cardiometabolim and Nutrition (ICAN) and Hospital Pitié Salpêtrière, de L'Hopital, Paris, France
| | - Vlad Ratziu
- Massachusetts General Hospital, Cambridge, MA
| | - Kathleen E Corey
- Icahn School of Medicine at Mount Sinai, Division of Liver Diseases, New York, NY
| | - Scott L Friedman
- Division of Gastroenterology and Hepatology, Duke University, Durham, NC
| | | | - Stephen A Harrison
- Division of Gastroenterology, Virginia Commonwealth University, Richmond, VA
| | - Arun J Sanyal
- Department of Pediatrics, Columbia College of Physicians and Surgeons, New York, NY
| | - Joel E Lavine
- Hôpital Claude Huriez Rue Michel Polonowski, Lille, France
| | | | - Michael R Charlton
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN
| | - Zachary D Goodman
- Department of Medicine and Betty and Guy Beatty Center for Integrated Research, Claude Moore, Inova Health Systems, Falls Church, VA
| | - Naga P Chalasani
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | | | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, Australia
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