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Wang JJ, Chen XY, Zhang YR, Shen Y, Zhu ML, Zhang J, Zhang JJ. Role of genetic variants and DNA methylation of lipid metabolism-related genes in metabolic dysfunction-associated steatotic liver disease. Front Physiol 2025; 16:1562848. [PMID: 40166716 PMCID: PMC11955510 DOI: 10.3389/fphys.2025.1562848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 02/25/2025] [Indexed: 04/02/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), is one of the most common chronic liver diseases, which encompasses a spectrum of diseases, from metabolic dysfunction-associated steatotic liver (MASL) to metabolic dysfunction-associated steatohepatitis (MASH), and may ultimately progress to MASH-related cirrhosis and hepatocellular carcinoma (HCC). MASLD is a complex disease that is influenced by genetic and environmental factors. Dysregulation of hepatic lipid metabolism plays a crucial role in the development and progression of MASLD. Therefore, the focus of this review is to discuss the links between the genetic variants and DNA methylation of lipid metabolism-related genes and MASLD pathogenesis. We first summarize the interplay between MASLD and the disturbance of hepatic lipid metabolism. Next, we focus on reviewing the role of hepatic lipid related gene loci in the onset and progression of MASLD. We summarize the existing literature around the single nucleotide polymorphisms (SNPs) associated with MASLD identified by genome-wide association studies (GWAS) and candidate gene analyses. Moreover, based on recent evidence from human and animal studies, we further discussed the regulatory function and associated mechanisms of changes in DNA methylation levels in the occurrence and progression of MASLD, with a particular emphasis on its regulatory role of lipid metabolism-related genes in MASLD and MASH. Furthermore, we review the alterations of hepatic DNA and blood DNA methylation levels associated with lipid metabolism-related genes in MASLD and MASH patients. Finally, we introduce potential value of the genetic variants and DNA methylation profiles of lipid metabolism-related genes in developing novel prognostic biomarkers and therapeutic targets for MASLD, intending to provide references for the future studies of MASLD.
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Affiliation(s)
- Jun-Jie Wang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Xiao-Yuan Chen
- Department of Publication Health and Health Management, Gannan Medical University, Ganzhou, China
| | - Yi-Rong Zhang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Yan Shen
- Department of Publication Health and Health Management, Gannan Medical University, Ganzhou, China
| | - Meng-Lin Zhu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Jun Zhang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Jun-Jie Zhang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
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Liu X, Chen S, Liu X, Wu X, Jiang X, Li Y, Yang Z. Enpp1 ameliorates MAFLD by regulating hepatocyte lipid metabolism through the AMPK/PPARα signaling pathway. Cell Biosci 2025; 15:22. [PMID: 39972484 PMCID: PMC11841222 DOI: 10.1186/s13578-025-01364-3] [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: 08/09/2024] [Accepted: 02/07/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the leading chronic liver disease globally, and there are no approved pharmacotherapies to treat this disease. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) has been found to be related to insulin resistance and lipid accumulation. However, the role and mechanism of Enpp1 in the development of MAFLD remain unknown. RESULTS Here we discovered that Enpp1 is lowly expressed in the liver of MAFLD patients by clinical investigation. Knocking out Enpp1 in the liver of mice aggravated obesity, insulin resistance and hepatic steatosis, and these effects were reversed by liver-specific Enpp1 overexpression. Through transcriptomic data mining and experimental validation, we demonstrated that Enpp1 deficiency inhibited the expression of AMPK (energy receptor) and PPARα (nuclear transcription factor for lipid metabolism), thereby promoting the transcription of lipid synthesis factors and mediating the progression of MAFLD. Mechanistically, Enpp1 enhanced the activity of AMPK by increasing the AMP-to-ATP ratio, which in turn raised PPARα levels and promoted the transcription of its downstream lipid metabolism factors. Pharmacological inhibition of AMPK activity abolished the promoting effect of Enpp1 on PPARα protein expression. CONCLUSIONS This study indicate that Enpp1 can effectively ameliorate MAFLD through effects on AMPK/PPARα signaling pathway-mediated lipid metabolism, revealing the significance of Enpp1 as a promising therapeutic target against MAFLD.
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Affiliation(s)
- Xiaohui Liu
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical College (PUMC), Beijing, 100021, China
| | - Shuai Chen
- Fuyang People's Hospital affiliated to Anhui Medical University, Fuyang, China
| | - Xing Liu
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical College (PUMC), Beijing, 100021, China
| | - Xianxian Wu
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical College (PUMC), Beijing, 100021, China
| | - Xiaoliang Jiang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical College (PUMC), Beijing, 100021, China
| | - Yuhan Li
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
| | - Zhiwei Yang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical College (PUMC), Beijing, 100021, China.
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Wu X, Zhang T, Park S. Dietary quality, perceived health, and psychological status as key risk factors for newly developed metabolic dysfunction-associated steatotic liver disease in a longitudinal study. Nutrition 2025; 130:112604. [PMID: 39549647 DOI: 10.1016/j.nut.2024.112604] [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: 06/15/2024] [Revised: 09/30/2024] [Accepted: 10/13/2024] [Indexed: 11/18/2024]
Abstract
OBJECTIVES This study investigated biomarkers in individuals with newly developed metabolic dysfunction-associated steatotic liver disease (ND-MASLD) and examined the interplay between genetic predisposition and environmental factors using a machine learning approach in a large longitudinal study. METHODS Participants were classified into four groups based on metabolic dysfunction-associated steatotic liver disease (MASLD) status between the first and second measurements with an approximate 5-y gap. A model was developed to identify early-stage biomarkers of ND-MASLD (n = 1603). Nutrient intake, dietary patterns, genetic variants, and psychosocial factors were compared among the no MASLD (n = 60 081), recovered MASLD (n = 3181), persistent MASLD (n = 670), and ND-MASLD (n = 1603) groups. Their association with ND-MASLD was also predicted using a machine learning approach. RESULTS The model incorporating ND-MASLD status, age, sex, dietary inflammatory index, and metabolic syndrome (MetS), especially low high-density lipoprotein cholesterol and hypertriglyceridemia, at the second measurement demonstrated an optimal fit. High carbohydrate intake with a high glycemic index was associated with elevated ND-MADSLD risk. Fatty liver index was lower in persistent MASLD followed by ND-MASLD, recovered MASLD, and no MASLD. Participants in the ND-MASLD group had lower vitamin D and total isoflavonoid intake and a lower modified healthy eating index, indicating unhealthy diets. The XGBoost and deep neural network models identified age, sex, MetS components, dietary antioxidants, self-rated health, psychological well-being indexes, and serum liver enzyme levels at the second measurement as significant predictors of ND-MASLD. However, polygenic risk scores were not included. CONCLUSIONS Early-stage biomarkers of ND-MASLD were closely linked to MetS incidence. Dietary quality, perceived health status, and psychological stress emerged as potential targets for MASLD prevention strategies, with lifestyle modifications potentially overriding genetic predispositions. The results indicate that preventive strategies about lifestyle modification should be developed for MASLD.
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Affiliation(s)
- Xuangao Wu
- Korea Department of Bioconvergence, Hoseo University, Asan, South Korea.
| | - Ting Zhang
- Korea Department of Bioconvergence, Hoseo University, Asan, South Korea.
| | - Sunmin Park
- Korea Department of Bioconvergence, Hoseo University, Asan, South Korea; Department of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, Asan, South Korea.
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Chen VL, Brady GF. Recent advances in MASLD genetics: Insights into disease mechanisms and the next frontiers in clinical application. Hepatol Commun 2025; 9:e0618. [PMID: 39774697 PMCID: PMC11717516 DOI: 10.1097/hc9.0000000000000618] [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: 11/05/2024] [Accepted: 11/14/2024] [Indexed: 01/11/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in the world and a growing cause of liver-related morbidity and mortality. Yet, at the same time, our understanding of the pathophysiology and genetic underpinnings of this increasingly common yet heterogeneous disease has increased dramatically over the last 2 decades, with the potential to lead to meaningful clinical interventions for patients. We have now seen the first pharmacologic therapy approved for the treatment of MASLD, and multiple other potential treatments are currently under investigation-including gene-targeted RNA therapies that directly extend from advances in MASLD genetics. Here we review recent advances in MASLD genetics, some of the key pathophysiologic insights that human genetics has provided, and the ways in which human genetics may inform our clinical practice in the field of MASLD in the near future.
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Moretti V, Romeo S, Valenti L. The contribution of genetics and epigenetics to MAFLD susceptibility. Hepatol Int 2024; 18:848-860. [PMID: 38662298 PMCID: PMC11450136 DOI: 10.1007/s12072-024-10667-5] [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: 01/11/2024] [Accepted: 02/25/2024] [Indexed: 04/26/2024]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide. The risk of developing MAFLD varies among individuals, due to a combination of environmental inherited and acquired genetic factors. Genome-wide association and next-generation sequencing studies are leading to the discovery of the common and rare genetic determinants of MAFLD. Thanks to the great advances in genomic technologies and bioinformatics analysis, genetic and epigenetic factors involved in the disease can be used to develop genetic risk scores specific for liver-related complications, which can improve risk stratification. Genetic and epigenetic factors lead to the identification of specific sub-phenotypes of MAFLD, and predict the individual response to a pharmacological therapy. Moreover, the variant transcripts and protein themselves represent new therapeutic targets. This review will discuss the current status of research into genetic as well as epigenetic modifiers of MAFLD development and progression.
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Affiliation(s)
- Vittoria Moretti
- Precision Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Via F Sforza 35, 20122, Milan, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Luca Valenti
- Precision Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Via F Sforza 35, 20122, Milan, Italy.
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
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Sun F, Wang J, Yang Y, Dong QQ, Jia L, Hu W, Tao H, Lu C, Yang JJ. Epitranscriptomic regulation of lipid oxidation and liver fibrosis via ENPP1 mRNA m 6A modification. Cell Mol Life Sci 2024; 81:387. [PMID: 39249529 PMCID: PMC11383905 DOI: 10.1007/s00018-024-05420-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 08/15/2024] [Accepted: 08/20/2024] [Indexed: 09/10/2024]
Abstract
BACKGROUND Dysregulated lipid oxidation occurs in several pathological processes characterized by cell proliferation and migration. Nonetheless, the molecular mechanism of lipid oxidation is not well appreciated in liver fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. METHODS We investigated the causes and consequences of lipid oxidation in liver fibrosis using cultured cells, animal models, and clinical samples. RESULTS Increased ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) expression caused increased lipid oxidation, resulting in the proliferation and migration of hepatic stellate cells (HSCs) that lead to liver fibrosis, whereas fibroblast-specific ENPP1 knockout reversing these results. Elevated ENPP1 and N6-methyladenosine (m6A) levels were associated with high expression of Wilms tumor 1 associated protein (WTAP). Mechanistically, WTAP-mediated m6A methylation of the 3'UTR of ENPP1 mRNA and induces its translation dependent of YTH domain family proteins 1 (YTHDF1). Additionally, ENPP1 could interact with hypoxia inducible lipid droplet associated (HILPDA) directly; overexpression of ENPP1 further recruits HILPDA-mediated lipid oxidation, thereby promotes HSCs proliferation and migration, while inhibition of ENPP1 expression produced the opposite effect. Clinically, increased expression of WTAP, YTHDF1, ENPP1, and HILPDA, and increased m6A mRNA content, enhanced lipid oxidation, and increased collagen deposition in human liver fibrosis tissues. CONCLUSIONS We describe a novel mechanism in which WTAP catalyzes m6A methylation of ENPP1 in a YTHDF1-dependent manner to enhance lipid oxidation, promoting HSCs proliferation and migration and liver fibrosis.
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Affiliation(s)
- Feng Sun
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Juan Wang
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yang Yang
- Department of General Surgery, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, 215153, China
| | - Qi-Qi Dong
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Lin Jia
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Wei Hu
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Hui Tao
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, People's Republic of China.
| | - Chao Lu
- First Affiliated Hospital, Anhui University of Science and Technology, Huainan, 232001, China.
| | - Jing-Jing Yang
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
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7
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Asadi A, Rostami M, Shafiee R, Ardalani A, Dehghanitafti A, Golshadi Z, Kohansal K, Ghasemi F, Najafi M, Mahmoudi T, Rezamand G, Dabiri R, Nobakht H, Farahani H, Tabaeian SP. Association of IRS1 gene Pro512Ala polymorphism with nonalcoholic fatty liver disease. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2024; 68:e230216. [PMID: 39420901 PMCID: PMC11460970 DOI: 10.20945/2359-4292-2023-0216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 10/02/2023] [Indexed: 10/19/2024]
Abstract
Objective This study was designed to investigate the possible effect of the insulin receptor substrate 1 (IRS1) gene rs1801276 polymorphism on the risk of nonalcoholic fatty liver disease (NAFLD). Subjects and methods The rs1801276 polymorphism was investigated in 127 controls and 123 biopsy-proven NAFLD patients using PCR-RFLP. Results No deviation from Hardy-Weinberg equilibrium was discovered for the rs1801276 variant of IRS1 in either NAFLD patients or controls (P>0.05). The distribution of different rs1801276 genotypes and alleles showed significant variations between controls and NAFLD patients. In comparison to rs1801276 'CC' genotype, the "GG+GC" genotype occurred less frequently in NAFLD patients than in controls, which also persisted after adjustment for confounding factors (P = 0.041, OR = 0.60, 95% CI = 0.45-0.93). In comparison with the IRS1 rs1801276 "C" allele, the "G" allele was significantly less prevalent in NAFLD patients than in controls (P = 0.045, OR = 0.69, 95% CI = 0.58-0.91). Conclusions For the first time, we reported a significant association between the IRS1 rs1801276 polymorphism and biopsy-proven NAFLD. More studies are required to further elucidate the contribution of the IRS1 gene to NAFLD susceptibility.
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Affiliation(s)
- Asadollah Asadi
- University of Mohaghegh ArdabiliFaculty of ScienceDepartment of BiologyArdabilIranDepartment of Biology, Faculty of Science, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Mitra Rostami
- Shahid Beheshti University of Medical SciencesResearch Institute for Gastroenterology and Liver DiseasesGastroenterology and Liver Diseases Research CenterTehranIranGastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Radmehr Shafiee
- Tehran UniversityFaculty of Veterinary MedicineDepartment of Clinical PathologyIranDepartment of Clinical Pathology, Faculty of Veterinary Medicine, Tehran University, Iran
| | - Abbas Ardalani
- Shahid Beheshti University of Medical SciencesResearch Institute for Gastroenterology and Liver DiseasesGastroenterology and Liver Diseases Research CenterTehranIranGastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atefeh Dehghanitafti
- Shahid Beheshti University of Medical SciencesResearch Institute for Gastroenterology and Liver DiseasesGastroenterology and Liver Diseases Research CenterTehranIranGastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zakieh Golshadi
- Shahid Beheshti University of Medical SciencesResearch Institute for Gastroenterology and Liver DiseasesGastroenterology and Liver Diseases Research CenterTehranIranGastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kiarash Kohansal
- Iran University of Medical SciencesPhysiology Research CenterTehranIranPhysiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ghasemi
- Shahid Beheshti University of Medical SciencesResearch Institute for Gastroenterology and Liver DiseasesGastroenterology and Liver Diseases Research CenterTehranIranGastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Najafi
- Shahid Beheshti University of Medical SciencesResearch Institute for Gastroenterology and Liver DiseasesGastroenterology and Liver Diseases Research CenterTehranIranGastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Touraj Mahmoudi
- Shahid Beheshti University of Medical SciencesResearch Institute for Gastroenterology and Liver DiseasesGastroenterology and Liver Diseases Research CenterTehranIranGastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Gholamreza Rezamand
- Iran University of Medical SciencesSchool of MedicineDepartment of Internal MedicineTehranIranDepartment of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Iran University of Medical SciencesColorectal Research CenterTehranIranColorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Dabiri
- Semnan University of Medical SciencesInternal Medicine DepartmentSemnanIranInternal Medicine Department, Semnan University of Medical Sciences, Semnan, Iran
| | - Hossein Nobakht
- Semnan University of Medical SciencesInternal Medicine DepartmentSemnanIranInternal Medicine Department, Semnan University of Medical Sciences, Semnan, Iran
| | - Hamid Farahani
- Qom University of Medical SciencesSchool of MedicineDepartment of Physiology and PharmacologyQomIranDepartment of Physiology and Pharmacology, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Seidamir Pasha Tabaeian
- Iran University of Medical SciencesSchool of MedicineDepartment of Internal MedicineTehranIranDepartment of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Iran University of Medical SciencesColorectal Research CenterTehranIranColorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
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Fan W, Bradford TM, Török NJ. Metabolic dysfunction-associated liver disease and diabetes: Matrix remodeling, fibrosis, and therapeutic implications. Ann N Y Acad Sci 2024; 1538:21-33. [PMID: 38996214 DOI: 10.1111/nyas.15184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/14/2024]
Abstract
Metabolic dysfunction-associated liver disease (MASLD) and steatohepatitis (MASH) are becoming the most common causes of chronic liver disease in the United States and worldwide due to the obesity and diabetes epidemics. It is estimated that by 2030 close to 100 million people might be affected and patients with type 2 diabetes are especially at high risk. Twenty to 30% of patients with MASLD can progress to MASH, which is characterized by steatosis, necroinflammation, hepatocyte ballooning, and in advanced cases, fibrosis progressing to cirrhosis. Clinically, it is recognized that disease progression in diabetic patients is accelerated and the role of various genetic and epigenetic factors, as well as cell-matrix interactions in fibrosis and stromal remodeling, have recently been recognized. While there has been great progress in drug development and clinical trials for MASLD/MASH, the complexity of these pathways highlights the need to improve diagnosis/early detection and develop more successful antifibrotic therapies that not only prevent but reverse fibrosis.
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Affiliation(s)
- Weiguo Fan
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
- Palo Alto VA Medical Center, Palo Alto, California, USA
| | - Toby M Bradford
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
| | - Natalie J Török
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
- Palo Alto VA Medical Center, Palo Alto, California, USA
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Portincasa P, Khalil M, Mahdi L, Perniola V, Idone V, Graziani A, Baffy G, Di Ciaula A. Metabolic Dysfunction-Associated Steatotic Liver Disease: From Pathogenesis to Current Therapeutic Options. Int J Mol Sci 2024; 25:5640. [PMID: 38891828 PMCID: PMC11172019 DOI: 10.3390/ijms25115640] [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: 04/02/2024] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
The epidemiological burden of liver steatosis associated with metabolic diseases is continuously growing worldwide and in all age classes. This condition generates possible progression of liver damage (i.e., inflammation, fibrosis, cirrhosis, hepatocellular carcinoma) but also independently increases the risk of cardio-metabolic diseases and cancer. In recent years, the terminological evolution from "nonalcoholic fatty liver disease" (NAFLD) to "metabolic dysfunction-associated fatty liver disease" (MAFLD) and, finally, "metabolic dysfunction-associated steatotic liver disease" (MASLD) has been paralleled by increased knowledge of mechanisms linking local (i.e., hepatic) and systemic pathogenic pathways. As a consequence, the need for an appropriate classification of individual phenotypes has been oriented to the investigation of innovative therapeutic tools. Besides the well-known role for lifestyle change, a number of pharmacological approaches have been explored, ranging from antidiabetic drugs to agonists acting on the gut-liver axis and at a systemic level (mainly farnesoid X receptor (FXR) agonists, PPAR agonists, thyroid hormone receptor agonists), anti-fibrotic and anti-inflammatory agents. The intrinsically complex pathophysiological history of MASLD makes the selection of a single effective treatment a major challenge, so far. In this evolving scenario, the cooperation between different stakeholders (including subjects at risk, health professionals, and pharmaceutical industries) could significantly improve the management of disease and the implementation of primary and secondary prevention measures. The high healthcare burden associated with MASLD makes the search for new, effective, and safe drugs a major pressing need, together with an accurate characterization of individual phenotypes. Recent and promising advances indicate that we may soon enter the era of precise and personalized therapy for MASLD/MASH.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.K.); (L.M.); (V.P.); (V.I.); (A.D.C.)
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.K.); (L.M.); (V.P.); (V.I.); (A.D.C.)
| | - Laura Mahdi
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.K.); (L.M.); (V.P.); (V.I.); (A.D.C.)
| | - Valeria Perniola
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.K.); (L.M.); (V.P.); (V.I.); (A.D.C.)
| | - Valeria Idone
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.K.); (L.M.); (V.P.); (V.I.); (A.D.C.)
- Aboca S.p.a. Società Agricola, 52037 Sansepolcro, Italy
| | - Annarita Graziani
- Institut AllergoSan Pharmazeutische Produkte Forschungs- und Vertriebs GmbH, 8055 Graz, Austria;
| | - Gyorgy Baffy
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
- Section of Gastroenterology, Department of Medicine, VA Boston Healthcare System, Boston, MA 02132, USA
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.K.); (L.M.); (V.P.); (V.I.); (A.D.C.)
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10
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Kokkorakis M, Muzurović E, Volčanšek Š, Chakhtoura M, Hill MA, Mikhailidis DP, Mantzoros CS. Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies. Pharmacol Rev 2024; 76:454-499. [PMID: 38697855 DOI: 10.1124/pharmrev.123.001087] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/22/2023] [Accepted: 01/25/2024] [Indexed: 05/05/2024] Open
Abstract
Steatotic liver disease (SLD) displays a dynamic and complex disease phenotype. Consequently, the metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) therapeutic pipeline is expanding rapidly and in multiple directions. In parallel, noninvasive tools for diagnosing and monitoring responses to therapeutic interventions are being studied, and clinically feasible findings are being explored as primary outcomes in interventional trials. The realization that distinct subgroups exist under the umbrella of SLD should guide more precise and personalized treatment recommendations and facilitate advancements in pharmacotherapeutics. This review summarizes recent updates of pathophysiology-based nomenclature and outlines both effective pharmacotherapeutics and those in the pipeline for MASLD/MASH, detailing their mode of action and the current status of phase 2 and 3 clinical trials. Of the extensive arsenal of pharmacotherapeutics in the MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, have shown only marginal benefits and are now being tested as part of combination therapies, yet others are still in development as monotherapies. Although the Food and Drug Administration (FDA) has recently approved resmetirom, additional therapeutic approaches in development will ideally target MASH and fibrosis while improving cardiometabolic risk factors. Due to the urgent need for the development of novel therapeutic strategies and the potential availability of safety and tolerability data, repurposing existing and approved drugs is an appealing option. Finally, it is essential to highlight that SLD and, by extension, MASLD should be recognized and approached as a systemic disease affecting multiple organs, with the vigorous implementation of interdisciplinary and coordinated action plans. SIGNIFICANCE STATEMENT: Steatotic liver disease (SLD), including metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, is the most prevalent chronic liver condition, affecting more than one-fourth of the global population. This review aims to provide the most recent information regarding SLD pathophysiology, diagnosis, and management according to the latest advancements in the guidelines and clinical trials. Collectively, it is hoped that the information provided furthers the understanding of the current state of SLD with direct clinical implications and stimulates research initiatives.
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Affiliation(s)
- Michail Kokkorakis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Emir Muzurović
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Špela Volčanšek
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Marlene Chakhtoura
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Michael A Hill
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Dimitri P Mikhailidis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
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Mahmoudi SK, Tarzemani S, Aghajanzadeh T, Kasravi M, Hatami B, Zali MR, Baghaei K. Exploring the role of genetic variations in NAFLD: implications for disease pathogenesis and precision medicine approaches. Eur J Med Res 2024; 29:190. [PMID: 38504356 PMCID: PMC10953212 DOI: 10.1186/s40001-024-01708-8] [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: 06/10/2023] [Accepted: 02/01/2024] [Indexed: 03/21/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver diseases, affecting more than one-quarter of people worldwide. Hepatic steatosis can progress to more severe forms of NAFLD, including NASH and cirrhosis. It also may develop secondary diseases such as diabetes and cardiovascular disease. Genetic and environmental factors regulate NAFLD incidence and progression, making it a complex disease. The contribution of various environmental risk factors, such as type 2 diabetes, obesity, hyperlipidemia, diet, and sedentary lifestyle, to the exacerbation of liver injury is highly understood. Nevertheless, the underlying mechanisms of genetic variations in the NAFLD occurrence or its deterioration still need to be clarified. Hence, understanding the genetic susceptibility to NAFLD is essential for controlling the course of the disease. The current review discusses genetics' role in the pathological pathways of NAFLD, including lipid and glucose metabolism, insulin resistance, cellular stresses, and immune responses. Additionally, it explains the role of the genetic components in the induction and progression of NAFLD in lean individuals. Finally, it highlights the utility of genetic knowledge in precision medicine for the early diagnosis and treatment of NAFLD patients.
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Affiliation(s)
- Seyedeh Kosar Mahmoudi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985714711, Iran
| | - Shadi Tarzemani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985714711, Iran
| | - Taha Aghajanzadeh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985714711, Iran.
| | - Mohammadreza Kasravi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985714711, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985714711, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985714711, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985714711, Iran.
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985714711, Iran.
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Wattacheril J, Kleinstein SE, Shea PR, Wilson LA, Subramanian GM, Myers RP, Lefkowitch J, Behling C, Xanthakos SA, Goldstein DB. Investigating the Relationship Between Rare Genetic Variants and Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.03.02.24303632. [PMID: 38496563 PMCID: PMC10942529 DOI: 10.1101/2024.03.02.24303632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Background and Aims Nonalcoholic Fatty Liver Disease (NAFLD) is a complex human disease. Common genetic variation in the patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes have been associated with an increased risk of developing NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis in adults. The role of rare genetic variants in the development and progression of NAFLD in children is not well known. We aimed to explore the role of rare genetic variants in pediatric patients with advanced fibrosis. Methods Whole exome sequencing data was generated for 229 pediatric patients diagnosed with NAFLD recruited from the NASH Clinical Research Network (NASH CRN). Case-control single variant and gene-based collapsing analyses were used to test for rare variants that were enriched or depleted within the pediatric NAFLD cohort specifically for advanced fibrosis (cases) versus those without fibrosis (controls) or six other histologic characteristics. Exome data from non-NAFLD population controls were also used for additional analyses. All results were adjusted for multiple testing using a Bonferroni correction. Results No genome-wide significant associations were found between rare variation and presence of advanced fibrosis or NASH, nor the severity of steatosis, inflammation, or hepatocellular ballooning. Significantly, no enrichment of rare variants in PNPLA3 or TM6SF2 was observed across phenotypes. Conclusion In a cohort of children with histologically proven NAFLD, no genome-wide significant associations were found between rare genetic variation and advanced fibrosis or six other histologic features. Of particular interest was the lack of association with genes of interest in adults: PNPLA3 and TM6SF2, though limitations in sample size may reduce the ability to detect associations, particularly with rare variation.
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Affiliation(s)
- Julia Wattacheril
- Columbia University Vagelos College of Physicians and Surgeons, Department of Medicine, Center for Liver Disease and Transplantation, New York Presbyterian Hospital
| | - Sarah E. Kleinstein
- Columbia University Vagelos College of Physicians and Surgeons, Institute for Genomic Medicine
| | - Patrick R. Shea
- Columbia University Vagelos College of Physicians and Surgeons, Institute for Genomic Medicine
| | | | | | | | - Jay Lefkowitch
- Columbia University Vagelos College of Physicians and Surgeons, Department of Pathology
| | | | - Stavra A. Xanthakos
- Department of Pediatrics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center
| | - David B. Goldstein
- Columbia University Vagelos College of Physicians and Surgeons, Institute for Genomic Medicine
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Zuo Q, Park NH, Lee JK, Santaliz-Casiano A, Madak-Erdogan Z. Navigating nonalcoholic fatty liver disease (NAFLD): Exploring the roles of estrogens, pharmacological and medical interventions, and life style. Steroids 2024; 203:109330. [PMID: 37923152 DOI: 10.1016/j.steroids.2023.109330] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/28/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023]
Abstract
The pursuit of studying this subject is driven by the urgency to address the increasing global prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) and its profound health implications. NAFLD represents a significant public health concern due to its association with metabolic disorders, cardiovascular complications, and the potential progression to more severe conditions like non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Liver estrogen signaling is important for maintaining liver function, and loss of estrogens increases the likelihood of NAFLD in postmenopausal women. Understanding the multifaceted mechanisms underlying NAFLD pathogenesis, its varied treatment strategies, and their effectiveness is crucial for devising comprehensive and targeted interventions. By unraveling the intricate interplay between genetics, lifestyle, hormonal regulation, and gut microbiota, we can unlock insights into risk stratification, early detection, and personalized therapeutic approaches. Furthermore, investigating the emerging pharmaceutical interventions and dietary modifications offers the potential to revolutionize disease management. This review reinforces the role of collaboration in refining NAFLD comprehension, unveiling novel therapeutic pathways, and ultimately improving patient outcomes for this intricate hepatic condition.
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Affiliation(s)
- Qianying Zuo
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
| | - Nicole Hwajin Park
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
| | - Jenna Kathryn Lee
- Department of Neuroscience, Northwestern University, Evanston, IL 60208, USA
| | - Ashlie Santaliz-Casiano
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
| | - Zeynep Madak-Erdogan
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute of Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
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Soto A, Spongberg C, Martinino A, Giovinazzo F. Exploring the Multifaceted Landscape of MASLD: A Comprehensive Synthesis of Recent Studies, from Pathophysiology to Organoids and Beyond. Biomedicines 2024; 12:397. [PMID: 38397999 PMCID: PMC10886580 DOI: 10.3390/biomedicines12020397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/04/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a widespread contributor to chronic liver disease globally. A recent consensus on renaming liver disease was established, and metabolic dysfunction-associated steatotic liver disease, MASLD, was chosen as the replacement for NAFLD. The disease's range extends from the less severe MASLD, previously known as non-alcoholic fatty liver (NAFL), to the more intense metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH), characterized by inflammation and apoptosis. This research project endeavors to comprehensively synthesize the most recent studies on MASLD, encompassing a wide spectrum of topics such as pathophysiology, risk factors, dietary influences, lifestyle management, genetics, epigenetics, therapeutic approaches, and the prospective trajectory of MASLD, particularly exploring its connection with organoids.
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Affiliation(s)
- Allison Soto
- Department of Surgery, University of Illinois College of Medicine, Chicago, IL 60607, USA;
| | - Colby Spongberg
- Touro College of Osteopathic Medicine, Great Falls, MT 59405, USA
| | | | - Francesco Giovinazzo
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
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Jiang H, Zang L. GLP-1/GLP-1RAs: New Options for the Drug Treatment of NAFLD. Curr Pharm Des 2024; 30:100-114. [PMID: 38532322 DOI: 10.2174/0113816128283153231226103218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 12/14/2023] [Indexed: 03/28/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a global public health concern. Currently, the cornerstone of NAFLD treatment is lifestyle modification and, if necessary, weight loss. However, compliance is a challenge, and this approach alone may not be sufficient to halt and treat the more serious disease development, so medication is urgently needed. Nevertheless, no medicines are approved to treat NAFLD. Glucagon-like peptide-1 (GLP-1) is an enteropeptide hormone that inhibits glucagon synthesis, promotes insulin secretion, and delays gastric emptying. GLP-1 has been found in recent studies to be beneficial for the management of NAFLD, and the marketed GLP-1 agonist drugs have different degrees of effectiveness for NAFLD while lowering blood glucose. In this article, we review GLP-1 and its physiological roles, the pathogenesis of NAFLD, the correlation between NAFLD and GLP-1 signaling, and potential strategies for GLP-1 treatment of NAFLD.
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Affiliation(s)
- Haoran Jiang
- Laboratory of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Linquan Zang
- Laboratory of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
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Sangro P, de la Torre Aláez M, Sangro B, D'Avola D. Metabolic dysfunction-associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment. J Physiol Biochem 2023; 79:869-879. [PMID: 36976456 PMCID: PMC10635944 DOI: 10.1007/s13105-023-00954-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 02/28/2023] [Indexed: 03/29/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is nowadays considered the liver manifestation of metabolic syndrome. Its prevalence is increasing worldwide in parallel to the epidemic of diabetes and obesity. MAFLD includes a wide spectrum of liver injury including simple steatosis and non-alcoholic steatohepatitis (NASH) that may lead to serious complications such as liver cirrhosis and liver cancer. The complexity of its pathophysiology and the intricate mechanisms underlying disease progression explains the huge variety of molecules targeting diverse biological mechanisms that have been tested in preclinical and clinical settings in the last two decades. Thanks to the large number of clinical trials of the last few years, most of them still ongoing, the pharmacotherapy scenario of MAFLD is rapidly evolving. The three major components of MAFLD, steatosis, inflammation, and fibrosis seem to be safely targeted with different agents at least in a large proportion of patients. Likely, in the next few years more than one drug will be approved for the treatment of MAFLD at different disease stages. The aim of this review is to synthesize the characteristics and the results of the most advanced clinical trials for the treatment of NASH to evaluate the recent advances of pharmacotherapy in this disease.
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Affiliation(s)
- Paloma Sangro
- Liver Unit Clínica, Universidad de Navarra, Madrid, Spain.
| | | | - Bruno Sangro
- Liver Unit Clínica, Universidad de Navarra, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Pamplona, Spain
| | - Delia D'Avola
- Liver Unit Clínica, Universidad de Navarra, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Pamplona, Spain
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Takahashi Y, Dungubat E, Kusano H, Fukusato T. Pathology and Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatic Tumors. Biomedicines 2023; 11:2761. [PMID: 37893134 PMCID: PMC10604511 DOI: 10.3390/biomedicines11102761] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/02/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the livers of patients without a history of alcohol abuse. It is classified as either simple steatosis (nonalcoholic fatty liver) or nonalcoholic steatohepatitis (NASH), which can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, it was suggested that the terms "metabolic dysfunction-associated steatotic liver disease (MASLD)" and "metabolic dysfunction-associated steatohepatitis (MASH)" should replace the terms "nonalcoholic fatty liver disease (NAFLD)" and "nonalcoholic steatohepatitis (NASH)", respectively, with small changes in the definitions. MASLD, a hepatic manifestation of metabolic syndrome, is rapidly increasing in incidence globally, and is becoming an increasingly important cause of HCC. Steatohepatitic HCC, a histological variant of HCC, is characterized by its morphological features resembling non-neoplastic steatohepatitis and is closely associated with underlying steatohepatitis and metabolic syndrome. Variations in genes including patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), and membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) are associated with the natural history of MASLD, including HCC development. The mechanisms of HCC development in MASLD have not been fully elucidated; however, various factors, including lipotoxicity, inflammation, reactive oxygen species, insulin resistance, and alterations in the gut bacterial flora, are important in the pathogenesis of MASLD-associated HCC. Obesity and MASLD are also recognized as risk factors for hepatocellular adenomas, and recent meta-analyses have shown an association between MASLD and intrahepatic cholangiocarcinoma. In this review, we outline the pathology and pathogenesis of MASLD-associated liver tumors.
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Affiliation(s)
- Yoshihisa Takahashi
- Department of Pathology, School of Medicine, International University of Health and Welfare, Narita 286-8686, Japan; (E.D.); (H.K.)
| | - Erdenetsogt Dungubat
- Department of Pathology, School of Medicine, International University of Health and Welfare, Narita 286-8686, Japan; (E.D.); (H.K.)
- Department of Pathology, School of Biomedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia
| | - Hiroyuki Kusano
- Department of Pathology, School of Medicine, International University of Health and Welfare, Narita 286-8686, Japan; (E.D.); (H.K.)
| | - Toshio Fukusato
- General Medical Education and Research Center, Teikyo University, Tokyo 173-8605, Japan;
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Chen Y, Du X, Kuppa A, Feitosa MF, Bielak LF, O'Connell JR, Musani SK, Guo X, Kahali B, Chen VL, Smith AV, Ryan KA, Eirksdottir G, Allison MA, Bowden DW, Budoff MJ, Carr JJ, Chen YDI, Taylor KD, Oliveri A, Correa A, Crudup BF, Kardia SLR, Mosley TH, Norris JM, Terry JG, Rotter JI, Wagenknecht LE, Halligan BD, Young KA, Hokanson JE, Washko GR, Gudnason V, Province MA, Peyser PA, Palmer ND, Speliotes EK. Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease. Nat Genet 2023; 55:1640-1650. [PMID: 37709864 PMCID: PMC10918428 DOI: 10.1038/s41588-023-01497-6] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 08/07/2023] [Indexed: 09/16/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.
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Affiliation(s)
- Yanhua Chen
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Xiaomeng Du
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Annapurna Kuppa
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Mary F Feitosa
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
| | - Lawrence F Bielak
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Jeffrey R O'Connell
- Department of Endocrinology, Diabetes and Nutrition, University of Maryland - Baltimore, Baltimore, MD, USA
| | - Solomon K Musani
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
| | - Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Bratati Kahali
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
- Centre for Brain Research, Indian Institute of Science, Bangalore, India
| | - Vincent L Chen
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Albert V Smith
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Kathleen A Ryan
- Department of Endocrinology, Diabetes and Nutrition, University of Maryland - Baltimore, Baltimore, MD, USA
| | | | - Matthew A Allison
- Department of Family Medicine, University of California San Diego, San Diego, CA, USA
| | - Donald W Bowden
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Matthew J Budoff
- Department of Internal Medicine, Lundquist Institute at Harbor-UCLA, Torrance, CA, USA
| | - John Jeffrey Carr
- Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Yii-Der I Chen
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Kent D Taylor
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Antonino Oliveri
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Adolfo Correa
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
| | - Breland F Crudup
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
| | - Sharon L R Kardia
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Thomas H Mosley
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
| | - Jill M Norris
- Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA
| | - James G Terry
- Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Lynne E Wagenknecht
- Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Brian D Halligan
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Kendra A Young
- Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA
| | - John E Hokanson
- Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA
| | - George R Washko
- Department of Medicine, Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA
| | - Vilmundur Gudnason
- Icelandic Heart Association, Kopavogur, Iceland
- Department of Medicine, University of Iceland, Reykjavik, Iceland
| | - Michael A Province
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
| | - Patricia A Peyser
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Nicholette D Palmer
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Elizabeth K Speliotes
- Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
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Samarasinghe SM, Hewage AS, Siriwardana RC, Tennekoon KH, Niriella MA, De Silva S. Genetic and metabolic aspects of non-alcoholic fatty liver disease (NAFLD) pathogenicity. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2023; 24:53. [DOI: 10.1186/s43042-023-00433-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 08/21/2023] [Indexed: 01/03/2025] Open
Abstract
Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease showing a rising prevalence globally. Genetic predisposition plays a key role in the development and progression of the disease pathogenicity.
Main body
This paper summarizes genetic associations based on their influence on several metabolic aspects such as lipid metabolism, glucose metabolism, hepatic iron accumulation and cholesterol metabolism toward the NAFLD pathogenicity. Furthermore, we present variations in some epigenetic characters and the microRNA profile with regard to NAFLD.
Conclusion
As reported in many studies, the PNPLA3 rs738409 variant seems to be significantly associated with NAFLD susceptibility. Other gene variants like TM6SF2 rs58542926, MBOAT7 rs641738 and GCKR variants also appear to be more prevalent among NAFLD patients. We believe these genetic variants may provide insights into new trends in developing noninvasive biomarkers and identify their suitability in clinical practice in the future.
Graphical abstract
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Khalifa O, Ouararhni K, Errafii K, Alajez NM, Arredouani A. Targeted MicroRNA Profiling Reveals That Exendin-4 Modulates the Expression of Several MicroRNAs to Reduce Steatosis in HepG2 Cells. Int J Mol Sci 2023; 24:11606. [PMID: 37511368 PMCID: PMC10380891 DOI: 10.3390/ijms241411606] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 06/25/2023] [Accepted: 07/03/2023] [Indexed: 07/30/2023] Open
Abstract
Excess hepatic lipid accumulation is the hallmark of non-alcoholic fatty liver disease (NAFLD), for which no medication is currently approved. However, glucagon-like peptide-1 receptor agonists (GLP-1RAs), already approved for treating type 2 diabetes, have lately emerged as possible treatments. Herein we aim to investigate how the GLP-1RA exendin-4 (Ex-4) affects the microRNA (miRNAs) expression profile using an in vitro model of steatosis. Total RNA, including miRNAs, was isolated from control, steatotic, and Ex-4-treated steatotic cells and used for probing a panel of 799 highly curated miRNAs using NanoString technology. Enrichment pathway analysis was used to find the signaling pathways and cellular functions associated with the differentially expressed miRNAs. Our data shows that Ex-4 reversed the expression of a set of miRNAs. Functional enrichment analysis highlighted many relevant signaling pathways and cellular functions enriched in the differentially expressed miRNAs, including hepatic fibrosis, insulin receptor, PPAR, Wnt/β-Catenin, VEGF, and mTOR receptor signaling pathways, fibrosis of the liver, cirrhosis of the liver, proliferation of hepatic stellate cells, diabetes mellitus, glucose metabolism disorder and proliferation of liver cells. Our findings suggest that miRNAs may play essential roles in the processes driving steatosis reduction in response to GLP-1R agonists, which warrants further functional investigation.
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Affiliation(s)
- Olfa Khalifa
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar
| | - Khalid Ouararhni
- Genomics Core Facility, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar
| | - Khaoula Errafii
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco
| | - Nehad M Alajez
- Translational Cancer and Immunity Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar
- College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar
| | - Abdelilah Arredouani
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar
- College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar
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Yamamoto R, Takeshita Y, Tsujiguchi H, Kannon T, Sato T, Hosomichi K, Suzuki K, Kita Y, Tanaka T, Goto H, Nakano Y, Yamashita T, Kaneko S, Tajima A, Nakamura H, Takamura T. Nutrigenetic interaction between apolipoprotein C3 polymorphism and fat intake in people with non-alcoholic fatty liver disease. Curr Dev Nutr 2023. [DOI: 10.1016/j.cdnut.2023.100051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2023] Open
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22
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Sabzikarian M, Mahmoudi T, Tabaeian SP, Rezamand G, Asadi A, Farahani H, Nobakht H, Dabiri R, Mansour-Ghanaei F, Derakhshan F, Zali MR. The common variant of rs6214 in insulin like growth factor 1 ( IGF1) gene: a potential protective factor for non-alcoholic fatty liver disease. Arch Physiol Biochem 2023; 129:10-15. [PMID: 32654522 DOI: 10.1080/13813455.2020.1791187] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE Regarding the central role of insulin resistance in NAFLD, we explored whether insulin-like growth factor 1 (IGF1) and insulin-like growth factor-binding protein 3 (IGFBP3) gene variants were associated with NAFLD susceptibility. METHODS IGF1 (rs6214) and IGFBP3 (rs3110697) gene variants were genotyped in 154 cases with biopsy-proven NAFLD and 156 controls using PCR-RFLP method. RESULTS The IGF1 rs6214 "AA + AG" genotype compared with the "GG" genotype appeared to be a marker of decreased NAFLD susceptibility (p = .006; OR = 0.47, 95%CI = 0.28-0.80). Furthermore, the IGF1 rs6214 "A" allele was underrepresented in the cases than controls (p = .024; OR = 0.61, 95%CI = 0.40-0.94). However, we observed no significant difference in genotype or allele frequencies between the cases and controls for IGFBP3 gene. CONCLUSIONS To our knowledge, these findings suggest, for the first time, that the IGF1 rs6214 "A" allele and "AA + AG" genotype have protective effects for NAFLD susceptibility. Nonetheless, further studies are needed to validate our findings.
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Affiliation(s)
| | - Touraj Mahmoudi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Gholamreza Rezamand
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Asadollah Asadi
- Department of Biology, Faculty of Science, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Hamid Farahani
- Department of Physiology and Pharmacology, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Hossein Nobakht
- Internal Medicine Department, Semnan University of Medical Sciences, Semnan, Iran
| | - Reza Dabiri
- Internal Medicine Department, Semnan University of Medical Sciences, Semnan, Iran
| | - Fariborz Mansour-Ghanaei
- Division of Gastroenterology and Hepatology, Gastrointestinal and Liver Diseases Research Center (GLDRC), Guilan University of Medical Sciences, Rasht, Iran
| | - Faramarz Derakhshan
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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23
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Suceveanu AI, Micu SI, Stoian AP, Mazilu L, Gherghina V, Parepa IR, Suceveanu AP. Genetics and Epigenetics in Nonalcoholic Fatty Liver Disease. ESSENTIALS OF NON-ALCOHOLIC FATTY LIVER DISEASE 2023:59-71. [DOI: 10.1007/978-3-031-33548-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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24
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Shah PA, Patil R, Harrison SA. NAFLD-related hepatocellular carcinoma: The growing challenge. Hepatology 2023; 77:323-338. [PMID: 35478412 PMCID: PMC9970023 DOI: 10.1002/hep.32542] [Citation(s) in RCA: 117] [Impact Index Per Article: 58.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality and morbidity worldwide. With the obesity pandemic, NAFLD-related HCC is contributing to the burden of disease exponentially. Genetic predisposition and clinical risk factors for NAFLD-related HCC have been identified. Cirrhosis is a well-known and major risk factor for NAFLD-related HCC. However, the occurrence of NAFLD-related HCC in patients without cirrhosis is increasingly recognized and poses a significant challenge regarding cancer surveillance. It is of paramount importance to develop optimal risk stratification scores and models to identify subsets of the population at high risk so they can be enrolled in surveillance programs. In this review, we will discuss the risks and prediction models for NAFLD-related HCC.
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Affiliation(s)
- Pir Ahmad Shah
- Department of Internal Medicine, University of Texas Health Science Center, San Antonio, Texas, USA
| | - Rashmee Patil
- South Texas Research Institute, Edinburg, Texas, USA
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25
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Prieto Ortíz JE, Sánchez Luque CB, Ortega Quiróz RJ. Hígado graso (parte 1): aspectos generales, epidemiología, fisiopatología e historia natural. REVISTA COLOMBIANA DE GASTROENTEROLOGÍA 2022; 37:420-433. [DOI: 10.22516/25007440.952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
El hígado graso no alcohólico (NAFLD) se define por la presencia de grasa o esteatosis en los hepatocitos y abarca un espectro que va desde la esteatosis simple, pasa por la esteatohepatitis no alcohólica (NASH) con inflamación y fibrosis, y finaliza en la cirrosis. Se considera una prevalencia mundial global cercana al 25% en la población general y se diagnóstica entre los 40 y 50 años, con variaciones respecto al sexo predominante y con diferencias étnicas (la población hispana es la más afectada). El hígado graso está asociado al síndrome metabólico (SM), y la obesidad se considera el principal factor de riesgo con su presencia y con su progresión.
El hígado graso es un trastorno complejo y muy heterogéneo en su fisiopatología, que resulta de la interacción de múltiples elementos: factores genéticos, epigenéticos, ambientales, culturales, entre otros. Todo ello en conjunto lleva a incremento paulatino de grasa hepática, resistencia a la insulina y alteraciones hormonales y de la microbiota intestinal, lo que genera un daño hepatocelular a través de la formación de radicales libres de oxígeno y activación de la fibrogénesis hepática.
La historia natural del hígado graso es dinámica: los pacientes con esteatosis simple tienen bajo riesgo de progresión a cirrosis, mientras que en los pacientes con NASH este riesgo se aumenta; sin embargo, el proceso puede ser reversible y algunas personas tendrán una mejoría espontánea. La fibrosis parece ser el determinante de la mortalidad global y de los desenlaces asociados a la enfermedad hepática; se considera que en todos los pacientes la fibrosis empeora una etapa cada 14 años y en NASH empeora en una etapa cada 7 años. Estudios previos concluyen que aproximadamente 20% de los casos de esteatosis simple progresan a NASH y que, de ellos, aproximadamente el 20% progresan a cirrosis, con presencia de hepatocarcinoma (HCC) en el 5% a 10% de ellos.
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26
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Josloff K, Beiriger J, Khan A, Gawel RJ, Kirby RS, Kendrick AD, Rao AK, Wang RX, Schafer MM, Pearce ME, Chauhan K, Shah YB, Marhefka GD, Halegoua-DeMarzio D. Comprehensive Review of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease. J Cardiovasc Dev Dis 2022; 9:419. [PMID: 36547416 PMCID: PMC9786069 DOI: 10.3390/jcdd9120419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 11/16/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) is a growing global phenomenon, and its damaging effects in terms of cardiovascular disease (CVD) risk are becoming more apparent. NAFLD is estimated to affect around one quarter of the world population and is often comorbid with other metabolic disorders including diabetes mellitus, hypertension, coronary artery disease, and metabolic syndrome. In this review, we examine the current evidence describing the many ways that NAFLD itself increases CVD risk. We also discuss the emerging and complex biochemical relationship between NAFLD and its common comorbid conditions, and how they coalesce to increase CVD risk. With NAFLD's rising prevalence and deleterious effects on the cardiovascular system, a complete understanding of the disease must be undertaken, as well as effective strategies to prevent and treat its common comorbid conditions.
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Affiliation(s)
- Kevan Josloff
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Jacob Beiriger
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Adnan Khan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard J. Gawel
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard S. Kirby
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Aaron D. Kendrick
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Abhinav K. Rao
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Roy X. Wang
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Michelle M. Schafer
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Margaret E. Pearce
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Kashyap Chauhan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Yash B. Shah
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Gregary D. Marhefka
- Department of Internal Medicine, Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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27
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Pansa CC, Molica LR, Moraes KCM. Non-alcoholic fatty liver disease establishment and progression: genetics and epigenetics as relevant modulators of the pathology. Scand J Gastroenterol 2022; 58:521-533. [PMID: 36426638 DOI: 10.1080/00365521.2022.2148835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) results from metabolic dysfunctions that affect more than one-third of the world population. Over the last decades, scientific investigations have clarified many details on the pathology establishment and development; however, effective therapeutics approaches are still evasive. In addition, studies demonstrated that NAFLD establishment and progression are related to several etiologies. Recently, genetics and epigenetics backgrounds have emerged as relevant elements to the pathology onset, and, hence, deserve deep investigation to clarify molecular details on NAFLD signaling, which may be correlated with population behavior. Thus, to minimize the global problem, public health and public policies should take advantage of studies on NAFLD over the next following decades. METHODS In this context, we have performed a selective literature review focusing on biochemistry of lipid metabolism, genetics, epigenetics, and the ethnicity as strong elements that drive NAFLD establishment. RESULTS Considering the etiological agents that acts on NAFLD development and progression, the genetics and the epigenetics emerged as relevant factors. Genetics acts as a powerful element in the establishment and progression of the NAFLD. Over the last decades, details concerning genes and their polymorphisms, as well as epigenetics, have been considered relevant elements in the systems biology of diseases, and their effects on NAFLD should be considered in-depth, as well as the ethnicity, clarifying whether people are susceptible to liver diseases. Moreover, the endemicity and social problems of hepatic disfunction are far to be solved, which require a combined effort of various sectors of society. CONCLUSION Hence, the elements presented and discussed in this short review demonstrated their relevance to the physiological control of NAFLD, opening perspectives for research to develop new strategy to treat fatty liver diseases.
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Affiliation(s)
- Camila Cristiane Pansa
- Departamento de Biologia Geral e Aplicada, Cellular Signalling and Gene Expression Laboratory, Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências, Rio Claro, Brazil
| | - Letícia Ramos Molica
- Departamento de Biologia Geral e Aplicada, Cellular Signalling and Gene Expression Laboratory, Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências, Rio Claro, Brazil
| | - Karen C M Moraes
- Departamento de Biologia Geral e Aplicada, Cellular Signalling and Gene Expression Laboratory, Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências, Rio Claro, Brazil
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28
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Creeden JF, Kipp ZA, Xu M, Flight RM, Moseley HNB, Martinez GJ, Lee W, Alganem K, Imami AS, McMullen MR, Roychowdhury S, Nawabi AM, Hipp JA, Softic S, Weinman SA, McCullumsmith R, Nagy LE, Hinds TD. Hepatic kinome atlas: An in-depth identification of kinase pathways in liver fibrosis of humans and rodents. Hepatology 2022; 76:1376-1388. [PMID: 35313030 PMCID: PMC9489820 DOI: 10.1002/hep.32467] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/02/2022] [Accepted: 03/12/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Resolution of pathways that converge to induce deleterious effects in hepatic diseases, such as in the later stages, have potential antifibrotic effects that may improve outcomes. We aimed to explore whether humans and rodents display similar fibrotic signaling networks. APPROACH AND RESULTS We assiduously mapped kinase pathways using 340 substrate targets, upstream bioinformatic analysis of kinase pathways, and over 2000 random sampling iterations using the PamGene PamStation kinome microarray chip technology. Using this technology, we characterized a large number of kinases with altered activity in liver fibrosis of both species. Gene expression and immunostaining analyses validated many of these kinases as bona fide signaling events. Surprisingly, the insulin receptor emerged as a considerable protein tyrosine kinase that is hyperactive in fibrotic liver disease in humans and rodents. Discoidin domain receptor tyrosine kinase, activated by collagen that increases during fibrosis, was another hyperactive protein tyrosine kinase in humans and rodents with fibrosis. The serine/threonine kinases found to be the most active in fibrosis were dystrophy type 1 protein kinase and members of the protein kinase family of kinases. We compared the fibrotic events over four models: humans with cirrhosis and three murine models with differing levels of fibrosis, including two models of fatty liver disease with emerging fibrosis. The data demonstrate a high concordance between human and rodent hepatic kinome signaling that focalizes, as shown by our network analysis of detrimental pathways. CONCLUSIONS Our findings establish a comprehensive kinase atlas for liver fibrosis, which identifies analogous signaling events conserved among humans and rodents.
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Affiliation(s)
- Justin F. Creeden
- Department of NeurosciencesUniversity of Toledo College of Medicine and Life SciencesToledoOhioUSA
| | - Zachary A. Kipp
- Department of Pharmacology and Nutritional SciencesUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Mei Xu
- Department of Pharmacology and Nutritional SciencesUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Robert M. Flight
- Department of Molecular & Cellular BiochemistryUniversity of KentuckyLexingtonKentuckyUSA
- Markey Cancer CenterUniversity of KentuckyLexingtonKentuckyUSA
- Resource Center for Stable Isotope Resolved MetabolomicsUniversity of KentuckyLexingtonKentuckyUSA
| | - Hunter N. B. Moseley
- Department of Molecular & Cellular BiochemistryUniversity of KentuckyLexingtonKentuckyUSA
- Markey Cancer CenterUniversity of KentuckyLexingtonKentuckyUSA
- Resource Center for Stable Isotope Resolved MetabolomicsUniversity of KentuckyLexingtonKentuckyUSA
- Institute for Biomedical InformaticsUniversity of KentuckyLexingtonKentuckyUSA
- Center for Clinical and Translational ScienceUniversity of KentuckyLexingtonKentuckyUSA
| | - Genesee J. Martinez
- Department of Pharmacology and Nutritional SciencesUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Wang‐Hsin Lee
- Department of Pharmacology and Nutritional SciencesUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Khaled Alganem
- Department of NeurosciencesUniversity of Toledo College of Medicine and Life SciencesToledoOhioUSA
| | - Ali S. Imami
- Department of NeurosciencesUniversity of Toledo College of Medicine and Life SciencesToledoOhioUSA
| | - Megan R. McMullen
- Department of Inflammation and ImmunityCleveland ClinicClevelandOhioUSA
| | | | - Atta M. Nawabi
- Division of Transplant and HepatobiliaryDepartment of SurgeryThe University of Kansas Medical CenterKansas CityKansasUSA
| | | | - Samir Softic
- Department of Pharmacology and Nutritional SciencesUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
- Department of PediatricsUniversity of KentuckyLexingtonKentuckyUSA
| | - Steven A. Weinman
- Department of Internal Medicine and Liver CenterUniversity of Kansas Medical CenterKansas CityKansasUSA
| | - Robert McCullumsmith
- Department of NeurosciencesUniversity of Toledo College of Medicine and Life SciencesToledoOhioUSA
- Neurosciences InstituteProMedicaToledoOhioUSA
| | - Laura E. Nagy
- Department of Inflammation and ImmunityCleveland ClinicClevelandOhioUSA
- Department of Gastroenterology and HepatologyCenter for Liver Disease ResearchCleveland ClinicClevelandOhioUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOhioUSA
| | - Terry D. Hinds
- Department of Pharmacology and Nutritional SciencesUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
- Markey Cancer CenterUniversity of KentuckyLexingtonKentuckyUSA
- Barnstable Brown Diabetes CenterUniversity of Kentucky College of MedicineLexingtonKentuckyUSA
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29
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Valenzuela-Vallejo L, Mantzoros CS. Time to transition from a negative nomenclature describing what NAFLD is not, to a novel, pathophysiology-based, umbrella classification of fatty liver disease (FLD). Metabolism 2022; 134:155246. [PMID: 35780909 DOI: 10.1016/j.metabol.2022.155246] [Citation(s) in RCA: 11] [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: 06/10/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 12/14/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a definition of a prevalent condition that has been given a name describing what the disease is not, mainly due to gaps in the physiopathological understanding of NAFLD when the name was given to it. NAFLD still remains an unmet clinical need to a large extent due to the heterogenicity of the disease and the lack of a more accurate physiology-based classification. In essence, fatty liver disease (FLD) has a multifactorial etiology, including metabolic abnormalities, environmental influences, genetic disorders, and/or their overlap which makes it difficult to diagnose, design appropriate trials for it and treat this disease. Therefore, we propose herein that as our knowledge about this disease continues to grow exponentially, it is time to consider ending this unspecific, negative and broad classification of NAFLD, and turn it into a positive and targeted one describing what the disease is and not what it is not. Thus, we propose the novel FLD "Mantzoros classification". This innovative classification proposes to classify the heterogeneous causes of FLD under one umbrella and eventually lead to a better nomenclature and classification system reflecting pathophysiology. This in turn could lead to both better clinical trials and more personalized care. An additional aim is to generate a dialogue among the experts in this field to eventually reach the right nomenclature for an appropriate disease classification that would facilitate our understanding, approach, diagnosis, and management of this epidemic of FLD. Overall, a novel classification, based on phenotypic manifestations, leading risk factors and probable causes of FLD, could help our understanding and clinically would be accurately defining and differentiating the disease, leading to a more accurate design and execution of clinical trials. This would in turn lead to tangible benefits for all patients suffering from FLD through targeted and more effective personalized treatments.
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Affiliation(s)
- Laura Valenzuela-Vallejo
- Department of Medicine, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Christos S Mantzoros
- Department of Medicine, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; Department of Medicine, Boston VA Healthcare System, Boston, MA 02130, United States.
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30
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Diaconu CT, Guja C. Nonalcoholic Fatty Liver Disease and Its Complex Relation with Type 2 Diabetes Mellitus—From Prevalence to Diagnostic Approach and Treatment Strategies. J Clin Med 2022; 11:jcm11175144. [PMID: 36079070 PMCID: PMC9456683 DOI: 10.3390/jcm11175144] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 08/28/2022] [Accepted: 08/30/2022] [Indexed: 11/30/2022] Open
Abstract
Prevalence of Nonalcoholic Fatty Liver Disease (NAFLD) and Type 2 Diabetes Mellitus (T2DM) are increasing rapidly worldwide, reaching epidemic proportions. Their association, based on common metabolic risk factors (obesity, insulin resistance (IR), unhealthy lifestyle), brings an additional risk of both hepatic and cardiovascular (CV) adverse clinical outcomes. The terminology of “NAFLD” is stigmatizing to some but not all patients, and a more practical one should be announced soon. Medical strategies can address both diseases simultaneously, as they have crossing pathophysiological mechanisms, mainly IR. Strategies vary from lifestyle intervention and pharmacological options, as more molecules designated for T2DM treatment may be helpful in NAFLD, to surgical procedures. This review focuses on the coexistence of NAFLD and T2DM, pointing out the utility of the appropriate terminology, its prevalence, and mortality rates among the diabetic population. Briefly, we have discussed the main pathophysiological mechanisms and the risk stratification algorithm for the development of NAFLD and nonalcoholic steatohepatitis (NASH) as well as the tools for evaluation of fibrosis. Finally, we have focused on the current therapeutic options for the treatment of NAFLD associated with T2DM.
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Affiliation(s)
- Cosmina-Theodora Diaconu
- Department of Diabetes, Nutrition and Metabolic Diseases, “Prof. Dr. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 030167 Bucharest, Romania
- Doctoral School of “Carol Davila” University of Medicine and Pharmacy, Dionisie Lupu 37, 020021 Bucharest, Romania
- Correspondence:
| | - Cristian Guja
- Department of Diabetes, Nutrition and Metabolic Diseases, “Prof. Dr. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 030167 Bucharest, Romania
- Department of Diabetes, Nutrition and Metabolic Diseases, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
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31
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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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32
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Furthner D, Weghuber D, Dalus C, Lukas A, Stundner-Ladenhauf HN, Mangge H, Pixner T. Nonalcoholic Fatty Liver Disease in Children with Obesity: Narrative Review and Research Gaps. Horm Res Paediatr 2022; 95:167-176. [PMID: 34351306 DOI: 10.1159/000518595] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/20/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the leading hepatic disease in children, ranging from steatosis to steatohepatitis and fibrosis. Age, sex, hormonal levels, pubertal stages, genetic risk- and epigenetic factors are among the many influencing factors. Appearing predominantly in children with obesity, but not exclusively, it is the liver's manifestation of the metabolic syndrome but can also exist as an isolated entity. SUMMARY Pediatric NAFLD differs from the adult phenotype. This narrative review on NAFLD in children with obesity provides an overview of the current knowledge on risk factors, screening, and diagnostic methods, as well state-of-the-art treatment. The recent discussion on the proposition of a new nomenclature - Metabolic [Dysfunction-] Associated Liver Disease - is featured, and current gaps of knowledge are discussed. KEY MESSAGES Currently, there is no international consensus on screening and monitoring of pediatric NAFLD. With lifestyle interventions being the cornerstone of treatment, no registered pharmacological treatment for pediatric NAFLD is available. Development and validation of additional noninvasive biomarkers, scores and imaging tools suitable to subcategorize, screen and monitor pediatric patients are necessary. With a variety of upcoming and promising agents, clear recommendations for pediatric nonalcoholic steatohepatitis trials are urgently needed.
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Affiliation(s)
- Dieter Furthner
- Department of Pediatric and Adolescent Medicine, Salzkammergutklinikum Voecklabruck, Voecklabruck, Austria.,Obesity Research Unit, Paracelsus Medical University, Salzburg, Austria
| | - Daniel Weghuber
- Obesity Research Unit, Paracelsus Medical University, Salzburg, Austria.,University Children's Hospital, Paracelsus Medical University, Salzburg, Austria
| | - Christopher Dalus
- Obesity Research Unit, Paracelsus Medical University, Salzburg, Austria.,University Children's Hospital, Paracelsus Medical University, Salzburg, Austria
| | - Andreas Lukas
- Department of Pediatric and Adolescent Medicine, Salzkammergutklinikum Voecklabruck, Voecklabruck, Austria.,Obesity Research Unit, Paracelsus Medical University, Salzburg, Austria
| | | | - Harald Mangge
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Thomas Pixner
- Department of Pediatric and Adolescent Medicine, Salzkammergutklinikum Voecklabruck, Voecklabruck, Austria.,Obesity Research Unit, Paracelsus Medical University, Salzburg, Austria
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33
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Almomani A, Hitawala AA, Kumar P, Alqaisi S, Alshaikh D, Alkhayyat M, Asaad I. Prevalence of hypothyroidism and effect of thyroid hormone replacement therapy in patients with non-alcoholic fatty liver disease: A population-based study. World J Hepatol 2022; 14:551-558. [PMID: 35582287 PMCID: PMC9055192 DOI: 10.4254/wjh.v14.i3.551] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/13/2021] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is currently considered as the most common cause of chronic liver disease worldwide. Risk factors for NAFLD have been well-described, including obesity, type 2 diabetes mellites (T2DM), dyslipidemia (DLP) and metabolic syndrome. Hypothyroidism has been identified as an independent risk factor for the development of NAFLD, although the literature is inconsistent
AIM To evaluate the prevalence of hypothyroidism in patients with NAFLD, assess if it is an independent risk factor and explore the effect of thyroxine replacement therapy.
METHODS Our cohort’s data was obtained using a validated, large, multicenter database (Explorys Inc, Cleveland, OH, United States) aggregated from pooled outpatient and inpatient records of 26 different healthcare systems, consisting of a total of 360 hospitals in the United States, and utilizing Systematized Nomenclature of Medicine-Clinical Terms for coding. We evaluated a cohort of patients with hypothyroidism and NAFLD. Multivariate analysis was performed to adjust for confounding risk factors including hypertension (HTN), T2DM, DLP, obesity and metabolic syndrome. SPSS version 25, IBM Corp was used for statistical analysis, and for all analyses, a 2-sided P value of < 0.05 was considered statistically significant. Exclusion criteria were limited to age < 18 years.
RESULTS Among the 37648180 included individuals in this database who are above the age of 18 years, there were a total of 2320 patients with NAFLD (6.16 per 100000) in the last five years (2015-2020), amongst which 520 patients (22.4%) had hypothyroidism. Baseline characteristics of patients in this database are described in Table 1. Patients with NAFLD were also more likely to have obesity, T2DM, DLP, HTN, and metabolic syndrome (Table 2). While males and females were equally affected, patients in the age group 18-65 years as well as Caucasians seem to be at a higher risk. There was an increased risk of NAFLD among patients with hypothyroidism (OR = 1.587). Furthermore, thyroid hormone replacement was not associated with a decreased risk for developing NAFLD (OR = 1.106, C = 0.952-1.285, P = 0.303).
CONCLUSION Hypothyroidism seems to be an independent risk factor for the development of NAFLD. Thyroid hormone replacement did not provide a statistically significant risk reduction. Further studies are needed to evaluate the effect of thyroid hormone replacement and assess if being euthyroid while on thyroid replacement therapy affects development and/or progression of NAFLD.
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Affiliation(s)
- Ashraf Almomani
- Department ofInternal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Asif Ali Hitawala
- Liver Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Bethesda, MD 20892, United States
| | - Prabhat Kumar
- Department ofInternal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Sura Alqaisi
- Department ofInternal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | | | - Motasem Alkhayyat
- Department ofInternal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44111, United States
| | - Imad Asaad
- Department of Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, United States
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34
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Meroni M, Longo M, Lombardi R, Paolini E, Macchi C, Corsini A, Sirtori CR, Fracanzani AL, Ruscica M, Dongiovanni P. Low Lipoprotein(a) Levels Predict Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease. Hepatol Commun 2022; 6:535-549. [PMID: 34677008 PMCID: PMC8870034 DOI: 10.1002/hep4.1830] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/30/2021] [Accepted: 09/08/2021] [Indexed: 12/21/2022] Open
Abstract
Dyslipidemia and cardiovascular complications are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis up to hepatocellular carcinoma. Lipoprotein(a) (Lp(a)) has been associated with cardiovascular risk and metabolic abnormalities, but its impact on the severity of liver damage in patients with NAFLD remains to be clarified. Circulating Lp(a) levels were assessed in 600 patients with biopsy-proven NAFLD. The association of Lp(a) with liver damage was explored by categorizing serum Lp(a) into quartiles. The receiver operating characteristic curve was used to analyze the accuracy of serum Lp(a) in hepatic fibrosis prediction. Hepatic expression of lipoprotein A (LPA) and of genes involved in lipid metabolism and fibrogenic processes were evaluated by RNA sequencing in a subset of patients with NAFLD for whom Lp(a) dosage was available (n = 183). In patients with NAFLD, elevated Lp(a) levels were modestly associated with circulating lipids, carotid plaques, and hypertension (P < 0.05). Conversely, patients with low serum Lp(a) displayed insulin resistance (P < 0.05), transaminase elevation (P < 0.05), and increased risk of developing severe fibrosis (P = 0.007) and cirrhosis (P = 0.002). In addition, the diagnostic accuracy of Lp(a) in predicting fibrosis increased by combining it with transaminases (area under the curve fibrosis stage 4, 0.87; P < 0.0001). Hepatic LPA expression reflected serum Lp(a) levels (P = 0.018), and both were reduced with the progression of NAFLD (P < 0.05). Hepatic LPA messenger RNA levels correlated with those of genes involved in lipoprotein release, lipid synthesis, and fibrogenesis (P < 0.05). Finally, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, apolipoprotein E (ApoE) rs445925, and proprotein convertase subtilisin/kexin type 9 (PCSK9) rs7552841, known variants that modulate circulating lipids, may influence serum Lp(a) levels (P < 0.05). Conclusion: Circulating Lp(a) combined with transaminases may represent a novel noninvasive biomarker to predict advanced fibrosis in patients with NAFLD.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic DiseasesFondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Miriam Longo
- General Medicine and Metabolic DiseasesFondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore PoliclinicoMilanItaly.,Department of Clinical Sciences and Community HealthUniversità degli Studi di MilanoMilanItaly
| | - Rosa Lombardi
- General Medicine and Metabolic DiseasesFondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore PoliclinicoMilanItaly.,Department of Pathophysiology and TransplantationUniversità degli Studi di MilanoMilanItaly
| | - Erika Paolini
- General Medicine and Metabolic DiseasesFondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore PoliclinicoMilanItaly.,Department of Pharmacological and Biomolecular SciencesUniversità degli Studi di MilanoMilanItaly
| | - Chiara Macchi
- Department of Pharmacological and Biomolecular SciencesUniversità degli Studi di MilanoMilanItaly
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular SciencesUniversità degli Studi di MilanoMilanItaly.,Multimedica IRCCSSesto San GiovanniMilanItaly
| | - Cesare R Sirtori
- Department of Pharmacological and Biomolecular SciencesUniversità degli Studi di MilanoMilanItaly
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic DiseasesFondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore PoliclinicoMilanItaly.,Department of Pathophysiology and TransplantationUniversità degli Studi di MilanoMilanItaly
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular SciencesUniversità degli Studi di MilanoMilanItaly
| | - Paola Dongiovanni
- General Medicine and Metabolic DiseasesFondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore PoliclinicoMilanItaly
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35
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Smirne C, Croce E, Di Benedetto D, Cantaluppi V, Comi C, Sainaghi PP, Minisini R, Grossini E, Pirisi M. Oxidative Stress in Non-Alcoholic Fatty Liver Disease. LIVERS 2022; 2:30-76. [DOI: 10.3390/livers2010003] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it still remains an orphan of adequate therapies. This review highlights the interaction between oxidative stress (OS) and disturbed lipid metabolism. Several reactive oxygen species generators, including those produced in the gastrointestinal tract, contribute to the lipotoxic hepatic (and extrahepatic) damage by fatty acids and a great variety of their biologically active metabolites in a “multiple parallel-hit model”. This leads to inflammation and fibrogenesis and contributes to NAFLD progression. The alterations of the oxidant/antioxidant balance affect also metabolism-related organelles, leading to lipid peroxidation, mitochondrial dysfunction, and endoplasmic reticulum stress. This OS-induced damage is at least partially counteracted by the physiological antioxidant response. Therefore, modulation of this defense system emerges as an interesting target to prevent NAFLD development and progression. For instance, probiotics, prebiotics, diet, and fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. The OS and its counter-regulation are under the influence of individual genetic and epigenetic factors as well. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors, coupled with new OS biomarkers, will likely assist in noninvasive diagnosis and monitoring of NAFLD progression and in further personalizing treatments.
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Affiliation(s)
- Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Eleonora Croce
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Davide Di Benedetto
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Vincenzo Cantaluppi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Cristoforo Comi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Pier Paolo Sainaghi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Elena Grossini
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
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36
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Metabolic Fatty Liver Disease in Children: A Growing Public Health Problem. Biomedicines 2021; 9:biomedicines9121915. [PMID: 34944730 PMCID: PMC8698722 DOI: 10.3390/biomedicines9121915] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/09/2021] [Accepted: 12/11/2021] [Indexed: 12/24/2022] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD), previously called nonalcoholic fatty liver diseases (NAFLD), is one of the most important causes of chronic liver disease worldwide and will likely become the leading cause of end-stage liver disease in the decades ahead. MAFLD covers a continuum of liver diseases from fatty liver to nonalcoholic steatohepatitis (NASH), liver fibrosis/cirrhosis and hepatocellular cancer. Importantly, the growing incidence of overweight and obesity in childhood, 4% in 1975 to 18% in 2016, with persisting obesity complications into adulthood, is likely to be harmful by increasing the incidence of severe MAFLD at an earlier age. Currently, MAFLD is the leading form of chronic liver disease in children and adolescents, with a global prevalence of 3 to 10%, pointing out that early diagnosis is therefore crucial. In this review, we highlight the current knowledge concerning the epidemiology, risk factors and potential pathogenic mechanisms, as well as diagnostic and therapeutic approaches, of pediatric MAFLD.
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37
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Non-alcoholic fatty liver disease as a medical and social problem. КЛИНИЧЕСКАЯ ПРАКТИКА 2021. [DOI: 10.17816/clinpract83782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The article considers the non-alcoholic fatty liver disease as an important medical and social problem. This problem include such questions as metabolic syndrome, essential lipoproteinemia, insulinoresistance. It is possible to consider non-alcoholic steatohepatitis as predictor of liver fibrosis and chirrosis. The questions of diagnosis and treatment are discussed.
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38
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Meroni M, Longo M, Tria G, Dongiovanni P. Genetics Is of the Essence to Face NAFLD. Biomedicines 2021; 9:1359. [PMID: 34680476 PMCID: PMC8533437 DOI: 10.3390/biomedicines9101359] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, 20122 Milano, Italy
| | - Giada Tria
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
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Bhatt SP, Guleria R. Association of IRS1 (Gly972Arg) and IRS2 (Gly1057Asp) genes polymorphisms with OSA and NAFLD in Asian Indians. PLoS One 2021; 16:e0245408. [PMID: 34449768 PMCID: PMC8396739 DOI: 10.1371/journal.pone.0245408] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 07/31/2021] [Indexed: 12/12/2022] Open
Abstract
AIM AND OBJECTIVE The aim of the study was to investigate the relationships between insulin receptor substrate (IRS) 1 (Gly972Arg) and IRS2 (Gly1057Asp) genes with obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) in Asian Indians. METHOD A total of 410 overweight/obese subjects (130 with OSA with NAFLD, 100 with OSA without NAFLD, 95 without OSA and with NAFLD and 85 without OSA and without NAFLD) were recruited. Degree of NAFLD was based on liver ultrasound and of OSA on overnight polysomnography. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and confirmed by gene sequencing. RESULT Mean values of blood pressure, body fat markers, blood glucose, lipids, liver function, and markers of insulin resistance were significantly increased in OSA and NAFLD subjects (p<0.05). In addition, according to age (years) categories, blood pressure, blood glucose, lipids, obesity markers, and markers of insulin resistance were significantly higher in 45-60 years group as compared to 20-45 years group (p<0.05). In IRS1 gene, the genotype frequency (%) of Arg/Arg was significantly higher in NAFLD and OSA subjects. In addition, Gly/Arg genotype of IRS1 gene was associated with significantly higher body mass index, fat mass, %body fat, triglycerides, cholesterol, alkaline phosphate, aspartate transaminase, fasting insulin and HOMA-IR levels in OSA and NAFLD subjects. No significant difference in genotype frequencies of IRS2 was observed between four groups. Further we found that subjects carrying IRS1 Gly/Arg (OR 4.49, 95% C.I. 1.06-12.52, p = 0.002) genotype possess a much higher risk of OSA and NAFLD compared to IRS2 Gly/Asp (OR 1.01, 95% C.I. 0.8-2.56, p = 0.05). In sub group analysis of IRS1 Gly/Arg have significant differences between the mild, moderate and severe group (P<0.05). In addition, patients with the 'Gly' allele were inclined to develop more severe OSA. CONCLUSION We concluded that Asian Indian subject carrying the allele Gly972Arg polymorphism of IRS1 is predisposed to develop OSA and NAFLD.
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Affiliation(s)
- Surya Prakash Bhatt
- Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
- * E-mail:
| | - Randeep Guleria
- Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
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NAFLD-Related Hepatocarcinoma: The Malignant Side of Metabolic Syndrome. Cells 2021; 10:cells10082034. [PMID: 34440803 PMCID: PMC8391372 DOI: 10.3390/cells10082034] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/02/2021] [Accepted: 08/04/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the second leading cause of cancer-related mortality. HCC typically arises within a cirrhotic liver, but in about 20% of cases occurs in absence of cirrhosis. Among non-cirrhotic risk factors, non-alcoholic fatty liver disease (NAFLD) currently represents the most important emerging cause of HCC in developed countries. It has been estimated that annual incidence of HCC among patients with non-cirrhotic NAFLD is approximately 0.1-1.3 per 1000 patients/year and ranges from 0.5% to 2.6% among patients with non-alcoholic steatohepatitis (NASH) cirrhosis. However, only a few clinical trials enrolling HCC patients actually distinguished NAFLD/NASH-related cases from other non-cirrhotic causes and therefore evidence is still lacking in this subset of patients. This review aims to describe the biology underpinning NAFLD development, to investigate the main molecular pathways involved in its progression to NASH and HCC and to describe how different pathogenetic mechanisms underlying the onset of HCC can have an impact in clinical practice. We hereby also provide an overview of current HCC treatment options, with a particular focus on the available data on NAFLD-related cases in practice-changing clinical trials.
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Pafili K, Roden M. Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Mol Metab 2021; 50:101122. [PMID: 33220492 PMCID: PMC8324683 DOI: 10.1016/j.molmet.2020.101122] [Citation(s) in RCA: 174] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/30/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) comprises hepatic alterations with increased lipid accumulation (steatosis) without or with inflammation (nonalcoholic steatohepatitis, NASH) and/or fibrosis in the absence of other causes of liver disease. NAFLD is developing as a burgeoning health challenge, mainly due to the worldwide obesity and diabetes epidemics. SCOPE OF REVIEW This review summarizes the knowledge on the pathogenesis underlying NAFLD by focusing on studies in humans and on hypercaloric nutrition, including effects of saturated fat and fructose, as well as adipose tissue dysfunction, leading to hepatic lipotoxicity, abnormal mitochondrial function, and oxidative stress, and highlights intestinal dysbiosis. These mechanisms are discussed in the context of current treatments targeting metabolic pathways and the results of related clinical trials. MAJOR CONCLUSIONS Recent studies have provided evidence that certain conditions, for example, the severe insulin-resistant diabetes (SIRD) subgroup (cluster) and the presence of an increasing number of gene variants, seem to predispose for excessive risk of NAFLD and its accelerated progression. Recent clinical trials have been frequently unsuccessful in halting or preventing NAFLD progression, perhaps partly due to including unselected cohorts in later stages of NAFLD. On the basis of this literature review, this study proposed screening in individuals with the highest genetic or acquired risk of disease progression, for example, the SIRD subgroup, and developing treatment concepts targeting the earliest pathophysiolgical alterations, namely, adipocyte dysfunction and insulin resistance.
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Affiliation(s)
- Kalliopi Pafili
- Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany
| | - Michael Roden
- Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany; Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
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Dongiovanni P, Paolini E, Corsini A, Sirtori CR, Ruscica M. Nonalcoholic fatty liver disease or metabolic dysfunction-associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches. Eur J Clin Invest 2021; 51:e13519. [PMID: 33583033 DOI: 10.1111/eci.13519] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND A consensus of experts has proposed to replace the term nonalcoholic fatty liver disease (NAFLD), whose global prevalence is 25%, with metabolic dysfunction-associated fatty liver disease (MAFLD), to describe more appropriately the liver disease related to metabolic derangements. MAFLD is closely intertwined with type 2 diabetes, obesity, dyslipidaemia, all linked to a rise in the risk of cardiovascular disease (CVDs). Since controversy still stands on whether or not NAFLD/MAFLD raises the odds of CVD, the present review aims to evaluate the impact of NAFLD/MAFLD aetiologies on CV health and the potential correction by dietary and drug approaches. RESULTS Epidemiological studies indicate that NAFLD raises risk of fatal or non-fatal CVD events. NAFLD patients have a higher prevalence of arterial plaques and stiffness, coronary calcification, and endothelial dysfunction. Although genetic and environmental factors strongly contribute to NAFLD pathogenesis, a Mendelian randomization analysis indicated that the PNPLA3 genetic variant leading to NAFLD may not be causally associated with CVD risk. Among other genetic variants related to NAFLD, TM6SF2 appears to be protective, whereas MBOAT7 may favour venous thromboembolism. CONCLUSIONS NAFLD is correlated to a higher CVD risk which may be ameliorated by dietary interventions. This is not surprising, since new criteria defining MAFLD include other metabolic risk abnormalities fuelling development of serious adverse extrahepatic outcomes, for example CVD. The present lack of a targeted pharmacological approach makes the identification of patients with liver disease at higher CVD risk (eg diabetes, hypertension, obesity or high levels of C-reactive protein) of major clinical interest.
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Affiliation(s)
- Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Erika Paolini
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.,Multimedica IRCCS, Sesto San Giovanni (MI), Milan, Italy
| | - Cesare R Sirtori
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
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Bedair RN, Magour GM, Ooda SA, Amar EM, Awad AM. Insulin receptor substrate-1 G972R single nucleotide polymorphism in Egyptian patients with chronic hepatitis C virus infection and type 2 diabetes mellitus. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-020-00069-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Abstract
Background
Insulin receptor substrate-1 (IRS1) plays a critical role in insulin signaling. IRS-1 gene polymorphism with glycine to arginine substitution (GGG ↔ AGG substitutions) in codon 972 (G972R) (rs1801278) is a common polymorphism of the IRS-1 gene, which may have a pathogenic role in the development of type 2 diabetes mellitus (type 2 DM) due to insulin resistance and impaired insulin secretion. In hepatitis C virus infection (HCV), the IRS proteins might be counter-regulated by degradation, differential expression, or modification by phosphorylation in cells expressing HCV core protein, which inhibits the interactions of IRS-1 with both the insulin receptor and the downstream effectors of IRS-1. The present retrospective case–control study aimed to evaluate IRS-1 G972R (rs 1801278) SNP in Egyptian patients with HCV and type 2 DM, two hundred and two subjects including 100 males and 102 females The present work is a retrospective case–control study aimed to detect IRS-1 G972R (rs 1801278) SNP in Egyptian patients with chronic HCV infection and DM. The subjects were divided into the control group (group I) which included 50 apparently healthy volunteers of comparable age, gender, and socioeconomic status to patients; group II included 50 type 2 diabetic patients without chronic hepatitis C infection; group III included 52 chronic HCV-infected patients without type 2 diabetes mellitus; and group IV included 50 chronic hepatitis C-infected patients with type 2 diabetes mellitus. IRS-1 G972R (rs 1801278) genotyping was done by using polymerase chain reaction (PCR-RFLP) technique with restriction enzymes BstNI.
Results
HOMA-IR and QUICKI index was significantly higher in the patient groups (groups II, III, and IV) than controls (P < 0.001, P = 0.019, and P < 0.001 respectively). There was a significant increase in minor allele (A) in groups II, III, and IV than controls (P = 0.007, P = 0.017, and P = 0.007 respectively). There was increased frequency of mutant allele (A) than wild allele (G) of IRS-1 G972R polymorphism in type 2 diabetic patients with BMI < 25 kg/m2. The DM patients without HCV infection (group II), HCV patients without DM (group III), and HCV patients with DM (group IV) showed a significant decrease in GG genotypes and a significant increase in AA genotypes than the controls (P = 0.017, P = 0.019, and P = 0.009 respectively). Body mass index and waist to hip ratio were significantly higher in DM patients without chronic hepatitis C infection (group II) and in HCV patients with type 2 diabetes (group IV) than controls, in hepatitis C patients with type 2 diabetes (group IV) than controls, and in group IV than group III (P < 0.001).
Conclusion
IRS-1 G972R (rs 1801278) polymorphism might be a contributing risk factor for the development of type 2 DM. The mutant allele (A) of IRS-1 suggests the role of this SNP as risk factors for type 2 diabetes mellitus even in subjects with normal body weight. The increase of body mass index may be an independent risk factor for the development of type 2 diabetes mellitus.
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Choudhary NS, Duseja A. Genetic and epigenetic disease modifiers: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Transl Gastroenterol Hepatol 2021; 6:2. [PMID: 33409397 DOI: 10.21037/tgh.2019.09.06] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 09/04/2019] [Indexed: 12/12/2022] Open
Abstract
Inter-individual and inter-ethnic differences and difference in the severity and progression of liver disease among patients with non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) suggests the involvement of genetic and epigenetic factors in their pathogenesis. This article reviews the genetic and epigenetic modifiers in patients with NAFLD and ALD. Evidence regarding the genetic and epigenetic disease modifiers of NAFLD and ALD was reviewed by searching the available literature. Both genome wide association studies (GWAS) and candidate gene studies pertaining to the pathogenesis in both diseases were included. Clinical implications of the available information are also discussed. Several studies have shown association of both NAFLD and ALD with I148M PNPLA3 variant. In addition to the higher prevalence of hepatic steatosis, the I148M PNPLA3 variant is also associated with severity of liver disease and risk of hepatocellular carcinoma (HCC). TM6SF2 is the other genetic variant shown to be significantly associated with hepatic steatosis and cirrhosis in patients with NAFLD and ALD. The Membrane bound O-acyltransferase domain-containing 7 (MBOAT7) genetic variant is also associated with both NAFLD and ALD. In addition to these mutations, several variants related to the genes involved in glucose metabolism, insulin resistance, lipid metabolism, oxidative stress, inflammatory pathways, fibrosis have also been shown to be the disease modifiers in patients with NAFLD and ALD. Epigenetics involving several micro RNAs and DNA methylation could also modify the disease course in NAFLD and ALD. In conclusion the available literature suggests that genetics and epigenetics are involved in the pathogenesis of NAFLD and ALD which may affect the disease prevalence, severity and response to treatment in these patients.
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Affiliation(s)
- Narendra Singh Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, The Medicity, Gurgaon, Delhi (NCR), India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Albhaisi S, Sanyal AJ. Gene-Environmental Interactions as Metabolic Drivers of Nonalcoholic Steatohepatitis. Front Endocrinol (Lausanne) 2021; 12:665987. [PMID: 34040583 PMCID: PMC8142267 DOI: 10.3389/fendo.2021.665987] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/19/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide in the past few decades as a consequence of the global obesity epidemic and is associated with significant morbidity and mortality. NAFLD is closely associated with components of the metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease, suggesting a plausible metabolic mechanistic basis. Metabolic inflexibility is considered a nidus for NAFLD pathogenesis, causing lipotoxicity, mitochondrial dysfunction and cellular stress leading to inflammation, apoptosis and fibrogenesis, thus mediating disease progression into nonalcoholic steatohepatitis (NASH) and ultimately cirrhosis. In this review, we describe they key metabolic drivers that contribute to development of NAFLD and NASH, and we explain how NASH is a metabolic disease. Understanding the metabolic basis of NASH is crucial for the prevention and treatment of this disease.
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Affiliation(s)
- Somaya Albhaisi
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Arun J. Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States
- *Correspondence: Arun J. Sanyal,
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Sharma P, Arora A. Approach to prevention of non-alcoholic fatty liver disease after liver transplantation. Transl Gastroenterol Hepatol 2020; 5:51. [PMID: 33073046 DOI: 10.21037/tgh.2020.03.02] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 10/15/2019] [Indexed: 12/22/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease and non-alcoholic steatohepatitis (NASH) related cirrhosis is third common indication for liver transplantation (LT). Patients who have NASH related cirrhosis and are candidates for LT often have multiple comorbidities. These comorbidities need to be addressed before and after transplantation as it affects overall survival. Like hepatitis B, hepatitis C, primary biliary cirrhosis, autoimmune hepatitis which recurs after transplantation, NASH also recurs after transplant however the impact of the recurrence on allograft and patient outcomes is unclear. Limited data suggests that it does not affect graft and patient survival. De novo NAFLD which is defined as occurrence of fatty liver in a patient who did not have fatty liver prior to LT can also occur in the allograft of patients transplanted for non-NAFLD liver disease. Obesity, hyperlipidemia, diabetes as well as steroid dose and duration after LT are common predictors of recurrence of NAFLD after transplantation. Studies on prevention and treatment of NASH in post-transplant patients are lacking. Prevention of weight gain, regular exercises, weight reducing surgery, limited steroid use or steroid free regimen have been tried with varying success. Future studies for the prevention of NAFLD/NASH are required especially in post liver transplant patient.
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Affiliation(s)
- Praveen Sharma
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Anil Arora
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
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Robinson KE, Shah VH. Pathogenesis and pathways: nonalcoholic fatty liver disease & alcoholic liver disease. Transl Gastroenterol Hepatol 2020; 5:49. [PMID: 33073044 DOI: 10.21037/tgh.2019.12.05] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 11/29/2019] [Indexed: 12/16/2022] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) account for the majority of hepatic morbidity and deaths due to cirrhosis in the United States. ALD is an umbrella term for a number of conditions linked to excessive alcohol consumption including simple steatosis, cirrhosis, acute alcoholic hepatitis (AH) with or without cirrhosis, and hepatocellular carcinoma (HCC) as a complication of cirrhosis. Although it presents with histological features resembling alcohol-induced liver injury, NAFLD occurs in patients with little or no history of alcohol consumption. NAFLD is a broad-spectrum term used to describe anything from fat accumulation in hepatocytes without inflammation or fibrosis (simple hepatic steatosis) to hepatic steatosis with a necroinflammatory component (steatohepatitis) with or without associated fibrosis. The pathogenesis is not fully understood for either disease. Development of severe liver disease is highly variable amongst chronic abusers of alcohol. Sex, age, genetics, host microbiome, and behavior are all factors linked to the development of ALD. These factors also contribute to NAFLD, but by contrast, insulin resistance is widely believed to be the main driver of nonalcoholic hepatic steatosis. The mechanism behind the transition from nonalcoholic steatosis to steatohepatitis remains a matter of debate with insulin resistance, oxidative injury, hepatic iron, gut hormones, antioxidant deficiency, and host microbiome all suspected to play part of the role.
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Affiliation(s)
- Kyle E Robinson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Meroni M, Longo M, Dongiovanni P. Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver disease. EXPLORATION OF MEDICINE 2020; 1:218-243. [DOI: 10.37349/emed.2020.00015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 06/20/2020] [Indexed: 01/04/2025] Open
Abstract
The prevalence of nonalcoholic or more recently re-defined metabolic associated fatty liver disease (MAFLD) is rapidly growing worldwide. It is characterized by hepatic fat accumulation exceeding 5% of liver weight not attributable to alcohol consumption. MAFLD refers to an umbrella of conditions ranging from simple steatosis to nonalcoholic steatohepatitis which may finally progress to cirrhosis and hepatocellular carcinoma. MAFLD is closely related to components of the metabolic syndrome and to environmental factors. In addition to the latter, genetic predisposition plays a key role in MAFLD pathogenesis and strictly contributes to its progressive forms. The candidate genes which have been related to MAFLD hereditability are mainly involved in lipids remodeling, lipid droplets assembly, lipoprotein packaging and secretion, de novo lipogenesis, and mitochondrial redox status. In the recent years, it has emerged the opportunity to translate the genetics into clinics by aggregating the genetic variants mostly associated with MAFLD in polygenic risk scores. These scores might be used in combination with metabolic factors to identify those patients at higher risk to develop more severe liver disease and to schedule an individual therapeutic approach.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milano, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy
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NOBAKHT H, MAHMOUDI T, SABZIKARIAN M, TABAEIAN SP, REZAMAND G, ASADI A, FARAHANI H, DABIRI R, MANSOUR-GHANAEI F, MALEKI I, ZALI MR. INSULIN AND INSULIN RECEPTOR GENE POLYMORPHISMS AND SUSCEPTIBILITY TO NONALCOHOLIC FATTY LIVER DISEASE. ARQUIVOS DE GASTROENTEROLOGIA 2020; 57:203-208. [DOI: 10.1590/s0004-2803.202000000-39] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 03/23/2020] [Indexed: 01/16/2023]
Abstract
ABSTRACT BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern defined by excessive hepatic fat content in the absence of excessive alcohol consumption. OBJECTIVE: Given the pivotal role of insulin resistance in NAFLD, we hypothesized that insulin (INS) and insulin receptor (INSR) gene polymorphisms may be associated with NAFLD risk. METHODS: A total of 312 subjects, including 153 cases with biopsy-proven NAFLD and 159 controls were enrolled in this case-control study. Four polymorphisms in INS (rs3842752, rs689) and INSR (rs1052371, rs1799817) genes were genotyped using PCR-RFLP method. RESULTS: The cases with NAFLD were older and had higher BMI, systolic blood pressure, diastolic blood pressure, as well as higher serum levels of aspartate aminotransferase, alanine aminotransferase, and gamma glutamyl transferase than the controls (P<0.001). The “TT” genotype of INSR rs1799817 compared with “CC” genotype occurred more frequently in the controls than the cases with NAFLD and the difference remained significant after adjustment for confounding factors (P=0.018; OR=0.10, 95%CI=0.02-0.76). However, no significant difference was found for INS rs3842752, INS rs689, and INSR rs1052371 gene polymorphisms between the cases with NAFLD and the controls either before or after adjustment for the confounders. CONCLUSION: These findings corroborate the hypothesis that genetic polymorphisms related to insulin resistance play a role in NAFLD susceptibility. Specifically, the INSR rs1799817 “TT” genotype had a protective effect for NAFLD. However, our results remain to be validated in other studies.
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50
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Hepatic lipid droplet homeostasis and fatty liver disease. Semin Cell Dev Biol 2020; 108:72-81. [PMID: 32444289 DOI: 10.1016/j.semcdb.2020.04.011] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 03/17/2020] [Accepted: 04/17/2020] [Indexed: 12/14/2022]
Abstract
In cells, lipids are stored in lipid droplets, dynamic organelles that adapt their size, abundance, lipid and protein composition and organelle interactions to metabolic changes. Lipid droplet accumulation in the liver is the hallmark of non-alcoholic fatty liver disease (NAFLD). Due to the prevalence of obesity, the strongest risk factor for steatosis, NAFLD and its associated complications are currently affecting more than 1 billion people worldwide. Here, we review how triglyceride and phospholipid homeostasis are regulated in hepatocytes and how imbalances between lipid storage, degradation and lipoprotein secretion lead to NAFLD. We discuss how organelle interactions are altered in NAFLD and provide insights how NAFLD progression is associated with changes in hepatocellular signaling and organ-crosstalk. Finally, we highlight unsolved questions in hepatic LD and lipoprotein biology and give an outlook on therapeutic options counteracting hepatic lipid accumulation.
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