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Panganiban J, Kehar M, Ibrahim SH, Hartmann P, Sood S, Hassan S, Ramirez CM, Kohli R, Censani M, Mauney E, Cuda S, Karjoo S. Metabolic dysfunction-associated steatotic liver disease (MASLD) in children with obesity: An Obesity Medicine Association (OMA) and expert joint perspective 2025. OBESITY PILLARS 2025; 14:100164. [PMID: 40230708 PMCID: PMC11995806 DOI: 10.1016/j.obpill.2025.100164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 04/16/2025]
Abstract
Introduction This Obesity Medicine Association (OMA) Expert Joint Perspective examines steatotic liver disease (SLD), which is composed of metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH) in children with obesity. The prevalence of obesity is increasing, rates have tripled since 1963 from 5 % to now 19 % of US children affected in 2018. MASLD, is the most common liver disease seen in children, can be a precursor to the development of Type 2 Diabetes (T2DM) and is the primary reason for liver transplant listing in young adults. We must be vigilant in prevention and treatment of MASLD in childhood to prevent further progression. Methods This joint clinical perspective is based upon scientific evidence, peer and clinical expertise. The medical literature was reviewed via PubMed search and appropriate articles were included in this review. This work was formulated from the collaboration of eight hepatologists/gastroenterologists with MASLD expertise and two physicians from the OMA. Results The authors who are experts in the field, determined sentinel questions often asked by clinicians regarding MASLD in children with obesity. They created a consensus and clinical guideline for clinicians on the screening, diagnosis, and treatment of MASLD associated with obesity in children. Conclusions Obesity and the comorbidity of MASLD is increasing in children, and this is a medical problem that needs to be addressed urgently. It is well known that children with metabolic associated chronic disease often continue to have these chronic diseases as adults, which leads to reduced life expectancy, quality of life, and increasing healthcare needs and financial burden. The authors of this paper recommend healthy weight reduction not only through lifestyle modification but through obesity pharmacotherapy and bariatric surgery. Therefore, this guidance reviews available therapies to achieve healthy weight reduction and reverse MASLD to prevent progressive liver fibrosis, and metabolic disease.
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Affiliation(s)
| | - Mohit Kehar
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Canada
| | - Samar H. Ibrahim
- Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Phillipp Hartmann
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Division of Gastroenterology, Hepatology & Nutrition, Rady Children’s Hospital San Diego, San Diego, CA, USA
| | - Shilpa Sood
- Division of Pediatric Gastroenterology, Boston Children's Health Physicians, New York Medical College, Valhalla, NY, USA
| | - Sara Hassan
- University of Texas Southwestern, Dallas, TX, United States
| | | | - Rohit Kohli
- Children's Hospital Los Angeles, CA, United States
| | - Marisa Censani
- Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, United States
| | - Erin Mauney
- Tufts Medical Center, Boston, MA, United States
| | - Suzanne Cuda
- Alamo City Healthy Kids and Families, San Antonio, TX, United States
| | - Sara Karjoo
- Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States
- University of South Florida, Tampa, FL, United States
- Florida State University, Tallahassee, FL, United States
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Speliotes EK, Schneider CV. PNPLA3 I148M Interacts With Environmental Triggers to Cause Human Disease. Liver Int 2025; 45:e16106. [PMID: 39559944 PMCID: PMC11815600 DOI: 10.1111/liv.16106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/03/2024] [Accepted: 09/08/2024] [Indexed: 11/20/2024]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) affects up to 30% of Western populations. While obesity is a recognized risk factor, MASLD does not develop in all obese individuals, highlighting the need to understand genetic and environmental interactions. The PNPLA3 I148M variant has been identified as a key genetic risk factor, significantly increasing the likelihood of MASLD development and progression. METHODS We reviewed current literature on the role of PNPLA3 I148M in MASLD, focusing on gene-environment interactions involving diet, physical activity, obesity, and insulin resistance. We included studies analysing ethnic differences in PNPLA3 I148M prevalence and its association with MASLD. Additionally, we reviewed data on how PNPLA3 I148M influences the response to therapies, including lipid-lowering medications and GLP-1 agonists. RESULTS The PNPLA3 I148M variant markedly heightens MASLD risk, particularly in Hispanic populations, where a higher prevalence of MASLD is observed. Lifestyle factors such as high sugar intake, alcohol consumption, and physical inactivity exacerbate MASLD risk among I148M carriers. Evidence shows that insulin resistance amplifies MASLD risk associated with the I148M variant, especially in non-diabetic individuals. Moreover, the PNPLA3 I148M variant interacts with other genetic loci, further modifying MASLD risk and disease course. The variant also influences treatment response, with variability observed in effectiveness of lipid-lowering therapies and GLP-1 agonists among carriers. CONCLUSION The interplay between PNPLA3 I148M and environmental factors underscores the need for personalized MASLD prevention and treatment strategies. Targeting both genetic and lifestyle contributors may enhance MASLD management, offering a tailored approach to reducing disease burden.
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Affiliation(s)
- Elizabeth K. Speliotes
- Division of Gastroenterology and Hepatology, Department of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
- Department of Computational Medicine and BioinformaticsUniversity of MichiganAnn ArborMichiganUSA
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Sookoian S, Rotman Y, Valenti L. Genetics of Metabolic Dysfunction-associated Steatotic Liver Disease: The State of the Art Update. Clin Gastroenterol Hepatol 2024; 22:2177-2187.e3. [PMID: 39094912 PMCID: PMC11512675 DOI: 10.1016/j.cgh.2024.05.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/18/2024] [Accepted: 05/28/2024] [Indexed: 08/04/2024]
Abstract
Recent advances in the genetics of metabolic dysfunction-associated steatotic liver disease (MASLD) are gradually revealing the mechanisms underlying the heterogeneity of the disease and have shown promising results in patient stratification. Genetic characterization of the disease has been rapidly developed using genome-wide association studies, exome-wide association studies, phenome-wide association studies, and whole exome sequencing. These advances have been powered by the increase in computational power, the development of new analytical algorithms, including some based on artificial intelligence, and the recruitment of large and well-phenotyped cohorts. This review presents an update on genetic studies that emphasize new biological insights from next-generation sequencing approaches. Additionally, we discuss innovative methods for discovering new genetic loci for MASLD, including rare variants. To comprehensively manage MASLD, it is important to stratify risks. Therefore, we present an update on phenome-wide association study associations, including extreme phenotypes. Additionally, we discuss whether polygenic risk scores and targeted sequencing are ready for clinical use. With particular focus on precision medicine, we introduce concepts such as the interplay between genetics and the environment in modulating genetic risk with lifestyle or standard therapies. A special chapter is dedicated to gene-based therapeutics. The limitations of approved pharmacological approaches are discussed, and the potential of gene-related mechanisms in therapeutic development is reviewed, including the decision to perform genetic testing in patients with MASLD.
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Affiliation(s)
- Silvia Sookoian
- Clinical and Molecular Hepatology. Translational Health Research Center (CENITRES). Maimónides University. Buenos Aires, Argentina
- Faculty of Health Science. Maimónides University. Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Yaron Rotman
- Liver & Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Luca Valenti
- Precision Medicine - Biological Resource Center, Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
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Zafirovska M, Zafirovski A, Režen T, Pintar T. The Outcome of Metabolic and Bariatric Surgery in Morbidly Obese Patients with Different Genetic Variants Associated with Obesity: A Systematic Review. Nutrients 2024; 16:2510. [PMID: 39125390 PMCID: PMC11313945 DOI: 10.3390/nu16152510] [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: 06/30/2024] [Revised: 07/22/2024] [Accepted: 07/27/2024] [Indexed: 08/12/2024] Open
Abstract
Metabolic and bariatric surgery (MBS) effectively treats obesity and related comorbidities, though individual responses vary. This systematic review examines how genetic variants influence MBS outcomes in morbidly obese patients. A comprehensive search in PubMed, Embase, Medline, and the Cochrane Library identified 1572 studies, with 52 meeting the inclusion criteria. Two reviewers independently filtered and selected studies, including relevant cross-references. Research focused on polymorphisms in genes such as UCP2, UCP3, 5-HT2C, MC4R, FKBP5, FTO, CAT haplotypes, LYPAL-1, PTEN, FABP-2, CNR1, LEP656, LEP223, GLP-1R, APOA-1, APOE, ADIPOQ, IL-6, PGC1a, TM6SF2, MBOAT7, PNPLA3, TCF7L2, ESR1, GHSR, GHRL, CD40L, DIO2, ACSL5, CG, TAS2R38, CD36, OBPIIa, NPY, BDNF, CLOCK, and CAMKK2. Most studies explored associations with post-surgery weight loss, while some examined metabolic, cardiovascular, taste, and eating behavior effects as well. Understanding the role of genetic factors in weight loss and metabolic outcomes post-MBS can help tailor personalized treatment plans for improved efficacy and long-term success. Further research with larger sample sizes and extended follow-up is needed to clarify the effects of many genetic variants on MBS outcomes in morbidly obese patients.
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Affiliation(s)
- Marija Zafirovska
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia; (M.Z.); (A.Z.)
- Association of General Practice/Family Medicine of South-East Europe (AGP/FM SEE), St. Vladimir Komarov No. 40/6, 1000 Skopje, North Macedonia
| | - Aleksandar Zafirovski
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia; (M.Z.); (A.Z.)
- General Hospital Jesenice, Cesta maršala Tita 112, 4270 Jesenice, Slovenia
- Clinical Institute of Radiology, University Medical Centre Ljubljana, Zaloška cesta 7, 1000 Ljubljana, Slovenia
| | - Tadeja Režen
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia; (M.Z.); (A.Z.)
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, 1000 Ljubljana, Slovenia
| | - Tadeja Pintar
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia; (M.Z.); (A.Z.)
- Department of Abdominal Surgery, University Medical Centre Ljubljana, Zaloška cesta 2, 1000 Ljubljana, Slovenia
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Butcko AJ, Putman AK, Mottillo EP. The Intersection of Genetic Factors, Aberrant Nutrient Metabolism and Oxidative Stress in the Progression of Cardiometabolic Disease. Antioxidants (Basel) 2024; 13:87. [PMID: 38247511 PMCID: PMC10812494 DOI: 10.3390/antiox13010087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/06/2023] [Accepted: 01/07/2024] [Indexed: 01/23/2024] Open
Abstract
Cardiometabolic disease (CMD), which encompasses metabolic-associated fatty liver disease (MAFLD), chronic kidney disease (CKD) and cardiovascular disease (CVD), has been increasing considerably in the past 50 years. CMD is a complex disease that can be influenced by genetics and environmental factors such as diet. With the increased reliance on processed foods containing saturated fats, fructose and cholesterol, a mechanistic understanding of how these molecules cause metabolic disease is required. A major pathway by which excessive nutrients contribute to CMD is through oxidative stress. In this review, we discuss how oxidative stress can drive CMD and the role of aberrant nutrient metabolism and genetic risk factors and how they potentially interact to promote progression of MAFLD, CVD and CKD. This review will focus on genetic mutations that are known to alter nutrient metabolism. We discuss the major genetic risk factors for MAFLD, which include Patatin-like phospholipase domain-containing protein 3 (PNPLA3), Membrane Bound O-Acyltransferase Domain Containing 7 (MBOAT7) and Transmembrane 6 Superfamily Member 2 (TM6SF2). In addition, mutations that prevent nutrient uptake cause hypercholesterolemia that contributes to CVD. We also discuss the mechanisms by which MAFLD, CKD and CVD are mutually associated with one another. In addition, some of the genetic risk factors which are associated with MAFLD and CVD are also associated with CKD, while some genetic risk factors seem to dissociate one disease from the other. Through a better understanding of the causative effect of genetic mutations in CMD and how aberrant nutrient metabolism intersects with our genetics, novel therapies and precision approaches can be developed for treating CMD.
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Affiliation(s)
- Andrew J. Butcko
- Hypertension and Vascular Research Division, Henry Ford Hospital, 6135 Woodward Avenue, Detroit, MI 48202, USA; (A.J.B.); (A.K.P.)
- Department of Physiology, Wayne State University, 540 E. Canfield Street, Detroit, MI 48202, USA
| | - Ashley K. Putman
- Hypertension and Vascular Research Division, Henry Ford Hospital, 6135 Woodward Avenue, Detroit, MI 48202, USA; (A.J.B.); (A.K.P.)
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, 784 Wilson Road, East Lansing, MI 48823, USA
| | - Emilio P. Mottillo
- Hypertension and Vascular Research Division, Henry Ford Hospital, 6135 Woodward Avenue, Detroit, MI 48202, USA; (A.J.B.); (A.K.P.)
- Department of Physiology, Wayne State University, 540 E. Canfield Street, Detroit, MI 48202, USA
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Caddeo A, Spagnuolo R, Maurotti S. MBOAT7 in liver and extrahepatic diseases. Liver Int 2023; 43:2351-2364. [PMID: 37605540 DOI: 10.1111/liv.15706] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/28/2023] [Accepted: 08/10/2023] [Indexed: 08/23/2023]
Abstract
MBOAT7 is a protein anchored to endomembranes by several transmembrane domains. It has a catalytic dyad involved in remodelling of phosphatidylinositol with polyunsaturated fatty acids. Genetic variants in the MBOAT7 gene have been associated with the entire spectrum of non-alcoholic fatty liver (NAFLD), recently redefined as metabolic dysfunction-associated fatty liver disease (MAFLD) and, lately, steatotic liver disease (SLD), and to an increasing number of extrahepatic conditions. In this review, we will (a) elucidate the molecular mechanisms by which MBOAT7 loss-of-function predisposes to MAFLD and neurodevelopmental disorders and (b) discuss the growing number of genetic studies linking MBOAT7 to hepatic and extrahepatic diseases. MBOAT7 complete loss of function causes severe changes in brain development resulting in several neurological manifestations. Lower MBOAT7 hepatic expression at both the mRNA and protein levels, due to missense nucleotide polymorphisms (SNPs) in the locus containing the MBOAT7 gene, affects specifically metabolic and viral diseases in the liver from simple steatosis to hepatocellular carcinoma, and potentially COVID-19 disease. This body of evidence shows that phosphatidylinositol remodelling is a key factor for human health.
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Affiliation(s)
- Andrea Caddeo
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Rocco Spagnuolo
- Department of Health Sciences, University Magna Graecia, Catanzaro, Italy
| | - Samantha Maurotti
- Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
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Gîlcă-Blanariu GE, Budur DS, Mitrică DE, Gologan E, Timofte O, Bălan GG, Olteanu VA, Ștefănescu G. Advances in Noninvasive Biomarkers for Nonalcoholic Fatty Liver Disease. Metabolites 2023; 13:1115. [PMID: 37999211 PMCID: PMC10672868 DOI: 10.3390/metabo13111115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/15/2023] [Accepted: 10/24/2023] [Indexed: 11/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) currently represents one of the most common liver diseases worldwide. Early diagnosis and disease staging is crucial, since it is mainly asymptomatic, but can progress to nonalcoholic steatohepatitis (NASH) or cirrhosis or even lead to the development of hepatocellular carcinoma. Over time, efforts have been put into developing noninvasive diagnostic and staging methods in order to replace the use of a liver biopsy. The noninvasive methods used include imaging techniques that measure liver stiffness and biological markers, with a focus on serum biomarkers. Due to the impressive complexity of the NAFLD's pathophysiology, biomarkers are able to assay different processes involved, such as apoptosis, fibrogenesis, and inflammation, or even address the genetic background and "omics" technologies. This article reviews not only the currently validated noninvasive methods to investigate NAFLD but also the promising results regarding recently discovered biomarkers, including biomarker panels and the combination of the currently validated evaluation methods and serum markers.
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Affiliation(s)
- Georgiana-Emmanuela Gîlcă-Blanariu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Daniela Simona Budur
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Dana Elena Mitrică
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Elena Gologan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Oana Timofte
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gheorghe Gh Bălan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Vasile Andrei Olteanu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gabriela Ștefănescu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
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Di Ciaula A, Bonfrate L, Shanmugam H, Weber SN, Krawczyk M, Portincasa P. Effects of MBOAT7 polymorphism and steatosis on liver function assessed by methacetin breath test. Eur J Clin Invest 2023; 53:e14003. [PMID: 37029745 DOI: 10.1111/eci.14003] [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: 03/06/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 04/09/2023]
Abstract
BACKGROUND MBOAT7 rs641738 variant is a risk factor for nonalcoholic fatty liver disease (NAFLD) and liver fibrosis, but the relationship between this polymorphism and early liver dysfunction remains uncertain. METHODS Eighty outpatients underwent blood analyses, liver imaging by ultrasound and acoustic radiation force impulse shear wave elastography and were genotyped for MBOAT7 (wild-type [WT], rs641738 heterozygous or homozygous) polymorphism using TaqMan assays. RESULTS NAFLD was confirmed in 53 patients. Portal uptake and hepatocyte microsomal metabolization of (13 C)-methacetin were explored by measuring 13 CO2 appearance in exhaled air. The distribution of the MBOAT7 genotypes was comparable in subjects with or without NAFLD. The majority of subjects with or without NAFLD had fibrosis ≤ F1 but decreased portal extraction of (13 C)-methacetin, i.e. 78.6% in homozygous, 45.0% in heterozygous and 46.2% in WT for the MBOAT7 variant. Both substrate extraction and microsomal metabolization were mostly defective in the homozygous carriers. The extraction efficiency from portal blood flow was minimal in subjects with both homozygous rs641738 polymorphism and NAFLD, as compared to those with WT/heterozygous polymorphism, with or without NAFLD. CONCLUSIONS The homozygous MBOAT7 rs641738 polymorphism per se is associated with a reduced extraction efficiency of (13 C)-methacetin from the portal flow pointing to subclinical liver dysfunction independently from liver fibrosis. Liver steatosis worsens (13 C)-methacetin extraction efficiency. We urge to better explore the mechanisms of interaction between external factors and multiple gene polymorphisms (including MBOAT7), paving the road to primary prevention and novel therapeutic strategies.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica "A. Murri", Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro" Medical School, Bari, Italy
| | - Leonilde Bonfrate
- Clinica Medica "A. Murri", Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro" Medical School, Bari, Italy
| | - Harshitha Shanmugam
- Clinica Medica "A. Murri", Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro" Medical School, Bari, Italy
| | - Susanne N Weber
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro" Medical School, Bari, Italy
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Agyapong G, Dashti F, Banini BA. Nonalcoholic liver disease: Epidemiology, risk factors, natural history, and management strategies. Ann N Y Acad Sci 2023; 1526:16-29. [PMID: 37400359 PMCID: PMC10524684 DOI: 10.1111/nyas.15012] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/05/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease worldwide and a leading indication for liver transplantation in the United States. NAFLD encompasses a heterogeneous clinicopathologic spectrum, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis, and progressive fibrosis, which can lead to end-stage liver disease including cirrhosis and hepatocellular cancer. Predictive models suggest that over 100 million adults in the United States will have NAFLD by 2030, representing over a third of the population. In this manuscript, we provide an overview of NAFLD risk factors, natural history (including hepatic and extra-hepatic outcomes), diagnosis, and current management strategies.
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Affiliation(s)
- George Agyapong
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Farzaneh Dashti
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Bubu A Banini
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
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Xu X, Xu H, Liu X, Zhang S, Cao Z, Qiu L, Du X, Liu Y, Wang G, Zhang L, Zhang Y, Zhang J. MBOAT7 rs641738 (C>T) is associated with NAFLD progression in men and decreased ASCVD risk in elder Chinese population. Front Endocrinol (Lausanne) 2023; 14:1199429. [PMID: 37424875 PMCID: PMC10324031 DOI: 10.3389/fendo.2023.1199429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/05/2023] [Indexed: 07/11/2023] Open
Abstract
Background and aim The MBOAT7 rs641738 (C>T) variant has demonstrated an association with non-alcoholic fatty liver disease (NAFLD) in both adult and pediatric patients, while few studies have been conducted in elderly populations. Hence, a case-control study was undertaken to assess their correlation in elderly residents in a Beijing community. Materials and methods A total of 1,287 participants were included. Medical history, abdominal ultrasound, and laboratory tests were recorded. Liver fat content and fibrosis stage were detected by Fibroscan. Genotyping of genomic DNA was performed using the 96.96 genotyping integrated fluidics circuit. Results Of the recruited subjects, 638 subjects (56.60%) had NAFLD, and 398 subjects (35.28%) had atherosclerotic cardiovascular disease (ASCVD). T allele carriage was associated with higher ALT (p=0.005) and significant fibrosis in male NAFLD patients (p=0.005) compared to CC genotype. TT genotype was associated with reduced risk of metabolic syndrome (OR=0.589, 95%CI: 0.114-0.683, p=0.005) and type 2 diabetes (OR=0.804, 95%CI: 0.277-0.296, p=0.048) in NAFLD population when compared to the CC genotype. In addition, TT genotype was also associated with reduced risk of ASCVD (OR=0.570, 95%CI:0.340-0.953, p=0.032) and less obesity (OR=0.545, 95%CI: 0.346-0.856, p=0.008) in the whole population. Conclusion MBOAT7 rs641738 (C>T) variant was associated with fibrosis in male NAFLD patients. The variant also reduced risk of metabolic traits and type 2 diabetes in NAFLD and ASCVD risk in Chinese elders.
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Affiliation(s)
- Xiaoyi Xu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Hangfei Xu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiaohui Liu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Shuang Zhang
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Menkuang Hospital, Beijing Jingmei Group General Hospital, Beijing, China
| | - Zhenhuan Cao
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Lixia Qiu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiaofei Du
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yali Liu
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Gang Wang
- Menkuang Hospital, Beijing Jingmei Group General Hospital, Beijing, China
| | - Li Zhang
- Menkuang Hospital, Beijing Jingmei Group General Hospital, Beijing, China
| | - Yang Zhang
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jing Zhang
- The Third Unit, The Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
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11
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Sohal A, Chaudhry H, Kowdley KV. Genetic Markers Predisposing to Nonalcoholic Steatohepatitis. Clin Liver Dis 2023; 27:333-352. [PMID: 37024211 DOI: 10.1016/j.cld.2023.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
The growing prevalence of nonalcoholic fatty liver disease (NAFLD) has sparked interest in understanding genetics and epigenetics associated with the development and progression of the disease. A better understanding of the genetic factors related to progression will be beneficial in the risk stratification of patients. These genetic markers can also serve as potential therapeutic targets in the future. In this review, we focus on the genetic markers associated with the progression and severity of NAFLD.
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Affiliation(s)
- Aalam Sohal
- Liver Institute Northwest, 3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA
| | - Hunza Chaudhry
- Department of Internal Medicine, UCSF Fresno, 155 North Fresno Street, Fresno, CA 93722, USA
| | - Kris V Kowdley
- Liver Institute Northwest, 3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA; Elson S. Floyd College of Medicine, Washington State University, WA, USA.
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12
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Harrison SA, Allen AM, Dubourg J, Noureddin M, Alkhouri N. Challenges and opportunities in NASH drug development. Nat Med 2023; 29:562-573. [PMID: 36894650 DOI: 10.1038/s41591-023-02242-6] [Citation(s) in RCA: 175] [Impact Index Per Article: 87.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 12/20/2022] [Indexed: 03/11/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), represent a growing worldwide epidemic and a high unmet medical need, as no licensed drugs have been approved thus far. Currently, histopathological assessment of liver biopsies is mandatory as a primary endpoint for conditional drug approval. This requirement represents one of the main challenges in the field, as there is substantial variability in this invasive histopathological assessment, which leads to dramatically high screen-failure rates in clinical trials. Over the past decades, several non-invasive tests have been developed to correlate with liver histology and, eventually, outcomes to assess disease severity and longitudinal changes non-invasively. However, further data are needed to ensure their endorsement by regulatory authorities as alternatives to histological endpoints in phase 3 trials. This Review describes the challenges of drug development in NAFLD-NASH trials and potential mitigating strategies to move the field forward.
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Affiliation(s)
| | - Alina M Allen
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA
| | | | | | - Naim Alkhouri
- Department of Hepatology, Arizona Liver Health, Chandler, AZ, USA
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13
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Zhang J, Xie H, Yao J, Jin W, Pan H, Pan Z, Xie D, Xie D. TRIM59 promotes steatosis and ferroptosis in non-alcoholic fatty liver disease via enhancing GPX4 ubiquitination. Hum Cell 2023; 36:209-222. [PMID: 36417114 DOI: 10.1007/s13577-022-00820-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 10/25/2022] [Indexed: 11/24/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease around the world. However, no specific medicine has been approved for NAFLD treatment. Our study was conducted to explore the role and mechanism of TRIM59 in NAFLD, aiming to provide a novel target for NAFLD treatment. Here, the expression of TRIM family members was detected in 10 mild and severe NAFLD tissues as well as 10 normal tissues. TRIM59 expression was verified in 10 normal tissues and 25 mild and severe NAFLD tissues. Palmitic acid and high-fatty diet were used for the construction of NAFLD models. Oil Red O staining was used to detect the level of steatosis. The content of TNF-α, IL-6, and IL-8 was measured to reflect the level of inflammation. Lipid reactive oxygen species was estimated by flow cytometry. We found that TRIM59 was highly expressed in NAFLD tissues compared with normal liver tissues. The inhibition of TRIM59 could inhibit the steatosis and inflammation in NAFLD, whereas its overexpression exhibited reversed effects. The application of ferroptosis inhibitor, deferoxamine, could markedly ameliorate steatosis and inflammation, which was mediated by overexpressed TRIM59. Besides, TRIM59 was demonstrated to interact with GPX4 and promoted its ubiquitination. The overexpression of GPX4 could significantly reverse the pathogenic effects of TRIM59 in NAFLD. Additionally, the inhibition of TRIM59 appeared to be a promising strategy to ameliorate NAFLD in mice model. In summary, our study revealed that TRIM59 could promote steatosis and ferroptosis in NAFLD via enhancing GPX4 ubiquitination. TRIM59 could be a potential target for NAFLD treatment.
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Affiliation(s)
- Jingxian Zhang
- Department of Pharmacy, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai, China
| | - Haina Xie
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jun Yao
- Department of Pharmacy, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai, China
| | - Wenye Jin
- Department of Pharmacy, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai, China
| | - Huijie Pan
- Department of Pharmacy, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai, China
| | - Zhiqiang Pan
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Dongyu Xie
- Department of Spleen-Stomach, Zhenjiang Affiliated Hospital of Nanjing University of Chinese Medicine, Zhenjiang, China. .,Department of Spleen-Stomach, Zhenjiang Hospital of Traditional Chinese Medicine, Zhenjiang, China.
| | - Donghao Xie
- Department of Pharmacy, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai, China. .,Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China.
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14
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Kalinowski P, Smyk W, Nowosad M, Paluszkiewicz R, Michałowski Ł, Ziarkiewicz-Wróblewska B, Weber SN, Milkiewicz P, Lammert F, Zieniewicz K, Krawczyk M. MTARC1 and HSD17B13 Variants Have Protective Effects on Non-Alcoholic Fatty Liver Disease in Patients Undergoing Bariatric Surgery. Int J Mol Sci 2022; 23:15825. [PMID: 36555467 PMCID: PMC9781679 DOI: 10.3390/ijms232415825] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/08/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
The severity of hepatic steatosis is modulated by genetic variants, such as patatin-like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) rs641738. Recently, mitochondrial amidoxime reducing component 1 (MTARC1) rs2642438 and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 polymorphisms were shown to have protective effects on liver diseases. Here, we evaluate these variants in patients undergoing bariatric surgery. A total of 165 patients who underwent laparoscopic sleeve gastrectomy and intraoperative liver biopsies and 314 controls were prospectively recruited. Genotyping was performed using TaqMan assays. Overall, 70.3% of operated patients presented with hepatic steatosis. NASH (non-alcoholic steatohepatitis) was detected in 28.5% of patients; none had cirrhosis. The increment of liver fibrosis stage was associated with decreasing frequency of the MTARC1 minor allele (p = 0.03). In multivariate analysis MTARC1 was an independent protective factor against fibrosis ≥ 1b (OR = 0.52, p = 0.03) and ≥ 1c (OR = 0.51, p = 0.04). The PNPLA3 risk allele was associated with increased hepatic steatosis, fibrosis, and NASH (OR = 2.22, p = 0.04). The HSD17B13 polymorphism was protective against liver injury as reflected by lower AST (p = 0.04) and ALT (p = 0.03) activities. The TM6SF2 polymorphism was associated with increased ALT (p = 0.04). In conclusion, hepatic steatosis is common among patients scheduled for bariatric surgery, but the MTARC1 and HSD17B13 polymorphisms lower liver injury in these individuals.
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Affiliation(s)
- Piotr Kalinowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Wiktor Smyk
- Department of Gastroenterology and Hepatology, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Małgorzata Nowosad
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Rafał Paluszkiewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Łukasz Michałowski
- Department of Pathology, Medical University of Warsaw, 02-091 Warsaw, Poland
| | | | - Susanne N. Weber
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421 Homburg, Germany
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421 Homburg, Germany
- Hannover Health Science Campus, Hannover Medical School (MHH), 30625 Hannover, Germany
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421 Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland
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15
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Zhou Y, Li Z, Xu M, Zhang D, Ling J, Yu P, Shen Y. O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease. Cells 2022; 11:cells11223637. [PMID: 36429065 PMCID: PMC9688300 DOI: 10.3390/cells11223637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/04/2022] [Accepted: 11/10/2022] [Indexed: 11/18/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease spectrum associated with insulin resistance (IR), from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). O-GlcNAcylation is a posttranslational modification, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Abnormal O-GlcNAcylation plays a key role in IR, fat deposition, inflammatory injury, fibrosis, and tumorigenesis. However, the specific mechanisms and clinical treatments of O-GlcNAcylation and NAFLD are yet to be elucidated. The modification contributes to understanding the pathogenesis and development of NAFLD, thus clarifying the protective effect of O-GlcNAcylation inhibition on liver injury. In this review, the crucial role of O-GlcNAcylation in NAFLD (from NAFL to HCC) is discussed, and the effect of therapeutics on O-GlcNAcylation and its potential mechanisms on NAFLD have been highlighted. These inferences present novel insights into the pathogenesis and treatments of NAFLD.
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Affiliation(s)
- Yicheng Zhou
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Zhangwang Li
- The Second Clinical Medical College of Nanchang University, Nanchang 330031, China
| | - Minxuan Xu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Deju Zhang
- Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Jitao Ling
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Peng Yu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
- Correspondence: (P.Y.); (Y.S.)
| | - Yunfeng Shen
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
- Correspondence: (P.Y.); (Y.S.)
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16
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Sveinbjornsson G, Ulfarsson MO, Thorolfsdottir RB, Jonsson BA, Einarsson E, Gunnlaugsson G, Rognvaldsson S, Arnar DO, Baldvinsson M, Bjarnason RG, Eiriksdottir T, Erikstrup C, Ferkingstad E, Halldorsson GH, Helgason H, Helgadottir A, Hindhede L, Hjorleifsson G, Jones D, Knowlton KU, Lund SH, Melsted P, Norland K, Olafsson I, Olafsson S, Oskarsson GR, Ostrowski SR, Pedersen OB, Snaebjarnarson AS, Sigurdsson E, Steinthorsdottir V, Schwinn M, Thorgeirsson G, Thorleifsson G, Jonsdottir I, Bundgaard H, Nadauld L, Bjornsson ES, Rulifson IC, Rafnar T, Norddahl GL, Thorsteinsdottir U, Sulem P, Gudbjartsson DF, Holm H, Stefansson K. Multiomics study of nonalcoholic fatty liver disease. Nat Genet 2022; 54:1652-1663. [PMID: 36280732 PMCID: PMC9649432 DOI: 10.1038/s41588-022-01199-5] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 09/02/2022] [Indexed: 11/09/2022]
Abstract
Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1 and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options.
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Affiliation(s)
| | - Magnus O Ulfarsson
- deCODE genetics/Amgen, Inc., Reykjavik, Iceland.,Faculty of Electrical and Computer Engineering, University of Iceland, Reykjavik, Iceland
| | | | | | | | | | | | - David O Arnar
- deCODE genetics/Amgen, Inc., Reykjavik, Iceland.,Faculty of Medicine, University of Iceland, Reykjavik, Iceland.,Internal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland
| | | | - Ragnar G Bjarnason
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland.,Children's Medical Center, Landspítali-The National University Hospital of Iceland, Reykjavík, Iceland
| | | | | | - Christian Erikstrup
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | | | | | | | | | - Lotte Hindhede
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | | | - David Jones
- Intermountain Healthcare, St. George, UT, USA
| | | | | | - Pall Melsted
- deCODE genetics/Amgen, Inc., Reykjavik, Iceland.,Faculty of Mechanical Engineering, Industrial Engineering and Computer Science, University of Iceland, Reykjavik, Iceland
| | | | - Isleifur Olafsson
- Clinical Laboratory Services, Diagnostics and Blood Bank, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland
| | - Sigurdur Olafsson
- Internal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland
| | | | - Sisse Rye Ostrowski
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Cophenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ole Birger Pedersen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark
| | | | - Emil Sigurdsson
- Development Centre for Primary Health Care in Iceland, Reykjavík, Iceland.,Department of Family Medicine, University of Iceland, Reykjavik, Iceland
| | | | - Michael Schwinn
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Cophenhagen, Denmark
| | - Gudmundur Thorgeirsson
- deCODE genetics/Amgen, Inc., Reykjavik, Iceland.,Internal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland
| | | | - Ingileif Jonsdottir
- deCODE genetics/Amgen, Inc., Reykjavik, Iceland.,Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Henning Bundgaard
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.,Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | | | - Einar S Bjornsson
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland.,Internal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland
| | | | | | | | - Unnur Thorsteinsdottir
- deCODE genetics/Amgen, Inc., Reykjavik, Iceland.,Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | | | - Daniel F Gudbjartsson
- deCODE genetics/Amgen, Inc., Reykjavik, Iceland.,Faculty of Electrical and Computer Engineering, University of Iceland, Reykjavik, Iceland.,School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
| | - Hilma Holm
- deCODE genetics/Amgen, Inc., Reykjavik, Iceland
| | - Kari Stefansson
- deCODE genetics/Amgen, Inc., Reykjavik, Iceland. .,Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
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17
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Chew NW, Chong B, Ng CH, Kong G, Chin YH, Xiao W, Lee M, Dan YY, Muthiah MD, Foo R. The genetic interactions between non-alcoholic fatty liver disease and cardiovascular diseases. Front Genet 2022; 13:971484. [PMID: 36035124 PMCID: PMC9399730 DOI: 10.3389/fgene.2022.971484] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 07/19/2022] [Indexed: 12/03/2022] Open
Abstract
The ongoing debate on whether non-alcoholic fatty liver disease (NAFLD) is an active contributor or an innocent bystander in the development of cardiovascular disease (CVD) has sparked interests in understanding the common mediators between the two biologically distinct entities. This comprehensive review identifies and curates genetic studies of NAFLD overlapping with CVD, and describes the colinear as well as opposing correlations between genetic associations for the two diseases. Here, CVD described in relation to NAFLD are coronary artery disease, cardiomyopathy and atrial fibrillation. Unique findings of this review included certain NAFLD susceptibility genes that possessed cardioprotective properties. Moreover, the complex interactions of genetic and environmental risk factors shed light on the disparity in genetic influence on NAFLD and its incident CVD. This serves to unravel NAFLD-mediated pathways in order to reduce CVD events, and helps identify targeted treatment strategies, develop polygenic risk scores to improve risk prediction and personalise disease prevention.
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Affiliation(s)
- Nicholas W.S. Chew
- Department of Cardiology, National University Heart Centre, Singapore, Singapore
- *Correspondence: Nicholas W.S. Chew, ; Roger Foo,
| | - Bryan Chong
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Gwyneth Kong
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Yip Han Chin
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Wang Xiao
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Disease Translational Research Programme, National University Health Systems, Singapore, Singapore
- Genome Institute of Singapore, Agency of Science Technology and Research, Bipolis way, Singapore
| | - Mick Lee
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Disease Translational Research Programme, National University Health Systems, Singapore, Singapore
- Genome Institute of Singapore, Agency of Science Technology and Research, Bipolis way, Singapore
| | - Yock Young Dan
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Mark D. Muthiah
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Roger Foo
- Department of Cardiology, National University Heart Centre, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Disease Translational Research Programme, National University Health Systems, Singapore, Singapore
- Genome Institute of Singapore, Agency of Science Technology and Research, Bipolis way, Singapore
- *Correspondence: Nicholas W.S. Chew, ; Roger Foo,
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18
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Varadharajan V, Massey WJ, Brown JM. Membrane-bound O-acyltransferase 7 (MBOAT7)-driven phosphatidylinositol remodeling in advanced liver disease. J Lipid Res 2022; 63:100234. [PMID: 35636492 PMCID: PMC9240865 DOI: 10.1016/j.jlr.2022.100234] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/12/2022] [Accepted: 05/16/2022] [Indexed: 01/21/2023] Open
Abstract
Advanced liver diseases account for approximately 2 million deaths annually worldwide. Roughly, half of liver disease-associated deaths arise from complications of cirrhosis and the other half driven by viral hepatitis and hepatocellular carcinoma. Unfortunately, the development of therapeutic strategies to treat subjects with advanced liver disease has been hampered by a lack of mechanistic understanding of liver disease progression and a lack of human-relevant animal models. An important advance has been made within the past several years, as several genome-wide association studies have discovered that an SNP near the gene encoding membrane-bound O-acyltransferase 7 (MBOAT7) is associated with severe liver diseases. This common MBOAT7 variant (rs641738, C>T), which reduces MBOAT7 expression, confers increased susceptibility to nonalcoholic fatty liver disease, alcohol-associated liver disease, and liver fibrosis in patients chronically infected with viral hepatitis. Recent studies in mice also show that Mboat7 loss of function can promote hepatic steatosis, inflammation, and fibrosis, causally linking this phosphatidylinositol remodeling enzyme to liver health in both rodents and humans. Herein, we review recent insights into the mechanisms by which MBOAT7-driven phosphatidylinositol remodeling influences liver disease progression and discuss how rapid progress in this area could inform drug discovery moving forward.
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Affiliation(s)
- Venkateshwari Varadharajan
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - William J Massey
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - J Mark Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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19
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Martínez-Montoro JI, Kuchay MS, Balaguer-Román A, Martínez-Sánchez MA, Frutos MD, Fernández-García JC, Ramos-Molina B. Gut microbiota and related metabolites in the pathogenesis of nonalcoholic steatohepatitis and its resolution after bariatric surgery. Obes Rev 2022; 23:e13367. [PMID: 34729904 DOI: 10.1111/obr.13367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/06/2021] [Accepted: 09/06/2021] [Indexed: 12/17/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is increasing in parallel with the rising prevalence of obesity, leading to major health and socioeconomic consequences. To date, the most effective therapeutic approach for NAFLD is weight loss. Accordingly, bariatric surgery (BS), which produces marked reductions in body weight, is associated with significant histopathological improvements in advanced stages of NAFLD, such as nonalcoholic steatohepatitis (NASH) and liver fibrosis. BS is also associated with substantial taxonomical and functional alterations in gut microbiota, which are believed to play a significant role in metabolic improvement after BS. Interestingly, gut microbiota and related metabolites may be implicated in the pathogenesis of NAFLD through diverse mechanisms, including specific microbiome signatures, short chain fatty acid production or the modulation of one-carbon metabolism. Moreover, emerging evidence highlights the potential association between gut microbiota changes after BS and NASH resolution. In this review, we summarize the current knowledge on the relationship between NAFLD severity and gut microbiota, as well as the role of the gut microbiome and related metabolites in NAFLD improvement after BS.
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Affiliation(s)
- José Ignacio Martínez-Montoro
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), Faculty of Medicine, University of Malaga, Malaga, Spain
| | - Mohammad Shafi Kuchay
- Division of Endocrinology and Diabetes, Medanta - The Medicity Hospital, Gurugram, Haryana, India
| | - Andrés Balaguer-Román
- Department of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, Murcia, Spain.,Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain
| | | | - María Dolores Frutos
- Department of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, Murcia, Spain
| | - José Carlos Fernández-García
- Department of Endocrinology and Nutrition, Regional University Hospital of Malaga, Institute of Biomedical Research in Malaga (IBIMA), Faculty of Medicine, University of Malaga, Malaga, Spain
| | - Bruno Ramos-Molina
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain
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Martínez-Montoro JI, Cornejo-Pareja I, Gómez-Pérez AM, Tinahones FJ. Impact of Genetic Polymorphism on Response to Therapy in Non-Alcoholic Fatty Liver Disease. Nutrients 2021; 13:4077. [PMID: 34836332 PMCID: PMC8625016 DOI: 10.3390/nu13114077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 12/13/2022] Open
Abstract
In the last decades, the global prevalence of non-alcoholic fatty liver disease (NAFLD) has reached pandemic proportions with derived major health and socioeconomic consequences; this tendency is expected to be further aggravated in the coming years. Obesity, insulin resistance/type 2 diabetes mellitus, sedentary lifestyle, increased caloric intake and genetic predisposition constitute the main risk factors associated with the development and progression of the disease. Importantly, the interaction between the inherited genetic background and some unhealthy dietary patterns has been postulated to have an essential role in the pathogenesis of NAFLD. Weight loss through lifestyle modifications is considered the cornerstone of the treatment for NAFLD and the inter-individual variability in the response to some dietary approaches may be conditioned by the presence of different single nucleotide polymorphisms. In this review, we summarize the current evidence on the influence of the association between genetic susceptibility and dietary habits in NAFLD pathophysiology, as well as the role of gene polymorphism in the response to lifestyle interventions and the potential interaction between nutritional genomics and other emerging therapies for NAFLD, such as bariatric surgery and several pharmacologic agents.
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Affiliation(s)
- José Ignacio Martínez-Montoro
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.I.M.-M.); (F.J.T.)
- Faculty of Medicine, University of Málaga, 29071 Málaga, Spain
| | - Isabel Cornejo-Pareja
- Instituto de Investigación Biomédica de Málaga (IBIMA), Virgen de la Victoria University Hospital, 29010 Málaga, Spain
- Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ana María Gómez-Pérez
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.I.M.-M.); (F.J.T.)
| | - Francisco J. Tinahones
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.I.M.-M.); (F.J.T.)
- Faculty of Medicine, University of Málaga, 29071 Málaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Virgen de la Victoria University Hospital, 29010 Málaga, Spain
- Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain
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21
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Abstract
The acronym nonalcoholic fatty-liver disease (NAFLD) groups a heterogeneous patient population. Although in many patients the primary driver is metabolic dysfunction, a complex and dynamic interaction of different factors (i.e., sex, presence of one or more genetic variants, coexistence of different comorbidities, diverse microbiota composition, and various degrees of alcohol consumption among others) takes place to determine disease subphenotypes with distinct natural history and prognosis and, eventually, different response to therapy. This review aims to address this topic through the analysis of existing data on the differential contribution of known factors to the pathogenesis and clinical expression of NAFLD, thus determining the different clinical subphenotypes observed in practice. To improve our understanding of NAFLD heterogeneity and the dominant drivers of disease in patient subgroups would predictably impact on the development of more precision-targeted therapies for NAFLD.
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Affiliation(s)
- Marco Arrese
- Department of Gastroenterology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Juan P. Arab
- Department of Gastroenterology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Francisco Barrera
- Department of Gastroenterology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Benedikt Kaufmann
- Department of Pediatric Gastroenterology, Rady Children's Hospital, University of California San Diego, California
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Translational Medicine, Department of Transfusion, Medicine and Hematology, Fondazione IRCCS Ca' Granda, Pad Marangoni, Milan, Italy
| | - Ariel E. Feldstein
- Department of Pediatric Gastroenterology, Rady Children's Hospital, University of California San Diego, California
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22
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Hu C, Jia W. Multi-omics profiling: the way towards precision medicine in metabolic diseases. J Mol Cell Biol 2021; 13:mjab051. [PMID: 34406397 PMCID: PMC8697344 DOI: 10.1093/jmcb/mjab051] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/19/2021] [Accepted: 06/21/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic diseases including type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome (MetS) are alarming health burdens around the world, while therapies for these diseases are far from satisfying as their etiologies are not completely clear yet. T2DM, NAFLD, and MetS are all complex and multifactorial metabolic disorders based on the interactions between genetics and environment. Omics studies such as genetics, transcriptomics, epigenetics, proteomics, and metabolomics are all promising approaches in accurately characterizing these diseases. And the most effective treatments for individuals can be achieved via omics pathways, which is the theme of precision medicine. In this review, we summarized the multi-omics studies of T2DM, NAFLD, and MetS in recent years, provided a theoretical basis for their pathogenesis and the effective prevention and treatment, and highlighted the biomarkers and future strategies for precision medicine.
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Affiliation(s)
- Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus,
Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth
People's Hospital, Shanghai 200233, China
- Institute for Metabolic Disease, Fengxian Central Hospital, The Third School of
Clinical Medicine, Southern Medical University, Shanghai 201499, China
| | - Weiping Jia
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus,
Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth
People's Hospital, Shanghai 200233, China
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Marques V, Afonso MB, Bierig N, Duarte-Ramos F, Santos-Laso Á, Jimenez-Agüero R, Eizaguirre E, Bujanda L, Pareja MJ, Luís R, Costa A, Machado MV, Alonso C, Arretxe E, Alustiza JM, Krawczyk M, Lammert F, Tiniakos DG, Flehmig B, Cortez-Pinto H, Banales JM, Castro RE, Normann A, Rodrigues CMP. Adiponectin, Leptin, and IGF-1 Are Useful Diagnostic and Stratification Biomarkers of NAFLD. Front Med (Lausanne) 2021; 8:683250. [PMID: 34249975 PMCID: PMC8260936 DOI: 10.3389/fmed.2021.683250] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 05/10/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease where liver biopsy remains the gold standard for diagnosis. Here we aimed to evaluate the role of circulating adiponectin, leptin, and insulin-like growth factor 1 (IGF-1) levels as non-invasive NAFLD biomarkers and assess their correlation with the metabolome. Materials and Methods: Leptin, adiponectin, and IGF-1 serum levels were measured by ELISA in two independent cohorts of biopsy-proven obese NAFLD patients and healthy-liver controls (discovery: 38 NAFLD, 13 controls; validation: 194 NAFLD, 31 controls) and correlated with clinical data, histology, genetic parameters, and serum metabolomics. Results: In both cohorts, leptin increased in NAFLD vs. controls (discovery: AUROC 0.88; validation: AUROC 0.83; p < 0.0001). The leptin levels were similar between obese and non-obese healthy controls, suggesting that obesity is not a confounding factor. In the discovery cohort, adiponectin was lower in non-alcoholic steatohepatitis (NASH) vs. non-alcoholic fatty liver (AUROC 0.87; p < 0.0001). For the validation cohort, significance was attained for homozygous for PNPLA3 allele c.444C (AUROC 0.63; p < 0.05). Combining adiponectin with specific serum lipids improved the assay performance (AUROC 0.80; p < 0.0001). For the validation cohort, IGF-1 was lower with advanced fibrosis (AUROC 0.67, p < 0.05), but combination with international normalized ratio (INR) and ferritin increased the assay performance (AUROC 0.81; p < 0.01). Conclusion: Serum leptin discriminates NAFLD, and adiponectin combined with specific lipids stratifies NASH. IGF-1, INR, and ferritin distinguish advanced fibrosis.
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Affiliation(s)
- Vanda Marques
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Marta B. Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | - Filipa Duarte-Ramos
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
- EPIUnit–Instituto de Saúde Pública, Universidade do Porto, Oporto, Portugal
| | - Álvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Raul Jimenez-Agüero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Emma Eizaguirre
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain
| | | | - Rita Luís
- Department of Pathological Anatomy, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Adília Costa
- Department of Pathological Anatomy, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Mariana V. Machado
- Faculdade de Medicina, Clinica Universitária de Gastrenterologia, Universidade de Lisboa, Lisbon, Portugal
- Department of Gastroenterology, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | | | - Enara Arretxe
- OWL Metabolomics, Bizkaia Technology Park, Derio, Spain
| | - José M. Alustiza
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Radiology Service, Osatek, Donostia, Spain
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Dina G. Tiniakos
- Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Department of Pathology, Aretaieio Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Helena Cortez-Pinto
- Faculdade de Medicina, Clinica Universitária de Gastrenterologia, Universidade de Lisboa, Lisbon, Portugal
- Department of Gastroenterology, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Rui E. Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | - Cecília M. P. Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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Armandi A, Schattenberg JM. NAFLD between genes and environment: what drives fibrogenesis? Gut 2021; 70:815-816. [PMID: 32759301 DOI: 10.1136/gutjnl-2020-321964] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 12/29/2022]
Affiliation(s)
- Angelo Armandi
- Department of Medical Sciences, Division of Gastroenterology and Hepatology, University of Turin, Torino, Piemonte, Italy
| | - Jörn M Schattenberg
- Department of Medicine, University Medical Center Mainz Department of Internal Medicine 1, Mainz, Rheinland-Pfalz, Germany .,Metabolic Liver Research Program, University Medical Center Mainz Department of Internal Medicine 1, Mainz, Rheinland-Pfalz, Germany
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Lonardo A, Arab JP, Arrese M. Perspectives on Precision Medicine Approaches to NAFLD Diagnosis and Management. Adv Ther 2021; 38:2130-2158. [PMID: 33829368 PMCID: PMC8107169 DOI: 10.1007/s12325-021-01690-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023]
Abstract
Precision medicine defines the attempt to identify the most effective approaches for specific subsets of patients based on their genetic background, clinical features, and environmental factors. Nonalcoholic fatty liver disease (NAFLD) encompasses the alcohol-like spectrum of liver disorders (steatosis, steatohepatitis with/without fibrosis, and cirrhosis and hepatocellular carcinoma) in the nonalcoholic patient. Recently, disease renaming to MAFLD [metabolic (dysfunction)-associated fatty liver disease] and positive criteria for diagnosis have been proposed. This review article is specifically devoted to envisaging some clues that may be useful to implementing a precision medicine-oriented approach in research and clinical practice. To this end, we focus on how sex and reproductive status, genetics, intestinal microbiota diversity, endocrine and metabolic status, as well as physical activity may interact in determining NAFLD/MAFLD heterogeneity. All these factors should be considered in the individual patient with the aim of implementing an individualized therapeutic plan. The impact of considering NAFLD heterogeneity on the development of targeted therapies for NAFLD subgroups is also extensively discussed.
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Affiliation(s)
- Amedeo Lonardo
- Department of Internal Medicine, Azienda Ospedaliero-Universitaria, Ospedale Civile di Baggiovara, 1135 Via Giardini, 41126, Modena, Italy.
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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26
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Seko Y, Yamaguchi K, Tochiki N, Yano K, Takahashi A, Okishio S, Kataoka S, Okuda K, Umemura A, Moriguchi M, Itoh Y. The Effect of Genetic Polymorphism in Response to Body Weight Reduction in Japanese Patients with Nonalcoholic Fatty Liver Disease. Genes (Basel) 2021; 12:628. [PMID: 33922278 PMCID: PMC8145113 DOI: 10.3390/genes12050628] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/11/2021] [Accepted: 04/21/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND weight loss as a result of lifestyle intervention is effective when treating non-alcoholic fatty liver disease (NAFLD). We estimated the effects of PNPLA3 rs738409 and HSD17B13 rs6834314 variants in response to diet therapy in Japanese patients with NAFLD. METHODS we analyzed the correlation between the change in liver stiffness and change in body weight in 140 patients administered diet therapy for 1-year, according to PNPLA3 and HSD17B13 genotypes. RESULTS the bodyweight (BW) reduction rate was greater in patients with the PNPLA3 genotype CC than CG and GG (p = 0.035). Change in liver stiffness measurement (LSM) was significantly associated with a change in BW in PNPLA3 CG/GG (r = 0.279/0.381), but not in PNPLA3 CC (p = 0.187). Change in LSM was correlated with change in BW only in patients with HSD17B13 AG/GG (r = 0.425), but not the AA genotype (p = 0.069). A multivariate analysis identified that a change in LSM was correlated with a change in BW in carriers of HSD17B13 AG/GG (B = 3.043, p = 0.032), but not HSD17B13 AA. The change in LSM of patients with a BW reduction of more than 7% (0.50) was significantly greater than that of patients with a BW reduction of less than 7% (0.83) (p = 0.038). CONCLUSIONS in Japanese patients with NAFLD, HSD17B13 rs6834314 polymorphism is associated with the change in LSM by lifestyle intervention. The approach, including genetic assessments, may contribute to the establishment of appropriate therapeutic strategies to treat NAFLD.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (Y.S.); (K.Y.); (N.T.); (K.Y.); (A.T.); (S.O.); (S.K.); (K.O.); (A.U.); (M.M.)
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Ismaiel A, Dumitrascu DL. Genetic predisposition in metabolic-dysfunction-associated fatty liver disease and cardiovascular outcomes-Systematic review. Eur J Clin Invest 2020; 50:e13331. [PMID: 32589269 DOI: 10.1111/eci.13331] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 06/02/2020] [Accepted: 06/18/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Despite the demonstrated increased cardiovascular (CV) risk associated with metabolic-dysfunction-associated fatty liver disease (MAFLD), genetic variants predisposing to MAFLD were not constantly associated with CV events. Recently, rs641738C > T near membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) has been studied in MAFLD and CV outcomes. Therefore, we aimed to evaluate the association between rs641738C > T in the presence and severity of hepatic steatosis, fibrosis, biochemical markers and progression to hepatocellular carcinoma (HCC), in addition to CV outcomes in MAFLD. MATERIALS AND METHODS An electronic search on PubMed, Embase and Cochrane Library for articles published till 23 March 2020 was systematically performed. Articles were screened, and data extracted from eligible studies by two reviewers independently. RESULTS Studies conducted on adults with MAFLD involving European, Hispanic and African American populations evaluating rs641738 reported reduced hepatic expression of MBOAT7, increased hepatic fat content, severity of MAFLD, susceptibility to develop NASH, advanced fibrosis and HCC in adults. However, most articles involving Asian individuals contradicted these findings. Studies involving obese children associated rs641738 with increased plasma alanine aminotransferase (ALT) levels, while its association with MAFLD remains inconsistent. The rs641738 variant was assessed as a MAFLD susceptibility gene in coronary artery disease (CAD) reporting neutral effects. CONCLUSIONS Despite inconclusive results in Asian populations, rs641738C > T near MBOAT7 is associated with increased hepatic fat, MAFLD severity, susceptibility to develop NASH, advanced fibrosis and HCC in adults from Caucasian, Hispanic and African American ethnicities with MAFLD, as well as elevated ALT levels in children, while exerting neutral effects in CAD.
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Affiliation(s)
- Abdulrahman Ismaiel
- Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2nd Department of Internal Medicine, Cluj-Napoca, Romania
| | - Dan L Dumitrascu
- Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2nd Department of Internal Medicine, Cluj-Napoca, Romania
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Tincopa MA. Diagnostic and interventional circulating biomarkers in nonalcoholic steatohepatitis. Endocrinol Diabetes Metab 2020; 3:e00177. [PMID: 33102798 PMCID: PMC7576258 DOI: 10.1002/edm2.177] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 06/17/2020] [Accepted: 07/18/2020] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION In the setting of the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become one of the most prevalent forms of chronic liver disease worldwide. Approximately 25% of adults globally have NAFLD which includes those with NAFL, or simple steatosis, and individuals with nonalcoholic steatohepatitis (NASH) where inflammation, hepatocyte injury and potentially hepatic fibrosis are found in conjunction with steatosis. Individuals with NASH, particularly those with hepatic fibrosis, have higher rates of liver-related and overall mortality, making this distinction of significant clinical importance. One of the core challenges in current clinical practice is identifying this subset of individuals with NASH without the use of liver biopsy, the gold standard for both diagnostics and staging disease severity. Identifying noninvasive biomarkers, an accurately measured and reproducible parameter, would aide in identifying patients eligible for NASH pharmacotherapy clinical trials and to help tailor intensity of monitoring required. METHODS RESULTS AND CONCLUSIONS In this review, we highlight both the currently available and novel diagnostic and interventional circulating biomarkers under investigation for NASH, underscoring their accuracy and limitations relevant to our patient population and current clinical practice.
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Affiliation(s)
- Monica A. Tincopa
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
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29
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Botello-Manilla AE, Chávez-Tapia NC, Uribe M, Nuño-Lámbarri N. Genetics and epigenetics purpose in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2020; 14:733-748. [PMID: 32552211 DOI: 10.1080/17474124.2020.1780915] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION nonalcoholic fatty liver disease (NAFLD) comprises a broad spectrum of diseases, which can progress from benign steatosis to nonalcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma. NAFLD is the most common chronic liver disease in developed countries, affecting approximately 25% of the general population. Insulin resistance, adipose tissue dysfunction, mitochondrial and endoplasmic reticulum stress, chronic inflammation, genetic and epigenetic factors are NAFLD triggers that control the disease susceptibility and progression. AREAS COVERED In recent years a large number of investigations have been carried out to elucidate genetic and epigenetic factors in the disease pathogenesis, as well as the search for diagnostic markers and therapeutic targets. This paper objective is to report the most studied genetic and epigenetic variants around NAFLD. EXPERT OPINION NAFLD lead to various comorbidities, which have a considerable impact on the patient wellness and life quality, as well as on the costs they generate for the country's health services. It is essential to continue with molecular research, since it could be used as a clinical tool for prognosis and disease severity. Specifically, in the field of hepatology, plasma miRNAs could provide a novel tool in liver diseases diagnosis and monitoring, representing an alternative to invasive diagnostic procedures.
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Affiliation(s)
| | - Norberto Carlos Chávez-Tapia
- Traslational Research Unit, Médica Sur Clinic & Foundation , Mexico City, Mexico.,Obesity and Digestive Diseases Unit, Médica Sur Clinic & Foundation , Mexico City, Mexico
| | - Misael Uribe
- Obesity and Digestive Diseases Unit, Médica Sur Clinic & Foundation , Mexico City, Mexico
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Liebe R, Keitel-Anselmino V. Genetisches Risiko bei metabolischer Fettlebererkrankung. DIABETOLOGE 2020. [DOI: 10.1007/s11428-020-00647-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Meroni M, Longo M, Fracanzani AL, Dongiovanni P. MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD. EBioMedicine 2020; 57:102866. [PMID: 32629394 PMCID: PMC7339032 DOI: 10.1016/j.ebiom.2020.102866] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/12/2020] [Accepted: 06/16/2020] [Indexed: 12/11/2022] Open
Abstract
Metabolic associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, which include steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, that is a critical risk factor for hepatocellular carcinoma (HCC) development. Its pathogenesis is intertwined with obesity and type 2 diabetes (T2D). However, the predisposition to develop MAFLD is severely influenced by environmental and inherited cues. The rs641738 variant close to MBOAT7 gene has been identified by a genome-wide association screening in heavy drinkers. Although this variant has been associated with the entire spectrum of MAFLD, these results have not been completely replicated and the debate is still opened. Thus, functional studies that unravel the biological mechanisms underlying the genetic association with fatty liver are required. This review aims to summarize the clinical and experimental findings regarding the rs641738 variation and MBOAT7 function, with the purpose to shed light to its role as novel player in MAFLD pathophysiology.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Anna L Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy.
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Carlsson B, Lindén D, Brolén G, Liljeblad M, Bjursell M, Romeo S, Loomba R. Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2020; 51:1305-1320. [PMID: 32383295 PMCID: PMC7318322 DOI: 10.1111/apt.15738] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/13/2020] [Accepted: 03/29/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) characterised by liver fat accumulation, inflammation and progressive fibrosis. Emerging data indicate that genetic susceptibility increases risks of NAFLD, NASH and NASH-related cirrhosis. AIMS To review NASH genetics and discuss the potential for precision medicine approaches to treatment. METHOD PubMed search and inclusion of relevant literature. RESULTS Single-nucleotide polymorphisms in PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 are clearly associated with NASH development or progression. These genetic variants are common and have moderate-to-large effect sizes for development of NAFLD, NASH and hepatocellular carcinoma (HCC). The genes play roles in lipid remodelling in lipid droplets, hepatic very low-density lipoprotein (VLDL) secretion and de novo lipogenesis. The PNPLA3 I148M variant (rs738409) has large effects, with approximately twofold increased odds of NAFLD and threefold increased odds of NASH and HCC per allele. Obesity interacts with PNPLA3 I148M to elevate liver fat content and increase rates of NASH. Although the isoleucine-to-methionine substitution at amino acid position 148 of the PNPLA3 enzyme inactivates its lipid remodelling activity, the effect of PNPLA3 I148M results from trans-repression of another lipase (ATGL/PNPLA2) by sequestration of a shared cofactor (CGI-58/ABHD5), leading to decreased hepatic lipolysis and VLDL secretion. In homozygous Pnpla3 I148M knock-in rodent models of NAFLD, targeted PNPLA3 mRNA knockdown reduces hepatic steatosis, inflammation and fibrosis. CONCLUSION The emerging genetic and molecular understanding of NASH paves the way for novel interventions, including precision medicines that can modulate the activity of specific genes associated with NASH.
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Affiliation(s)
- Björn Carlsson
- Research and Early DevelopmentCardiovascular, Renal and MetabolismBioPharmaceuticals R&DAstraZenecaGothenburgSweden
| | - Daniel Lindén
- Research and Early DevelopmentCardiovascular, Renal and MetabolismBioPharmaceuticals R&DAstraZenecaGothenburgSweden,Division of EndocrinologyDepartment of Neuroscience and PhysiologySahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Gabriella Brolén
- Precision MedicineCardiovascular, Renal and MetabolismR&DAstraZenecaGothenburgSweden
| | - Mathias Liljeblad
- Research and Early DevelopmentCardiovascular, Renal and MetabolismBioPharmaceuticals R&DAstraZenecaGothenburgSweden
| | - Mikael Bjursell
- Research and Early DevelopmentCardiovascular, Renal and MetabolismBioPharmaceuticals R&DAstraZenecaGothenburgSweden
| | - Stefano Romeo
- Department of Molecular and Clinical MedicineUniversity of GothenburgGothenburgSweden,Clinical Nutrition UnitDepartment of Medical and Surgical SciencesMagna Graecia UniversityCatanzaroItaly,Cardiology DepartmentSahlgrenska University HospitalGothenburgSweden
| | - Rohit Loomba
- NAFLD Research CenterDivision of GastroenterologyUniversity of California San DiegoSan DiegoCAUSA
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Krawczyk M, Liebe R, Lammert F. Toward Genetic Prediction of Nonalcoholic Fatty Liver Disease Trajectories: PNPLA3 and Beyond. Gastroenterology 2020; 158:1865-1880.e1. [PMID: 32068025 DOI: 10.1053/j.gastro.2020.01.053] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 01/29/2020] [Accepted: 01/29/2020] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is on the verge of becoming the leading cause of liver disease. NAFLD develops at the interface between environmental factors and inherited predisposition. Genome-wide association studies, followed by exome-wide analyses, led to identification of genetic risk variants (eg, PNPLA3, TM6SF2, and SERPINA1) and key pathways involved in fatty liver disease pathobiology. Functional studies improved our understanding of these genetic factors and the molecular mechanisms underlying the trajectories from fat accumulation to fibrosis, cirrhosis, and cancer over time. Here, we summarize key NAFLD risk genes and illustrate their interactions in a 3-dimensional "risk space." Although NAFLD genomics sometimes appears to be "lost in translation," we envision clinical utility in trial design, outcome prediction, and NAFLD surveillance.
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Affiliation(s)
- Marcin Krawczyk
- Department of Medicine II (Gastroenterology and Endocrinology), Saarland University Medical Center, Saarland University, Homburg; Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Roman Liebe
- Department of Medicine II (Gastroenterology and Endocrinology), Saarland University Medical Center, Saarland University, Homburg; Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Frank Lammert
- Department of Medicine II (Gastroenterology and Endocrinology), Saarland University Medical Center, Saarland University, Homburg.
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Abstract
Nonalcoholic fatty liver disease is strongly associated with obesity and the metabolic syndrome, but genetic factors also contribute to disease susceptibility. Human genetic studies have identified several common genetic variants contributing to nonalcoholic fatty liver disease initiation and progression. These findings have provided new insights into the pathogenesis of nonalcoholic fatty liver disease and opened up new avenues for the development of therapeutic interventions. In this review, we summarize the current state of knowledge about the genetic determinants of nonalcoholic fatty liver disease, focusing on the most robustly validated genetic risk factors and on recently discovered modifiers of disease progression.
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Affiliation(s)
- Julia Kozlitina
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8591, USA.
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Risk of chemotherapy-associated liver injury (CALI) in PNPLA3 p.148M allele carriers: Preliminary results of a transient elastography-based study. Dig Liver Dis 2020; 52:102-106. [PMID: 31669075 DOI: 10.1016/j.dld.2019.09.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 08/23/2019] [Accepted: 09/19/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Liver steatosis is one of the side effects of chemotherapy. The PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 p.G17E variants represent genetic determinants for progressive liver diseases. Here, we investigate their association with chemotherapy-associated steatosis. PATIENTS AND METHODS Prospectively, we recruited 87 patients undergoing systemic chemotherapy for gastrointestinal cancers. Hepatic fat (controlled attenuation parameter, CAP) and liver stiffness (LSM) were measured non-invasively before the initiation of chemotherapy (T0) and after at least two (T1) and four cycles (T2). Genetic variants were genotyped using allelic discrimination assays. RESULTS In the final dataset (n = 60) patients demonstrated the following CAP values: T0 - 215.0 ± 55.7 dB/m, T1 - 223.3 ± 53.6 dB/m, T2 - 223.4 ± 56.7 dB/m, consistent with mild steatosis. Initial CAP correlated with BMI (P < 0.01) and serum triglyceride concentrations (P = 0.03). Whereas at T0 none of the variants was associated with CAP or LSM, carriers of the prosteatotic PNPLA3 p.148M allele showed significantly (P = 0.008) higher steatosis at T1 as compared to patients carrying the homozygous wild-type genotype [II]. CONCLUSIONS Our preliminary results show that patients carrying the PNPLA3 p.I148 M risk allele might be prone to hepatic fat accumulation during chemotherapy. Further studies are be needed to validate the clinical value of these findings.
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Molina-Molina E, Krawczyk M, Stachowska E, Lammert F, Portincasa P. Non-Alcoholic Fatty Liver Disease in Non-Obese Individuals: Prevalence, Pathogenesis and Treatment. Clin Res Hepatol Gastroenterol 2019; 43:638-645. [PMID: 31196707 DOI: 10.1016/j.clinre.2019.04.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 03/28/2019] [Accepted: 04/25/2019] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) parallels comorbidities such as metabolic syndrome, dyslipidaemia or diabetes. Although NAFLD is very prevalent in overweight-obese individuals (i.e. body mass index ≥25 kg/m2), recent studies point to the presence of NAFLD in non-obese individuals, for both the Asian (<25 kg/m2) and Caucasian (<30 kg/m2) populations. This paper discusses the pathogenic pathways and current treatment options of NAFLD in non-obese populations. In this respect, non-obese subjects also need to undergo the medical screening for NAFLD. Across the scientific community, we aim to promote the advancement of knowledge in this emerging field.
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Affiliation(s)
- Emilio Molina-Molina
- Clinica Medica "A. Murri", Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Ewa Stachowska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, 71-210 Szczecin, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy.
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Xia MF, Bian H, Gao X. NAFLD and Diabetes: Two Sides of the Same Coin? Rationale for Gene-Based Personalized NAFLD Treatment. Front Pharmacol 2019; 10:877. [PMID: 31447675 PMCID: PMC6691129 DOI: 10.3389/fphar.2019.00877] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 07/10/2019] [Indexed: 12/14/2022] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing rapidly and at the forefront of worldwide concern. Characterized by excessive fat accumulation in the liver, NAFLD regularly coexists with metabolic disorders, including type 2 diabetes, obesity, and cardiovascular disease. It has been well established that the presence of NAFLD increases the incidence of type 2 diabetes, while diabetes aggravates NAFLD to more severe forms of steatohepatitis, cirrhosis, and hepatocellular carcinoma. However, recent progress on the genotype/phenotype relationships in NAFLD patients indicates the development of NAFLD with a relative conservation of glucose metabolism in individuals with specific gene variants, such as the patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 protein (TM6SF2) variants. This review will focus on the clinical and pathophysiological connections between NAFLD and type 2 diabetes and will also discuss a disproportionate progression of NAFLD and diabetes, and the different responses to lifestyle and drug intervention in NAFLD patients with specific gene variants that may give insight into personalized treatment for NAFLD.
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Affiliation(s)
- Ming-Feng Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Fudan University, Shanghai, China
| | - Hua Bian
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Fudan University, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Fudan University, Shanghai, China
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Xia MF, Lin HD, Chen LY, Wu L, Ma H, Li Q, Aleteng Q, Hu Y, He WY, Gao J, Bian H, Li XY, Gao X. The PNPLA3 rs738409 C>G variant interacts with changes in body weight over time to aggravate liver steatosis, but reduces the risk of incident type 2 diabetes. Diabetologia 2019; 62:644-654. [PMID: 30673802 DOI: 10.1007/s00125-018-4805-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 12/04/2018] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS The rs738409 C>G variant of the patatin-like phospholipase domain containing 3 gene (PNPLA3) increases the risk of non-alcoholic fatty liver disease (NAFLD) with no predisposition for insulin resistance. In this study, we aimed to investigate the influence of PNPLA3 polymorphisms on liver fat content (LFC) and glucose metabolic variables, and the associations between these, during the natural course of body weight changes in a Chinese adult cohort. METHODS The LFC, measured using a quantitative ultrasound method, was prospectively monitored in 2189 middle-aged and elderly adults from the Shanghai Changfeng Study, together with changes in body weight and metabolic variables. General linear models were used to detect interactive effects between the PNPLA3 rs738409 genotype and 4 year changes in body weight on liver steatosis and glucose metabolism. RESULTS The PNPLA3 homozygous GG genotype dissociated the changes in the LFC and OGTT 2 h post-load blood glucose (PBG) in relation to 4 year changes in body weight. PNPLA3 GG genotype carriers showed greater increases in the LFC and serum alanine aminotransferase (ALT) but lower PBG elevation and incident diabetes than PNPLA3 wild-type (CC) genotype carriers exhibiting the same degree of body weight increase. The interactions between the PNPLA3 genotype and changes in body weight on the LFC (false discovery rate [FDR]-adjusted pinteraction = 0.044) and ALT (FDR-adjusted pinteraction = 0.044) were significant. Subgroup analyses showed that the effect of the PNPLA3 GG genotype on changes in the LFC and PBG was only observed in metabolically unhealthy participants with insulin resistance or abdominal obesity. CONCLUSIONS/INTERPRETATION The PNPLA3 GG genotype interacted with changes in body weight to aggravate liver steatosis but reduced the risk of incident type 2 diabetes in metabolically unhealthy participants.
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Affiliation(s)
- Ming-Feng Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Huan-Dong Lin
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Ling-Yan Chen
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li Wu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Hui Ma
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qian Li
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Qiqige Aleteng
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Yu Hu
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wan-Yuan He
- Department of Ultrasonography, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Gao
- Center of Clinical Epidemiology and EBM of Fudan University, Shanghai, China
- Department of Nutrition, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Hua Bian
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Xiao-Ying Li
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
- Fudan Institute for Metabolic Diseases, Shanghai, China.
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Carulli L, Zanca G, Schepis F, Villa E. The OMICs Window into Nonalcoholic Fatty Liver Disease (NAFLD). Metabolites 2019; 9:25. [PMID: 30717274 PMCID: PMC6409793 DOI: 10.3390/metabo9020025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 01/26/2019] [Accepted: 01/30/2019] [Indexed: 12/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common cause of hepatic abnormalities worldwide. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD and leads to progressive liver disease, such as cirrhosis and hepatocellular carcinoma. In NASH patient, fibrosis represents the major predictor of liver-related mortality; therefore, it is important to have an early and accurate diagnosis of NASH. The current gold standard for the diagnosis of NASH is still liver biopsy. The development of biomarkers able to predict disease severity, prognosis, as well as response to therapy without the need for a biopsy is the focus of most up-to-date genomic, transcriptomic, proteomic, and metabolomic research. In the future, patients might be diagnosed and treated according to their molecular signatures. In this short review, we discuss how information from genomics, proteomics, and metabolomics contribute to the understanding of NAFLD pathogenesis.
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Affiliation(s)
- Lucia Carulli
- Division of Gastroenterology, Department of Medical Specialties, University of Modena and Reggio Emilia, 41124 Modena, Italy.
| | - Giulia Zanca
- Division of Gastroenterology, Department of Medical Specialties, University of Modena and Reggio Emilia, 41124 Modena, Italy.
| | - Filippo Schepis
- Division of Gastroenterology, Department of Medical Specialties, University of Modena and Reggio Emilia, 41124 Modena, Italy.
| | - Erica Villa
- Division of Gastroenterology, Department of Medical Specialties, University of Modena and Reggio Emilia, 41124 Modena, Italy.
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PNPLA3 p.I148M and TM6SF2 p.E167K variants do not predispose to liver injury in cholestatic liver diseases: A prospective analysis of 178 patients with PSC. PLoS One 2018; 13:e0202942. [PMID: 30161167 PMCID: PMC6117000 DOI: 10.1371/journal.pone.0202942] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 08/13/2018] [Indexed: 02/07/2023] Open
Abstract
Background The adiponutrin (PNPLA3) p.I148M and transmembrane 6 superfamily member 2 (TM6SF2) p.E167K variants represent major genetic risk factors for progressive liver injury in nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD) and chronic viral hepatitis. The aim of this study was to find out whether these variants have a detrimental impact on the progression of chronic liver disease in patients with prolonged cholestasis induced by primary sclerosing cholangitis (PSC). Methods We prospectively recruited 178 PSC patients (112 male, age range 17–75 years, 55 with liver cirrhosis, 94 with ulcerative colitis, 48 transplanted during follow-up). PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms were genotyped using dedicated TaqMan assays. Associations between genotypes, biochemical and clinical phenotypes were analyzed using contingency tables. Results Allele and genotype distribution of both variants were consistent with Hardy-Weinberg equilibrium. No significant differences in the genotype distribution of PNPLA3 (P = 0.90) or TM6SF2 (P = 0.72) were observed between patients with cirrhosis and patients without cirrhosis. Serum liver enzyme activities were not modified by the presence of PNPLA3 (ALT P = 0.88, AST P = 0.77) or TM6SF2 (ALT P = 0.92, AST P = 0.49) risk variants. Increasing number of risk alleles had no impact on serum liver enzyme activities, as demonstrated by a separate analysis of patients carrying 0 (n = 99), 1 (n = 64), 2 (n = 12) or 3 (n = 3) risk alleles (P>0.05). No impact of PNPLA3 or TM6SF2 risk variants was detectable in patients with PSC and ulcerative colitis, and none of the variants increased the odds of transplantation. Conclusions Neither PNPLA3 nor TM6SF2 polymorphisms seem to contribute significantly towards an increased risk for deterioration of liver function in patients with PSC. These results underscore the divergent mechanisms of liver damage in cholestatic conditions as compared to metabolic and viral liver diseases.
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Wang JZ, Cao HX, Chen JN, Pan Q. PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease. World J Clin Cases 2018; 6:167-175. [PMID: 30148144 PMCID: PMC6107533 DOI: 10.12998/wjcc.v6.i8.167] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 05/16/2018] [Accepted: 06/08/2018] [Indexed: 02/05/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has now become the leading cause of chronic liver disease with its growing incidence worldwide. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C > G reflects one of the critical genetic factors that confers high-risk to NAFLD. However, the role of PNPLA3 polymorphism in NAFLD treatment remains uncertain. Here, the present review reveals that NAFLD patients with G-allele at PNPLA3 rs738409 (PNPLA3 148M variant) are sensitive to therapies of lifestyle modification, dipeptidyl peptidase-4 inhibitors, and bariatric surgery. They exhibit much significant reduction of liver fat content, in concurrence with weigh loss and abolished insulin resistance, as compared to those of C-allele carriers. In contrast, patients bearing PNPLA3 rs738409 C-allele (PNPLA3 148I variant), instead of G-allele, demonstrate greater beneficial effects by omega-3 poly-unsaturated fatty acids and statin intervention. Improved adipose tissue-liver interaction and decrease in intrahepatic triglyceride efflux may contribute to the PNPLA3 rs738409 related diversities in therapeutic efficacy. Therefore, PNPLA3 rs738409 underlies the response to a variety of treatments, which warrants a personalized, precise medicine in NAFLD on the basis of genotype stratification.
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Affiliation(s)
- Jin-Zhi Wang
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Hai-Xia Cao
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Jian-Neng Chen
- Department of Hepatology, Zhengxing Hospital, Zhangzhou 363000, Fujian Province, China
| | - Qin Pan
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
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Molina-Molina E, Baccetto RL, Wang DQH, de Bari O, Krawczyk M, Portincasa P. Exercising the hepatobiliary-gut axis. The impact of physical activity performance. Eur J Clin Invest 2018; 48:e12958. [PMID: 29797516 PMCID: PMC8118139 DOI: 10.1111/eci.12958] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 05/21/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Physical inactivity puts the populations at risk of several health problems, while regular physical activity brings beneficial effects on cardiovascular disease, mortality and other health outcomes, including obesity, glycaemic control and insulin resistance. The hepatobiliary tract is greatly involved in several metabolic aspects which include digestion and absorption of nutrients in concert with intestinal motility, bile acid secretion and flow across the enterohepatic circulation and intestinal microbiota. Several metabolic abnormalities, including nonalcoholic fatty liver as well as cholesterol cholelithiasis, represent two conditions explained by changes of the aforementioned pathways. MATERIALS AND METHODS This review defines different training modalities and discusses the effects of physical activity in two metabolic disorders, that is nonalcoholic fatty liver disease (NAFLD) and cholelithiasis. Emphasis is given to pathogenic mechanisms involving intestinal bile acids, microbiota and inflammatory status. RESULTS A full definition of physical activity includes the knowledge of aerobic and endurance exercise, metabolic equivalent tasks, duration, frequency and intensity, beneficial and harmful effects. Physical activity influences the hepatobiliary-gut axis at different levels and brings benefits to fat distribution, liver fat and gallbladder disease while interacting with bile acids as signalling molecules, intestinal microbiota and inflammatory changes in the body. CONCLUSIONS Several beneficial effects of physical activity are anticipated on metabolic disorders linking liver steatosis, gallstone disease, gut motility, enterohepatic circulation of signalling bile acids in relation to intestinal microbiota and inflammatory changes.
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Affiliation(s)
- Emilio Molina-Molina
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy
| | - Raquel Lunardi Baccetto
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy
| | - David Q.-H. Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Ornella de Bari
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy
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Abstract
Nonalcoholic fatty liver disease (NAFLD) affects 25% of the global adult population and is the most common chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH) is the active form of NAFLD, with hepatic necroinflammation and faster fibrosis progression. With an increasing number of patients developing NASH-related end-stage liver disease and pharmacological treatments on the horizon, there is a pressing need to develop NAFLD and NASH biomarkers for prognostication, selection of patients for treatment and monitoring. This requirement is particularly true as liver biopsy utility is limited by its invasive nature, poor patient acceptability and sampling variability. This article reviews current and potential biomarkers for different features of NAFLD, namely, steatosis, necroinflammation and fibrosis. For each biomarker, we evaluate its accuracy, reproducibility, responsiveness, feasibility and limitations. We cover biochemical, imaging and genetic biomarkers and discuss biomarker discovery in the omics era.
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Speliotes EK. Thwart your destiny; effect of nonacoholic fatty liver disease genes on steatosis, liver injury and cirrhosis varies by body mass index. Hepatology 2018; 68:372-374. [PMID: 29251787 PMCID: PMC6005706 DOI: 10.1002/hep.29739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 12/08/2017] [Accepted: 12/11/2017] [Indexed: 12/07/2022]
Affiliation(s)
- Elizabeth K. Speliotes
- Divisions of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
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Pirola CJ, Sookoian S. Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity. World J Gastroenterol 2018; 24:1601-1615. [PMID: 29686467 PMCID: PMC5910543 DOI: 10.3748/wjg.v24.i15.1601] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/13/2018] [Accepted: 03/30/2018] [Indexed: 02/06/2023] Open
Abstract
This review intends to uncover how information from large-scale genetic profiling (whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease (NAFLD), as well as information from circulating transcriptomics (cell-free miRNAs) and metabolomics, contributes to the understanding of NAFLD pathogenesis. A further aim is to address the question of whether OMICs information is ready to be implemented in the clinics. The available evidence suggests that any new knowledge pertaining to molecular signatures associated with NAFLD and nonalcoholic steatohepatitis should be promptly translated into the clinical setting. Nevertheless, rigorous steps that must include validation and replication are mandatory before utilizing OMICs biomarkers in diagnostics to identify patients at risk of advanced disease, including liver cancer.
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Affiliation(s)
- Carlos J Pirola
- Department of Genetics and Molecular Biology of Complex Diseases. University of Buenos Aires, Institute of Medical Research A Lanari, Buenos Aires, Argentina, National Scientific and Technical Research Council-University of Buenos Aires. Institute of Medical Research (IDIM), CABA 1427, Argentina
| | - Silvia Sookoian
- Clinical and Molecular Hepatology, University of Buenos Aires, Institute of Medical Research A Lanari, Buenos Aires, Argentina, National Scientific and Technical Research Council-University of Buenos Aires. Institute of Medical Research (IDIM), CABA 1427, Argentina
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Beier JI, Banales JM. Pyroptosis: An inflammatory link between NAFLD and NASH with potential therapeutic implications. J Hepatol 2018; 68:643-645. [PMID: 29408544 PMCID: PMC6185810 DOI: 10.1016/j.jhep.2018.01.017] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 01/18/2018] [Accepted: 01/20/2018] [Indexed: 12/16/2022]
Affiliation(s)
- Juliane I. Beier
- Department of Pharmacology and Toxicology, Hepatobiology and Toxicology Program, University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292, USA;,Corresponding authors. Addresses: Department of Pharmacology & Toxicology, University of Louisville, 505 S. Hancock St, Louisville, KY 40292, USA. Tel.: +1 502 852 5157; fax: +1 502 852 3422 (J.I. Beier), or Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, Paseo del Dr. Begiristain s/n, E-20014 San Sebastian, Spain. Tel.: +34 943006067. (J. Banales). (J.I. Beier), (J.M. Banales)
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital – University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain,Corresponding authors. Addresses: Department of Pharmacology & Toxicology, University of Louisville, 505 S. Hancock St, Louisville, KY 40292, USA. Tel.: +1 502 852 5157; fax: +1 502 852 3422 (J.I. Beier), or Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, Paseo del Dr. Begiristain s/n, E-20014 San Sebastian, Spain. Tel.: +34 943006067. (J. Banales). (J.I. Beier), (J.M. Banales)
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Sookoian S, Flichman D, Garaycoechea ME, Gazzi C, Martino JS, Castaño GO, Pirola CJ. Lack of evidence supporting a role of TMC4-rs641738 missense variant-MBOAT7- intergenic downstream variant-in the Susceptibility to Nonalcoholic Fatty Liver Disease. Sci Rep 2018; 8:5097. [PMID: 29572551 PMCID: PMC5865142 DOI: 10.1038/s41598-018-23453-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 03/13/2018] [Indexed: 02/06/2023] Open
Abstract
Current knowledge on the genetic basis of nonalcoholic fatty liver disease (NAFLD) suggests that variants contributing not only to the disease predisposition but histological severity as well are located in genes that regulate lipid metabolism. We explored the role of rs641738 C/T located in TMC4 (transmembrane channel-like 4) exon 1 (p.Gly17Glu) and 500 bases- downstream of MBOAT7 gene (TMC4/MBOAT7), in the genetic risk for developing NAFLD in a case-control study. Our sample included 634 individuals (372 patients with NAFLD diagnosed by liver biopsy and 262 control subjects); genotyping was performed by a Taqman assay. Genotype frequencies in controls (CC: 84, CT: 137, TT: 41) and patients (CC: 134, CT: 178, TT: 60) were in Hardy-Weinberg equilibrium; minor allele frequency 40.8%. Our sample had 84–99% power if an additive genetic model is assumed for estimated odds ratios of 1.3–1.5, respectively. We found no evidence of association between rs641738 and either NAFLD (Cochran-Armitage test for trend, p = 0.529) or the disease severity (p = 0.61). Low levels of MBOAT7 protein expression were found in the liver of patients with NAFLD, which were unrelated to the rs641738 genotypes. In conclusion, the role of rs641738 in the pathogenesis of NAFLD is inconclusive.
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Affiliation(s)
- Silvia Sookoian
- University of Buenos Aires, Institute of Medical Research A Lanari, Buenos Aires, Argentina. .,National Scientific and Technical Research Council (CONICET)-University of Buenos Aires. Institute of Medical research (IDIM), Department of Clinical and Molecular Hepatology, Buenos Aires, Argentina.
| | - Diego Flichman
- University of Buenos Aires, School of Pharmacy and Biochemistry, Department of Virology, and National Scientific and Technical Research Council (CONICET), Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
| | - Martin E Garaycoechea
- Hospital de Alta Complejidad en Red El Cruce, Department of Surgery, Buenos Aires, Argentina
| | - Carla Gazzi
- University of Buenos Aires, Institute of Medical Research A Lanari, Department of Pathology, Buenos Aires, Argentina
| | - Julio San Martino
- Hospital Diego Thompson, San Martin, Department of Pathology, Buenos Aires, Argentina
| | - Gustavo O Castaño
- Hospital Abel Zubizarreta, Department of Medicine and Surgery, Liver Unit, Buenos Aires, Argentina
| | - Carlos J Pirola
- University of Buenos Aires, Institute of Medical Research A Lanari, Buenos Aires, Argentina. .,National Scientific and Technical Research Council (CONICET)-University of Buenos Aires. Institute of Medical research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, Buenos Aires, Argentina.
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Saeed A, Dullaart RPF, Schreuder TCMA, Blokzijl H, Faber KN. Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD). Nutrients 2017; 10:nu10010029. [PMID: 29286303 PMCID: PMC5793257 DOI: 10.3390/nu10010029] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 12/13/2017] [Accepted: 12/19/2017] [Indexed: 12/22/2022] Open
Abstract
Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites.
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Affiliation(s)
- Ali Saeed
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
- Institute of Molecular Biology & Bio-Technology, Bahauddin Zakariya University, Multan 60800, Pakistan.
| | - Robin P F Dullaart
- Department of Endocrinology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
| | - Tim C M A Schreuder
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
| | - Hans Blokzijl
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
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Pillai S, Duvvuru S, Bhatnagar P, Foster W, Farmen M, Shankar S, Harris C, Bastyr E, Hoogwerf B, Haupt A. The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro. THE PHARMACOGENOMICS JOURNAL 2017; 18:487-493. [DOI: 10.1038/tpj.2017.45] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 07/24/2017] [Accepted: 08/04/2017] [Indexed: 12/27/2022]
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