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Vilar-Gomez E, Gawrieh S, Vuppalanchi R, Kettler C, Pike F, Samala N, Chalasani N. PNPLA3 rs738409, environmental factors and liver-related mortality in the US population. J Hepatol 2025; 82:571-581. [PMID: 39389267 DOI: 10.1016/j.jhep.2024.09.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 09/23/2024] [Accepted: 09/29/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND & AIMS Little is known about the interplay between patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409 C>G), environmental factors, and the risk of liver-related death. METHODS A total of 4,361 adults were selected from NHANES III, 1991-1994. All participants were linked to the National Death Index until 2019 (mean follow-up: 23.2 years). Liver-related death was the study outcome. Associations of PNPLA3, diet, light alcohol intake, smoking, and BMI (kg/m2) with liver-related death were examined using competing risk regression models. RESULTS The PNPLA3 G-allele was significantly associated with liver-related death (adjusted subhazard ratio [adj.sHR] 2.9, 95% CI 1.4-5.8). Light alcohol intake (adj.sHR 2.2, 95% CI 1.1-4.5), top quartiles of monounsaturated fat (adj.sHR 0.43, 95% CI 0.12-0.99) and cholesterol (adj.sHR 2.6, 95% CI 1.00-8.8), coffee intake ≥3 cups/day (adj.sHR 0.05, 95% CI 0.06-0.10), former/current smoking (adj.sHR 1.8, 95% CI 1.2-2.6), BMI (adj.sHR 1.1, 95% CI 1.03-1.2), and healthy eating index (adj.sHR 0.96, 95% CI 0.93-0.98) were associated with liver-related death. Joint effects between PNPLA3 and environmental factors showed that the risk of liver-related death was significantly increased in carriers of the G-allele with light alcohol intake (adj.sHR 3.7), higher consumption (top quartile) of cholesterol (adj.sHR 4.1), former (adj.sHR 4.3) or current (adj.sHR 3.5) smoking, or BMI ≥30 (adj.sHR 4.0) kg/m2. The effects of the G-allele on the risk of LRD were significantly attenuated in those with top quartile consumption of monounsaturated fat (adj.sHR 0.5) or coffee intake ≥3 cups/day (adj.sHR 0.09). Healthy eating index was inversely associated with liver-related death across all PNPLA3 genotypes (adj.sHR 0.94, 0.96, and 0.97 for CC, CG, and GG, respectively). CONCLUSIONS PNPLA3 is associated with liver-related death and this relationship is significantly modified by anthropometric and environmental factors. IMPACT AND IMPLICATIONS Light alcohol intake, dietary factors (healthy eating index, monounsaturated fat, cholesterol), coffee intake, smoking status, and BMI are independently associated with the risk of liver-related death. The increased inherited risk of liver-related death associated with PNPLA3 rs738409 appears to be attenuated by healthy eating index, monounsaturated fat, and coffee intake, and exacerbated by light alcohol intake, smoking, and BMI. Reducing harmful environmental exposures and increasing healthy eating habits may help mitigate the risk of liver-specific mortality even in those with high genetic risk.
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Affiliation(s)
- Eduardo Vilar-Gomez
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Samer Gawrieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Raj Vuppalanchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Carla Kettler
- Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Francis Pike
- Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Niharika Samala
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States.
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Venu S, Gopalakrishna R, Pillai BV, Biswas L, Poojara R, Raj M. Assessment of dietary, genetic and metabolic factors in South Indian adolescents with metabolic dysfunction-associated steatotic liver disease: a case-control study protocol. BMJ Paediatr Open 2025; 9:e003138. [PMID: 40127963 PMCID: PMC11934355 DOI: 10.1136/bmjpo-2024-003138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 03/02/2025] [Indexed: 03/26/2025] Open
Abstract
INTRODUCTION Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of liver disease among adolescents. The objectives of this study are to investigate the associations of dietary, genetic and metabolic factors with MASLD in South Indian adolescents. METHODS AND ANALYSIS The study will employ a case-control study design. We will recruit 280 adolescents (140 cases and 140 controls) from hospital and school settings. The hospital setting will be the paediatric gastroenterology outpatient department (OPD) at the study institution and the school setting will be selected urban schools from Ernakulam, Kerala. At the hospital, cases and controls will be selected from the patients who are attending the paediatric gastroenterology OPD with complaints of generalised abdominal pain or constipation with no other significant medical complaints or use of medications. A sensitisation programme on MASLD for parents of adolescents will be conducted in schools. All consenting parents along with their adolescent wards will be invited for study participation. Cases will be defined as adolescents having evidence of hepatic steatosis in ultrasound and meeting any one of the paediatric cardiometabolic criteria for MASLD. Those who fail to satisfy this criteria will be defined as controls. All participants will undergo nutritional and physical activity assessments using validated questionnaires along with blood sampling for biochemical analysis and genetic testing. We will examine the associations between MASLD and dietary parameters using Pearson's χ2 tests after stratifying dietary variables into categorical groups. Logistic regression will be used to assess the impact of dietary parameters and single-nucleotide polymorphisms (SNPs) on the risk of MASLD. ETHICS AND DISSEMINATION Ethics approval was obtained from the Ethics Committee of Amrita School of Medicine, Kochi. Informed consent will be obtained from participants and their legal guardians before enrolment. The study findings will provide valuable insights into the evolution of MASLD among adolescents in South India.
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Affiliation(s)
- Swathilakshmi Venu
- Amrita Institute of Medical Sciences and Research Centre, Ernakulam, Kerala, India
| | - Rajesh Gopalakrishna
- Department of Gastroenterology and Hepatology, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India
| | - Bhanu Vikraman Pillai
- Department of Gastroenterology and Hepatology, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India
| | - Lalitha Biswas
- Amrita Vishwa Vidyapeetham, Coimbatore, Tamil Nadu, India
| | - Rashmi Poojara
- Department of Home Science, St Teresa's College, Ernakulam, Kerala, India
| | - Manu Raj
- Department of Pediatrics, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India
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Speliotes EK, Schneider CV. PNPLA3 I148M Interacts With Environmental Triggers to Cause Human Disease. Liver Int 2025; 45:e16106. [PMID: 39559944 PMCID: PMC11815600 DOI: 10.1111/liv.16106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/03/2024] [Accepted: 09/08/2024] [Indexed: 11/20/2024]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) affects up to 30% of Western populations. While obesity is a recognized risk factor, MASLD does not develop in all obese individuals, highlighting the need to understand genetic and environmental interactions. The PNPLA3 I148M variant has been identified as a key genetic risk factor, significantly increasing the likelihood of MASLD development and progression. METHODS We reviewed current literature on the role of PNPLA3 I148M in MASLD, focusing on gene-environment interactions involving diet, physical activity, obesity, and insulin resistance. We included studies analysing ethnic differences in PNPLA3 I148M prevalence and its association with MASLD. Additionally, we reviewed data on how PNPLA3 I148M influences the response to therapies, including lipid-lowering medications and GLP-1 agonists. RESULTS The PNPLA3 I148M variant markedly heightens MASLD risk, particularly in Hispanic populations, where a higher prevalence of MASLD is observed. Lifestyle factors such as high sugar intake, alcohol consumption, and physical inactivity exacerbate MASLD risk among I148M carriers. Evidence shows that insulin resistance amplifies MASLD risk associated with the I148M variant, especially in non-diabetic individuals. Moreover, the PNPLA3 I148M variant interacts with other genetic loci, further modifying MASLD risk and disease course. The variant also influences treatment response, with variability observed in effectiveness of lipid-lowering therapies and GLP-1 agonists among carriers. CONCLUSION The interplay between PNPLA3 I148M and environmental factors underscores the need for personalized MASLD prevention and treatment strategies. Targeting both genetic and lifestyle contributors may enhance MASLD management, offering a tailored approach to reducing disease burden.
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Affiliation(s)
- Elizabeth K. Speliotes
- Division of Gastroenterology and Hepatology, Department of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
- Department of Computational Medicine and BioinformaticsUniversity of MichiganAnn ArborMichiganUSA
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Chen VL, Vespasiani‐Gentilucci U. Integrating PNPLA3 into clinical risk prediction. Liver Int 2025; 45:e16103. [PMID: 39282715 PMCID: PMC11815612 DOI: 10.1111/liv.16103] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/02/2024] [Accepted: 09/04/2024] [Indexed: 02/05/2025]
Abstract
The PNPLA3-rs738409-G variant was the first common variant associated with hepatic fat accumulation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, to date, the clinical translation of this discovery has been minimal because it has not yet been clearly demonstrated where the genetic information may play an independent and additional role in clinical risk prediction. In this mini-review, we will discuss the most relevant evidence regarding the potential integration of the PNPLA3 variant into scores and algorithms for liver disease diagnostics and risk stratification, specifically focusing on MASLD but also extending to liver diseases of other etiologies. The PNPLA3 variant adds little in diagnosing the current state of the disease, whether in terms of presence/absence of metabolic dysfunction-associated steatohepatitis or the stage of fibrosis. While it can play an important role in prediction, allowing for the early definition of risk profiles that enable tailored monitoring and interventions over time, this is most valuable when applied to populations with relatively high pre-test probability of having significant fibrosis based on either non-invasive tests (e.g. Fibrosis-4) or demographics (e.g. diabetes). Indeed, in this context, integrating FIB4 with the PNPLA3 genotype can refine risk stratification, though there is still no evidence that genetic information adds to liver stiffness determined by elastography. Similarly, in patients with known liver cirrhosis, knowing the PNPLA3 genotype can play a role in predicting the risk of hepatocellular carcinoma, while more doubts remain about the risk of decompensation.
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Affiliation(s)
- Vincent L. Chen
- Division of Gastroenterology and Hepatology, Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Umberto Vespasiani‐Gentilucci
- Research Unit of HepatologyUniversità Campus Bio‐Medico di RomeRomeItaly
- Hepatology and Clinical Medicine UnitFondazione Policlinico Universitario Campus‐Biomedico di RomaRomeItaly
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Sualeheen A, Tan SY, Georgousopoulou E, Daly RM, Tierney AC, Roberts SK, George ES. Mediterranean diet for the management of metabolic dysfunction-associated steatotic liver disease in non-Mediterranean, Western countries: What's known and what's needed? NUTR BULL 2024; 49:444-462. [PMID: 39258424 DOI: 10.1111/nbu.12707] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 08/14/2024] [Accepted: 08/14/2024] [Indexed: 09/12/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide, affecting 30% of the population in Western countries. MASLD is considered the hepatic manifestation of the metabolic syndrome, pathophysiologically underpinned by insulin resistance and frequently co-exists with hypertension, central obesity and dyslipidaemia. Currently, safe and effective pharmacotherapies for MASLD are limited, making weight loss with lifestyle changes the mainstay therapy. A Mediterranean diet (MedDiet) has emerged as an effective dietary pattern for preventing and managing MASLD, but most studies have been conducted in Mediterranean countries, necessitating further investigation into its benefits in Western populations. Additionally, the effect of holistic multimodal lifestyle interventions, including physical activity combined with the MedDiet, is not well established. Finally, MASLD's widespread prevalence and rapid growth require improved accessibility to interventions. Digital health delivery platforms, designed for remote access, could be a promising approach to providing timely support to individuals with MASLD. This narrative review summarises the current evidence related to the effects of the MedDiet in Western, multicultural populations with MASLD. This includes a detailed description of the composition, prescription and adherence to dietary interventions in terms of how they have been designed and applied. The evidence related to the role of physical activity or exercise interventions prescribed in combination with the MedDiet for MASLD will also be reviewed. Finally, recommendations for the design and delivery of dietary and physical activity or exercise interventions to inform the design of future randomised controlled trials to facilitate the optimal management of MASLD are outlined.
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Affiliation(s)
- Ayesha Sualeheen
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - Sze-Yen Tan
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - Ekavi Georgousopoulou
- Discipline of Nutrition and Dietetics, Faculty of Health, University of Canberra, Canberra, New South Wales, Australia
| | - Robin M Daly
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - Audrey C Tierney
- School of Allied Health, Centre for Implementation Research, Health Research Institute, University of Limerick, Limerick, Ireland
| | - Stuart K Roberts
- Department of Gastroenterology, Alfred Health, Prahran, Victoria, Australia
- Central Clinical School, Monash University, Clayton, Victoria, Australia
| | - Elena S George
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
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Hermanson JB, Tolba SA, Chrisler EA, Leone VA. Gut microbes, diet, and genetics as drivers of metabolic liver disease: a narrative review outlining implications for precision medicine. J Nutr Biochem 2024; 133:109704. [PMID: 39029595 PMCID: PMC11480923 DOI: 10.1016/j.jnutbio.2024.109704] [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: 04/05/2024] [Revised: 07/01/2024] [Accepted: 07/15/2024] [Indexed: 07/21/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing in prevalence, impacting over a third of the global population. The advanced form of MASLD, Metabolic dysfunction-associated steatohepatitis (MASH), is on track to become the number one indication for liver transplant. FDA-approved pharmacological agents are limited for MASH, despite over 400 ongoing clinical trials, with only a single drug (resmetirom) currently on the market. This is likely due to the heterogeneous nature of disease pathophysiology, which involves interactions between highly individualized genetic and environmental factors. To apply precision medicine approaches that overcome interpersonal variability, in-depth insights into interactions between genetics, nutrition, and the gut microbiome are needed, given that each have emerged as dynamic contributors to MASLD and MASH pathogenesis. Here, we discuss the associations and molecular underpinnings of several of these factors individually and outline their interactions in the context of both patient-based studies and preclinical animal model systems. Finally, we highlight gaps in knowledge that will require further investigation to aid in successfully implementing precision medicine to prevent and alleviate MASLD and MASH.
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Affiliation(s)
- Jake B Hermanson
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Samar A Tolba
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Evan A Chrisler
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Vanessa A Leone
- Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
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Chen VL, Du X, Oliveri A, Chen Y, Kuppa A, Halligan BD, Province MA, Speliotes EK. Genetic risk accentuates dietary effects on hepatic steatosis, inflammation and fibrosis in a population-based cohort. J Hepatol 2024; 81:379-388. [PMID: 38582304 PMCID: PMC11347099 DOI: 10.1016/j.jhep.2024.03.045] [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: 10/08/2023] [Revised: 03/16/2024] [Accepted: 03/23/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND & AIMS Steatotic liver disease (SLD), characterized by elevated liver fat content (LFC), is influenced by genetics and diet. However, whether diet has a differential effect based on genetic risk is not well-characterized. We aimed to determine how genetic factors interact with diet to affect SLD in a large national biobank. METHODS We included UK Biobank participants with dietary intake measured by 24-hour recall and genotyping. The primary predictors were dietary pattern, PNPLA3-rs738409-G, TM6SF2-rs58542926-T, a 16-variant hepatic steatosis polygenic risk score (PRS), and gene-environment interactions. The primary outcome was LFC, and secondary outcomes were iron-controlled T1 time (cT1, a measure of liver inflammation and fibrosis) and liver-related events/mortality. RESULTS A total of 21,619 participants met inclusion criteria. In non-interaction models, Mediterranean diet and intake of fruit/vegetables/legumes and fish associated with lower LFC, while higher red/processed meat intake and all genetic predictors associated with higher LFC. In interaction models, all genetic predictors interacted with Mediterranean diet and fruit/vegetable/legume intake, while the steatosis PRS interacted with fish intake and the TM6SF2 genotype interacted with red/processed meat intake, to affect LFC. Dietary effects on LFC were up to 3.8-fold higher in PNPLA3-rs738409-GG vs. -CC individuals, and 1.4-3.0-fold higher in the top vs. bottom quartile of the steatosis PRS. Gene-diet interactions were stronger in participants with vs. without overweight. The steatosis PRS interacted with Mediterranean diet and fruit/vegetable/legume intake to affect cT1 and most dietary and genetic predictors associated with risk of liver-related events or mortality by age 70. CONCLUSIONS Effects of diet on LFC and cT1 were markedly accentuated in patients at increased genetic risk for SLD, implying dietary interventions may be more impactful in these populations. IMPACT AND IMPLICATIONS Genetic variants and diet both influence risk of hepatic steatosis, inflammation/fibrosis, and hepatic decompensation; however, how gene-diet interactions influence these outcomes has previously not been comprehensively characterized. We investigated this topic in the community-based UK Biobank and found that genetic risk and dietary quality interacted to influence hepatic steatosis and inflammation/fibrosis on liver MRI, so that the effects of diet were greater in people at elevated genetic risk. These results are relevant for patients and medical providers because they show that genetic risk is not fixed (i.e. modifiable factors can mitigate or exacerbate this risk) and realistic dietary changes may result in meaningful improvement in liver steatosis and inflammation/fibrosis. As genotyping becomes more routinely used in clinical practice, patients identified to be at high baseline genetic risk may benefit even more from intensive dietary counseling than those at lower risk, though future prospective studies are required.
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Affiliation(s)
- Vincent L Chen
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Xiaomeng Du
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Antonino Oliveri
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Yanhua Chen
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Annapurna Kuppa
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Brian D Halligan
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Michael A Province
- Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
| | - Elizabeth K Speliotes
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
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Alvares-da-Silva MR, Ivancovsky-Wajcman D, Oliveira CP, Rabie S, Longo L, Uribe-Cruz C, Yoshimura SM, Joveleviths D, Ben-Yehoyada M, Grinshpan LS, Shibolet O, Kariv R, Zelber-Sagi S. High red meat consumption among PNPLA3 polymorphism carriers is associated with NAFLD in a multi-center cross-sectional study. Eur J Clin Nutr 2024; 78:442-448. [PMID: 38403728 DOI: 10.1038/s41430-024-01416-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 02/10/2024] [Accepted: 02/14/2024] [Indexed: 02/27/2024]
Abstract
BACKGROUND & AIM Patatin-like phospholipase domain-containing 3 gene (PNPLA3) polymorphism has been implicated in susceptibility to non-alcoholic fatty liver disease (NAFLD), with evidence for potential interaction with nutrition. However, the combination of meat consumption with genetic polymorphism has not been tested. Therefore, this study aims to test the association between the joint presence of PNPLA3 rs738409 G-allele with high meat consumption and NAFLD in populations with diverse meat consumption. METHODS A cross-sectional study among Israeli screening and Brazilian primary healthcare populations. Food consumption was assessed by a food-frequency questionnaire. PNPLA3 polymorphism was defined as homozygous (GG) or heterozygous (GC). Inconclusive/probable NAFLD was defined as a fatty liver index (FLI) ≥ 30 and probable NAFLD as FLI ≥ 60. RESULTS The sample included 511 subjects from the screening and primary healthcare populations (n = 213 and n = 298, respectively). Genetic polymorphism (homozygous GG or heterozygous GC) combined with high consumption of total meat, red and/or processed meat, unprocessed red meat, and processed meat was associated with the highest odds for inconclusive/probable NAFLD (OR = 2.75, 95%CI 1.27-5.97, p = 0.011; OR = 3.24, 1.43-7.34, p = 0.005; OR = 2.92, 1.32-6.47, p = 0.008; OR = 3.16, 1.46-6.83, p = 0.003, respectively), adjusting for age, gender, BMI, alcohol consumption, carbohydrate, and saturated fat intake. In addition, genetic polymorphism combined with high processed meat consumption was associated with the highest odds for probable NAFLD (OR = 2.40, 95%CI 1.04-5.56, p = 0.040). CONCLUSIONS High red meat intake may confer a greater risk for NAFLD among PNPLA3 polymorphism carriers. Prospective studies are needed to confirm these findings and consider minimizing red and processed meat consumption among PNPLA3 polymorphism carriers.
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Affiliation(s)
- Mario Reis Alvares-da-Silva
- GI/Liver Unit, Hospital de Clinicas de Porto Alegre, School of Medicine, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2350, Porto Alegre, 90035-903, Brazil
- CNPq researcher, Brasília, Brazil
| | | | - Claudia P Oliveira
- CNPq researcher, Brasília, Brazil
- Division of Clinical Gastroenterology and Hepatology (LIM-07), Hospital das Clinicas, Department of Gastroenterology, University of São Paulo School of Medicine, Av. Dr. Arnaldo 455, 3115, Cerqueira Cesar, 01246-903, Sao Paulo, Brazil
| | - Soheyla Rabie
- GI/Liver Unit, Hospital de Clinicas de Porto Alegre, School of Medicine, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2350, Porto Alegre, 90035-903, Brazil
| | - Larisse Longo
- GI/Liver Unit, Hospital de Clinicas de Porto Alegre, School of Medicine, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2350, Porto Alegre, 90035-903, Brazil
| | - Carolina Uribe-Cruz
- GI/Liver Unit, Hospital de Clinicas de Porto Alegre, School of Medicine, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2350, Porto Alegre, 90035-903, Brazil
| | - Silvia Massami Yoshimura
- Division of Clinical Gastroenterology and Hepatology (LIM-07), Hospital das Clinicas, Department of Gastroenterology, University of São Paulo School of Medicine, Av. Dr. Arnaldo 455, 3115, Cerqueira Cesar, 01246-903, Sao Paulo, Brazil
| | - Dvora Joveleviths
- GI/Liver Unit, Hospital de Clinicas de Porto Alegre, School of Medicine, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2350, Porto Alegre, 90035-903, Brazil
| | - Merav Ben-Yehoyada
- Department of Gastroenterology Tel-Aviv Medical Center, 6 Weizman St., Tel-Aviv, 6423906, Israel
| | - Laura Sol Grinshpan
- School of Public Health, University of Haifa, 199 Aba Khoushy Ave., Haifa, 3498838, Israel
| | - Oren Shibolet
- Department of Gastroenterology Tel-Aviv Medical Center, 6 Weizman St., Tel-Aviv, 6423906, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, 30 Haim Lebanon St., Tel-Aviv, 6139601, Israel
| | - Revital Kariv
- Department of Gastroenterology Tel-Aviv Medical Center, 6 Weizman St., Tel-Aviv, 6423906, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, 30 Haim Lebanon St., Tel-Aviv, 6139601, Israel
| | - Shira Zelber-Sagi
- School of Public Health, University of Haifa, 199 Aba Khoushy Ave., Haifa, 3498838, Israel.
- Department of Gastroenterology Tel-Aviv Medical Center, 6 Weizman St., Tel-Aviv, 6423906, Israel.
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Calcaterra V, Degrassi I, Taranto S, Porro C, Bianchi A, L’assainato S, Silvestro GS, Quatrale A, Zuccotti G. Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) and Thyroid Function in Childhood Obesity: A Vicious Circle? CHILDREN (BASEL, SWITZERLAND) 2024; 11:244. [PMID: 38397356 PMCID: PMC10887660 DOI: 10.3390/children11020244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/10/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a multisystem disorder characterized by the presence of fatty liver degeneration associated with excess adiposity or prediabetes/type 2 diabetes or metabolic dysregulation. An intricate relationship between the liver and thyroid has been reported in both health and disease. Simultaneously, there is a strong correlation between obesity and both MAFLD and thyroid dysfunction. In this narrative review, we highlighted the relationship between MAFLD and thyroid function in children and adolescents with obesity in order to explore how thyroid hormones (THs) act as predisposing factors in the onset, progression, and sustainability of MAFLD. THs are integral to the intricate balance of metabolic activities, ensuring energy homeostasis, and are indispensable for growth and development. Regarding liver homeostasis, THs have been suggested to interact with liver lipid homeostasis through a series of processes, including stimulating the entry of free fatty acids into the liver for esterification into triglycerides and increasing mitochondrial β-oxidation of fatty acids to impact hepatic lipid accumulation. The literature supports a correlation between MAFLD and obesity, THs and obesity, and MAFLD and THs; however, results in the pediatric population are very limited. Even though the underlying pathogenic mechanism involved in the relationship between MAFLD and thyroid function remains not fully elucidated, the role of THs as predisposing factors of MAFLD could be postulated. A potential vicious circle among these three conditions cannot be excluded. Identifying novel elements that may contribute to MAFLD could offer a practical approach to assessing children at risk of developing the condition.
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Affiliation(s)
- Valeria Calcaterra
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, 27100 Pavia, Italy
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Irene Degrassi
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Silvia Taranto
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Cecilia Porro
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Alice Bianchi
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Sara L’assainato
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Giustino Simone Silvestro
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Antonia Quatrale
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Gianvincenzo Zuccotti
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
- Department of Biomedical and Clinical Science “L. Sacco”, University of Milan, 20157 Milan, Italy
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10
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Liu Z, Huang H, Xie J, Shen QE, Xu C. Modifiable lifestyle factors, genetic and acquired risk, and the risk of severe liver disease in the UK Biobank cohort: (Lifestyle factors and SLD). Dig Liver Dis 2024; 56:130-136. [PMID: 37407315 DOI: 10.1016/j.dld.2023.06.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/04/2023] [Accepted: 06/19/2023] [Indexed: 07/07/2023]
Abstract
BACKGROUND Lifestyle intervention is important for the treatment of liver diseases. AIMS To clarify the association of healthy lifestyle with severe liver disease (SLD) and assessed whether genetic susceptibility and acquired fibrosis risk can modify the association. METHODS We included 417,986 UK Biobank participants who were free of SLD at baseline. Information on seven modifiable lifestyle factors was collected through a baseline questionnaire. SLD was defined as a medical diagnosis of cirrhosis, hepatocellular carcinoma or liver failure. Cox proportional hazards models were used to evaluate the association between healthy lifestyle factors and risk of incident SLD. The polygenic risk score (PRS) and fibrosis-4 index (FIB-4) were calculated and set as an interaction term. RESULTS During a median follow-up of 12.6 years, 4542 fatal and non-fatal SLD incidents were identified. A higher overall lifestyle score was associated with a significantly lower SLD risk (Ptrend <0.001). An increment of 1-point lifestyle score combined with a 1-SD increment in FIB-4 or PRS was associated with an additional reduction of 3% or 2% in SLD risk. CONCLUSIONS In European individuals, a healthy lifestyle is associated with a lower risk of incident SLD, which is more pronounced among individuals with a higher genetic and fibrosis risk.
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Affiliation(s)
- Zhening Liu
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, PR China
| | - Hangkai Huang
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, PR China
| | - Jiarong Xie
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, PR China; Department of Gastroenterology, Ningbo First Hospital, Ningbo 315010, PR China; Zhejiang Provincial Clinical Research Center for Digestive Diseases, Hangzhou 310003, PR China
| | - Qi-En Shen
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, PR China
| | - Chengfu Xu
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, PR China; Zhejiang Provincial Clinical Research Center for Digestive Diseases, Hangzhou 310003, PR China.
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11
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Lopez-Pentecost M, Tamez M, Mattei J, Jacobs ET, Thomson CA, Garcia DO. Adherence to a Traditional Mexican Diet Is Associated with Lower Hepatic Steatosis in US-Born Hispanics of Mexican Descent with Overweight or Obesity. Nutrients 2023; 15:4997. [PMID: 38068856 PMCID: PMC10708445 DOI: 10.3390/nu15234997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/22/2023] [Accepted: 11/28/2023] [Indexed: 12/18/2023] Open
Abstract
Hispanics of Mexican descent have disproportionate rates of non-alcoholic fatty liver disease (NAFLD). The purpose of this work is to investigate the association between the traditional Mexican diet score (tMexS) and hepatic steatosis and fibrosis, two NAFLD-related clinical endpoints, in Hispanic adults of Mexican descent. Data from 280 Hispanic adults of Mexican descent (n = 102 men, 178 women) with overweight or obesity enrolled in a cross-sectional observational study were analyzed. The tMexS was calculated from 24 h dietary recalls. Hepatic steatosis and fibrosis measurements were assessed using transient elastography (Fibroscan®). Linear regression models testing the association between tMexS and hepatic steatosis and fibrosis were run individually and through the stratification of significant modifiers. Mean tMexS were 5.9 ± 2.1, hepatic steatosis scores were 288.9 ± 48.9 dB/m, and fibrosis scores were 5.6 ± 2.2 kPa. Among the US-born group, with every point increase in the tMexS, there was a statistically significant 5.7 lower hepatic steatosis point (95% CI: -10.9, -0.6, p-value = 0.07). Higher adherence to a traditional Mexican diet was associated with lower hepatic steatosis in US-born Hispanics of Mexican descent. Findings from the current work may serve to inform future culturally relevant interventions for NAFLD prevention and management in individuals of Mexican descent.
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Affiliation(s)
- Melissa Lopez-Pentecost
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Martha Tamez
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA; (M.T.); (J.M.)
| | - Josiemer Mattei
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA; (M.T.); (J.M.)
| | - Elizabeth T. Jacobs
- University of Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA (C.A.T.); (D.O.G.)
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA
| | - Cynthia A. Thomson
- University of Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA (C.A.T.); (D.O.G.)
- Department of Health Promotion Sciences, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA
| | - David O. Garcia
- University of Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA (C.A.T.); (D.O.G.)
- Department of Health Promotion Sciences, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA
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12
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Younossi ZM, Zelber-Sagi S, Henry L, Gerber LH. Lifestyle interventions in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2023; 20:708-722. [PMID: 37402873 DOI: 10.1038/s41575-023-00800-4] [Citation(s) in RCA: 133] [Impact Index Per Article: 66.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/26/2023] [Indexed: 07/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a dynamic chronic liver disease that develops in close association with metabolic irregularities. Between 2016 and 2019, the global prevalence among adults was reported as 38% and among children and adolescents it was about 10%. NAFLD can be progressive and is associated with increased mortality from cardiovascular disease, extrahepatic cancers and liver complications. Despite these numerous adverse outcomes, no pharmacological treatments currently exist to treat nonalcoholic steatohepatitis, the progressive form of NAFLD. Therefore, the main treatment is the pursuit of a healthy lifestyle for both children and adults, which includes a diet rich in fruits, nuts, seeds, whole grains, fish and chicken and avoiding overconsumption of ultra-processed food, red meat, sugar-sweetened beverages and foods cooked at high heat. Physical activity at a level where one can talk but not sing is also recommended, including leisure-time activities and structured exercise. Avoidance of smoking and alcohol is also recommended. Policy-makers, community and school leaders need to work together to make their environments healthy by developing walkable and safe spaces with food stores stocked with culturally appropriate and healthy food items at affordable prices as well as providing age-appropriate and safe play areas in both schools and neighbourhoods.
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Affiliation(s)
- Zobair M Younossi
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA.
- Center for Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA, USA.
- Inova Medicine, Inova Health System, Falls Church, VA, USA.
| | | | - Linda Henry
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
- Inova Medicine, Inova Health System, Falls Church, VA, USA
| | - Lynn H Gerber
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
- Inova Medicine, Inova Health System, Falls Church, VA, USA
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13
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Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) refers to the accumulation of lipid laden vacuoles in hepatocytes, occurring in the context of visceral adiposity, insulin resistance and other features of the metabolic syndrome. Its more severe form (NASH, Non-Alcoholic Steatohepatitis) is becoming the leading aetiology of end-stage liver disease and hepatocellular carcinoma, and also contributes to cardiovascular disease, diabetes and extrahepatic malignancy. Management is currently limited to lifestyle modification and optimisation of the metabolic co-morbidities, with some of the drugs used for the latter also having shown some benefit for the liver. Licensed treatment modalities are currently lacking. A particular difficulty is the notorious heterogeneity of the patient population, which is poorly understood. A spectrum of disease severity associates in a non-linear way with a spectrum of severity of underlying metabolic factors. Heterogeneity of the liver in terms of mechanisms to cope with the metabolic and inflammatory stress and in terms of repair mechanisms, and a lack of knowledge hereof, further complicate the understanding of inter-individual variability. Genetic factors act as disease modifiers and potentially allow for some risk stratification, but also only explain a minor fraction of disease heterogeneity. Response to treatment shows a large variation in treatment response, again with little understanding of what is driving the absence of response in individual patients. Management can be tailored to patient's preferences in terms of diet modification, but tailoring treatment to knowledge on disease driving mechanisms in an individual patient is still in its infancy. Recent progress in analysing liver tissue as well as non-invasive tests hold, however, promise to rapidly improve our understanding of disease heterogeneity in NAFLD and provide individualised management.
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Affiliation(s)
- Sven M Francque
- Department of Gastroenterology Hepatology, Antwerp University Hospital, Drie Eikenstraat 655, B-2650, Edegem, Belgium.
- InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610, Wilrijk, Belgium.
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14
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Montemayor S, García S, Monserrat-Mesquida M, Tur JA, Bouzas C. Dietary Patterns, Foods, and Nutrients to Ameliorate Non-Alcoholic Fatty Liver Disease: A Scoping Review. Nutrients 2023; 15:3987. [PMID: 37764771 PMCID: PMC10534915 DOI: 10.3390/nu15183987] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/11/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease without pharmacological treatment yet. There is also a lack of specific dietary recommendations and strategies to treat the negative health impacts derived from NAFLD. OBJECTIVE This scoping review aimed to compile dietary patterns, foods, and nutrients to ameliorate NAFLD. METHODS A literature search was performed through MEDLINE, Scopus, Web of Science, and Google Scholar. RESULTS Several guidelines are available through the literature. Hypocaloric Mediterranean diet is the most accepted dietary pattern to tackle NAFLD. Coffee consumption (sugar free) may have a protective effect for NAFLD. Microbiota also plays a role in NAFLD; hence, fibre intake should be guaranteed. CONCLUSIONS A high-quality diet could improve liver steatosis. Weight loss through hypocaloric diet together with physical activity and limited sugar intake are good strategies for managing NAFLD. Specific dietary recommendations and a Mediterranean plate have been proposed to ameliorate NAFLD.
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Affiliation(s)
- Sofía Montemayor
- Research Group on Community Nutrition & Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain (C.B.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain
| | - Silvia García
- Research Group on Community Nutrition & Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain (C.B.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Margalida Monserrat-Mesquida
- Research Group on Community Nutrition & Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain (C.B.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Josep A. Tur
- Research Group on Community Nutrition & Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain (C.B.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Cristina Bouzas
- Research Group on Community Nutrition & Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain (C.B.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
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15
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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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16
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Kalafati IP, Dimitriou M, Revenas K, Kokkinos A, Deloukas P, Dedoussis GV. TM6SF2-rs58542926 Genetic Variant Modifies the Protective Effect of a "Prudent" Dietary Pattern on Serum Triglyceride Levels. Nutrients 2023; 15:1112. [PMID: 36904112 PMCID: PMC10005630 DOI: 10.3390/nu15051112] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/18/2023] [Accepted: 02/21/2023] [Indexed: 02/25/2023] Open
Abstract
The epidemic prevalence of non-alcoholic fatty liver disease (NAFLD), despite extensive research in the field, underlines the importance of focusing on personalized therapeutic approaches. However, nutrigenetic effects on NAFLD are poorly investigated. To this end, we aimed to explore potential gene-dietary pattern interactions in a NAFLD case-control study. The disease was diagnosed with liver ultrasound and blood collection was performed after an overnight fast. Adherence to four a posteriori, data-driven, dietary patterns was used to investigate interactions with PNPLA3-rs738409, TM6SF2-rs58542926, MBOAT7-rs641738, and GCKR-rs738409 in disease and related traits. IBM SPSS Statistics/v21.0 and Plink/v1.07 were used for statistical analyses. The sample consisted of 351 Caucasian individuals. PNPLA3-rs738409 was positively associated with disease odds (OR = 1.575, p = 0.012) and GCKR-rs738409 with lnC-reactive protein (CRP) (beta = 0.098, p = 0.003) and Fatty Liver Index (FLI) levels (beta = 5.011, p = 0.007). The protective effect of a "Prudent" dietary pattern on serum triglyceride (TG) levels in this sample was significantly modified by TM6SF2-rs58542926 (pinteraction = 0.007). TM6SF2-rs58542926 carriers may not benefit from a diet rich in unsaturated fatty acids and carbohydrates in regard to TG levels, a commonly elevated feature in NAFLD patients.
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Affiliation(s)
- Ioanna Panagiota Kalafati
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, 17671 Athens, Greece
- Department of Nutrition and Dietetics, School of Physical Education, Sport Science and Dietetics, University of Thessaly, 42100 Trikala, Greece
| | - Maria Dimitriou
- Department of Nutrition and Dietetics, School of Health Sciences, University of the Peloponnese, Antikalamos, 24100 Kalamata, Greece
| | | | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece
| | - Panos Deloukas
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - George V. Dedoussis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, 17671 Athens, Greece
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17
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Semmler G, Datz C, Trauner M. Eating, diet, and nutrition for the treatment of non-alcoholic fatty liver disease. Clin Mol Hepatol 2023; 29:S244-S260. [PMID: 36517001 PMCID: PMC10029946 DOI: 10.3350/cmh.2022.0364] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/06/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022] Open
Abstract
Nutrition and dietary interventions are a central component in the pathophysiology, but also a cornerstone in the management of patients with non-alcoholic fatty liver disease (NAFLD). Summarizing our rapidly advancing understanding of how our diet influences our metabolism and focusing on specific effects on the liver, we provide a comprehensive overview of dietary concepts to counteract the increasing burden of NAFLD. Specifically, we emphasize the importance of dietary calorie restriction independently of the macronutrient composition together with adherence to a Mediterranean diet low in added fructose and processed meat that seems to exert favorable effects beyond calorie restriction. Also, we discuss intermittent fasting as a type of diet specifically tailored to decrease liver fat content and increase ketogenesis, awaiting future study results in NAFLD. Finally, personalized dietary recommendations could be powerful tools to increase the effectiveness of dietary interventions in patients with NAFLD considering the genetic background and the microbiome, among others.
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Affiliation(s)
- Georg Semmler
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Christian Datz
- Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Oberndorf, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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18
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Vasconcellos C, Ferreira O, Lopes MF, Ribeiro AF, Vasques J, Guerreiro CS. Nutritional Genomics in Nonalcoholic Fatty Liver Disease. Biomedicines 2023; 11:biomedicines11020319. [PMID: 36830856 PMCID: PMC9953045 DOI: 10.3390/biomedicines11020319] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 01/24/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common chronic condition associated with genetic and environmental factors in which fat abnormally accumulates in the liver. NAFLD is epidemiologically associated with obesity, type 2 diabetes, and dyslipidemia. Environmental factors, such as physical inactivity and an unbalanced diet, interact with genetic factors, such as epigenetic mechanisms and polymorphisms for the genesis and development of the condition. Different genetic polymorphisms seem to be involved in this context, including variants in PNPLA3, TM6SF2, PEMT, and CHDH genes, playing a role in the disease's susceptibility, development, and severity. From carbohydrate intake and weight loss to omega-3 supplementation and caloric restriction, different dietary and nutritional factors appear to be involved in controlling the onset and progression of NAFLD conditions influencing metabolism, gene, and protein expression. The polygenic risk score represents a sum of trait-associated alleles carried by an individual and seems to be associated with NAFLD outcomes depending on the dietary context. Understanding the exact extent to which lifestyle interventions and genetic predispositions can play a role in the prevention and management of NAFLD can be crucial for the establishment of a personalized and integrative approach to patients.
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Affiliation(s)
- Carolina Vasconcellos
- Laboratório de Nutrição, Faculdade de Medicina, Centro Académico de Medicina de Lisboa, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Oureana Ferreira
- Laboratório de Nutrição, Faculdade de Medicina, Centro Académico de Medicina de Lisboa, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Marta Filipa Lopes
- Laboratório de Nutrição, Faculdade de Medicina, Centro Académico de Medicina de Lisboa, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - André Filipe Ribeiro
- Laboratório de Nutrição, Faculdade de Medicina, Centro Académico de Medicina de Lisboa, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - João Vasques
- Laboratório de Nutrição, Faculdade de Medicina, Centro Académico de Medicina de Lisboa, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Catarina Sousa Guerreiro
- Laboratório de Nutrição, Faculdade de Medicina, Centro Académico de Medicina de Lisboa, Universidade de Lisboa, 1649-028 Lisboa, Portugal
- Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
- Correspondence:
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19
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Barbieri E, Santoro N, Umano GR. Clinical features and metabolic complications for non-alcoholic fatty liver disease (NAFLD) in youth with obesity. Front Endocrinol (Lausanne) 2023; 14:1062341. [PMID: 36733529 PMCID: PMC9887046 DOI: 10.3389/fendo.2023.1062341] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 01/02/2023] [Indexed: 01/18/2023] Open
Abstract
Pediatric obesity has become in the last forty years the most common metabolic disease in children and adolescents affecting about 25% of the pediatric population in the western world. As obesity worsens, a whole-body insulin resistance (IR) occurs. This phenomenon is more pronounced during adolescence, when youth experience a high degree of insulin resistance due the production of growth hormone. As IR progresses, the blunted control of insulin on adipose tissue lipolysis causes an increased flux of fatty acids with FFA deposition in ectopic tissues and organs such as the liver, leading to the development of NAFLD. In this brief review, we will discuss the clinical implications of IR and NAFLD in the context of pediatric obesity. We will review the pathogenesis and the link between these two entities, the major pathophysiologic underpinnings, including the role of genetics and metagenomics, how these two entities lead to the development of type 2 diabetes, and which are the therapeutic options for NAFLD in youth.
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Affiliation(s)
| | - Nicola Santoro
- Department of Pediatrics, Kansas University Medical Center, Kansas City, KS, United States
- Department of Medicine and Health Sciences, “V. Tiberio” University of Molise, Campobasso, Italy
- Department of Pediatrics, Yale School of Medicine, New Haven, CT, United States
| | - Giuseppina Rosaria Umano
- Department of the Woman, the Child, and General and Specialized Surgery, University of Campania, Luigi Vanvitelli, Naples, Italy
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20
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What do we know about nutrient-based strategies targeting molecular mechanisms associated with obesity-related fatty liver disease? Ann Hepatol 2023; 28:100874. [PMID: 36371078 DOI: 10.1016/j.aohep.2022.100874] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 10/20/2022] [Indexed: 11/11/2022]
Abstract
Obesity is a risk factor for developing nonalcoholic fatty liver disease (NAFLD), and the associated molecular mechanisms could be targeted with nutrient-based strategies. Therefore, it is necessary to review the current mechanisms to propose further treatments. Obesity facilitates the onset of insulin resistance, lipidic abnormalities, hepatic fat accumulation, lipid peroxidation, mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, and inflammation, all related to further steatosis progression and fibrosis. Microbiota alterations can also influence liver disease by the translocation of pathogenic bacteria, energy extraction from short chain fatty acids (SCFAs), intestinal suppression of the expression of fasting-induced adipose factor (FIAF), reduction of bile acids, and altered choline metabolism. There are also genetic polymorphisms in metabolic proteins that predispose to a higher risk of liver diseases, such as those found in the patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) or also known as lysophosphatidylinositol acyltransferase 1 (LPIAT1), transmembrane channel-like 4 genes (TMC4), fat mass and obesity-associated protein (FTO), the b Klotho (KLB) and carboxylesterase (CES1). No clear dietary guidelines target all mechanisms related to NAFLD development and progression. However, energy and carbohydrate intake restriction, regular physical exercise, supplementation of antioxidants, and restoration of gut microbiota seem to have beneficial effects on the new proposed features of NAFLD.
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21
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Paolini E, Longo M, Meroni M, Tria G, Cespiati A, Lombardi R, Badiali S, Maggioni M, Fracanzani AL, Dongiovanni P. The I148M PNPLA3 variant mitigates niacin beneficial effects: How the genetic screening in non-alcoholic fatty liver disease patients gains value. Front Nutr 2023; 10:1101341. [PMID: 36937355 PMCID: PMC10018489 DOI: 10.3389/fnut.2023.1101341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 02/15/2023] [Indexed: 03/06/2023] Open
Abstract
Background The PNPLA3 p.I148M impact on fat accumulation can be modulated by nutrients. Niacin (Vitamin B3) reduced triglycerides synthesis in in vitro and in vivo NAFLD models. Objectives In this study, we aimed to investigate the niacin-I148M polymorphism crosstalk in NAFLD patients and examine niacin's beneficial effect in reducing fat by exploiting hepatoma cells with different PNPLA3 genotype. Design We enrolled 172 (Discovery cohort) and 358 (Validation cohort) patients with non-invasive and histological diagnosis of NAFLD, respectively. Dietary niacin was collected from food diary, while its serum levels were quantified by ELISA. Hepatic expression of genes related to NAD metabolism was evaluated by RNAseq in bariatric NAFLD patients (n = 183; Transcriptomic cohort). Hep3B (148I/I) and HepG2 (148M/M) cells were silenced (siHep3B) or overexpressed (HepG2I148+ ) for PNPLA3, respectively. Results In the Discovery cohort, dietary niacin was significantly reduced in patients with steatosis ≥ 2 and in I148M carriers. Serum niacin was lower in subjects carrying the G at risk allele and negatively correlated with obesity. The latter result was confirmed in the Validation cohort. At multivariate analysis, the I148M polymorphism was independently associated with serum niacin, supporting that it may be directly involved in the modulation of its availability. siHep3B cells showed an impaired NAD biosynthesis comparable to HepG2 cells which led to lower niacin efficacy in clearing fat, supporting a required functional protein to guarantee its effectiveness. Conversely, the restoration of PNPLA3 Wt protein in HepG2I148+ cells recovered the NAD pathway and improved niacin efficacy. Finally, niacin inhibited de novo lipogenesis through the ERK1/2/AMPK/SIRT1 pathway, with the consequent SREBP1-driven PNPLA3 reduction only in Hep3B and HepG2I148M+ cells. Conclusions We demonstrated a niacin-PNPLA3 I148M interaction in NAFLD patients which possibly pave the way to vitamin B3 supplementation in those with a predisposing genetic background.
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Affiliation(s)
- Erika Paolini
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, Milan, Italy
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giada Tria
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Annalisa Cespiati
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università Degli Studi di Milano, Milan, Italy
| | - Rosa Lombardi
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università Degli Studi di Milano, Milan, Italy
| | - Sara Badiali
- Department of Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Marco Maggioni
- Department of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università Degli Studi di Milano, Milan, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- *Correspondence: Paola Dongiovanni,
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22
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Ramos-Lopez O. Multi-Omics Nutritional Approaches Targeting Metabolic-Associated Fatty Liver Disease. Genes (Basel) 2022; 13:2142. [PMID: 36421817 PMCID: PMC9690481 DOI: 10.3390/genes13112142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 10/29/2023] Open
Abstract
Currently, metabolic-associated fatty liver disease (MAFLD) is a leading global cause of chronic liver disease, and is expected to become one of the most common indications of liver transplantation. MAFLD is associated with obesity, involving multiple mechanisms such as alterations in lipid metabolism, insulin resistance, hyperinflammation, mitochondrial dysfunction, cell apoptosis, oxidative stress, and extracellular matrix formation. However, the onset and progression of MAFLD is variable among individuals, being influenced by intrinsic (personal) and external environmental factors. In this context, sequence structural variants across the human genome, epigenetic phenomena (i.e., DNA methylation, histone modifications, and long non-coding RNAs) affecting gene expression, gut microbiota dysbiosis, and metabolomics/lipidomic fingerprints may account for differences in MAFLD outcomes through interactions with nutritional features. This knowledge may contribute to gaining a deeper understanding of the molecular and physiological processes underlying MAFLD pathogenesis and phenotype heterogeneity, as well as facilitating the identification of biomarkers of disease progression and therapeutic targets for the implementation of tailored nutritional strategies. This comprehensive literature review highlights the potential of nutrigenetic, nutriepigenetic, nutrimetagenomic, nutritranscriptomics, and nutrimetabolomic approaches for the prevention and management of MAFLD in humans through the lens of precision nutrition.
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Affiliation(s)
- Omar Ramos-Lopez
- Medicine and Psychology School, Autonomous University of Baja California, Tijuana 22390, Mexico
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23
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Cavalcante LN, Porto J, Mazo D, Longatto-Filho A, Stefano JT, Lyra AC, Carrilho FJ, Reis RM, Alves VAF, Sanyal AJ, Oliveira CP. African genetic ancestry is associated with lower frequency of PNPLA3 G allele in non-alcoholic fatty liver in an admixed population. Ann Hepatol 2022; 27:100728. [PMID: 35710086 DOI: 10.1016/j.aohep.2022.100728] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/06/2022] [Accepted: 05/19/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES PNPLA3 (rs738409) and TM6SF2 (rs58542926) variants, interindividual and ethnic differences may be risk factors for non-alcoholic fatty liver disease (NAFLD). The PNPLA3 G allele is associated with worse NAFLD evolution in Hispanics and Caucasians. TM6SF2 is associated with hypertriglyceridemia, NAFLD, and cardiovascular disease. We aimed to evaluate the association between genetic ancestry by Ancestry Informative Markers (AIM), PNPLA3 and TM6SF2 polymorphisms in patients with biopsy-proven NAFLD in an admixed population. METHODS We included adults with biopsy-proven NAFLD and excluded patients with the presence of other chronic liver disease, alcohol intake >100g/week, HIV, drug-induced fatty liver disease, or liver transplantation. We classified NAFLD using the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH-CRN) histological scoring system. The PNPLA3 (rs738409 c.444C>G) and TM6SF2 (rs58542926 c.449C>T) genotyping were performed by RT-PCR. Genetic ancestry was determined using 46 insertion-deletion AIM; α<0.05 was considered significant. RESULTS A total of 248 patients with NAFLD were enrolled [34 with simple steatosis (NAFL); 214 with NASH]. Overall, we detected a greater European ancestry contribution (0.645), followed by African (0.173), Amerindian (0.095), and East Asian (0.087) ancestry contribution, without differences between NAFL and NASH patients. However, we found a higher African genetic ancestry contribution among patients with NAFL who had the PNPLA3 C/C genotype than those with the G allele (0.216 ± 0.205 versus 0.105 ± 0.101, respectively; p=0.047). Ancestry contributions did not differ among TM6SF2 genotypes. CONCLUSION Among NAFL patients, greater African genetic ancestry was associated to a lower frequency of the PNPLA3 G allele, demonstrating a possible NASH ancestry-related protective factor.
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Affiliation(s)
| | - Jun Porto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos-SP, Brazil
| | - Daniel Mazo
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Adhemar Longatto-Filho
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Department of Pathology (LIM-14), Faculty of Medicine, University of São Paulo, Brazil; Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - José Tadeu Stefano
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Andre Castro Lyra
- Federal University of Bahia, School of Medicine, Gastroenterology and Hepatology Services & Salvador-BA, Brazil
| | - Flair Jose Carrilho
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil; Department of Pathology (LIM-14), Faculty of Medicine, University of São Paulo, Brazil; Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal
| | - Venâncio A F Alves
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Department of Pathology (LIM-14), Faculty of Medicine, University of São Paulo, Brazil
| | - Arun J Sanyal
- Institute of Liver Disease and Metabolic Health; Interim Chair, Div. of Gastroenterology; Virginia Commonwealth University, USA
| | - Claudia P Oliveira
- University of Sao Paulo, School of Medicine, Sao Paulo-SP, Brazil; Laboratory of Clinical and Experimental Gastroenterology (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
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24
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Zelber-Sagi S, Grinshpan LS, Ivancovsky-Wajcman D, Goldenshluger A, Gepner Y. One size does not fit all; practical, personal tailoring of the diet to NAFLD patients. Liver Int 2022; 42:1731-1750. [PMID: 35675167 DOI: 10.1111/liv.15335] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/03/2022] [Accepted: 06/06/2022] [Indexed: 02/13/2023]
Abstract
Different dietary regimens for weight loss have developed over the years. Since the most evidenced treatment for non-alcoholic fatty liver disease (NAFLD) is weight reduction, it is not surprising that more diets targeting obesity are also utilized for NAFLD treatment. However, beyond the desired weight loss effects, one should not ignore the dietary composition of each diet, which may not necessarily be healthy or safe over the long term for hepatic and extrahepatic outcomes, especially cardiometabolic outcomes. Some of these diets are rich in saturated fat and red meat, are very strict, and require close medical supervision. Some may also be very difficult to adhere to for long periods, thus reducing the patient's motivation. The evidence for a direct benefit to NAFLD by restrictive diets such as very-low-carb, ketogenic, very-low-calorie diets, and intermittent fasting is scarce, and the long-term safety has not been tested. Nowadays, the approach is that the diet should be tailored to the patient's cultural and personal preferences. There is strong evidence for the independent protective association of NAFLD with a diet based on healthy eating patterns of minimally-processed foods, low in sugar and saturated fat, high in polyphenols, and healthy types of fats. This leads to the conclusion that a Mediterranean diet should serve as a basis that can be restructured into other kinds of diets. This review will elaborate on the different diets and their role in NAFLD. It will provide a practical guide to tailor the diet to the patients without compromising its composition and safety.
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Affiliation(s)
- Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel.,Department of Gastroenterology Tel Aviv Medical Center, Tel Aviv, Israel
| | - Laura Sol Grinshpan
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel.,Department of Gastroenterology Tel Aviv Medical Center, Tel Aviv, Israel
| | - Dana Ivancovsky-Wajcman
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel.,Department of Gastroenterology Tel Aviv Medical Center, Tel Aviv, Israel
| | - Ariela Goldenshluger
- Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, and Sylvan Adams Sports Institute, Tel-Aviv University, Tel-Aviv, Israel
| | - Yftach Gepner
- Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, and Sylvan Adams Sports Institute, Tel-Aviv University, Tel-Aviv, Israel
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25
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Riccio S, Melone R, Vitulano C, Guida P, Maddaluno I, Guarino S, Marzuillo P, Miraglia del Giudice E, Di Sessa A. Advances in pediatric non-alcoholic fatty liver disease: From genetics to lipidomics. World J Clin Pediatr 2022; 11:221-238. [PMID: 35663007 PMCID: PMC9134151 DOI: 10.5409/wjcp.v11.i3.221] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/05/2021] [Accepted: 04/02/2022] [Indexed: 02/06/2023] Open
Abstract
As a result of the obesity epidemic, non-alcoholic fatty liver disease (NAFLD) represents a global medical concern in childhood with a closely related increased cardiometabolic risk. Knowledge on NAFLD pathophysiology has been largely expanded over the last decades. Besides the well-known key NAFLD genes (including the I148M variant of the PNPLA3 gene, the E167K allele of the TM6SF2, the GCKR gene, the MBOAT7-TMC4 rs641738 variant, and the rs72613567:TA variant in the HSD17B13 gene), an intriguing pathogenic role has also been demonstrated for the gut microbiota. More interestingly, evidence has added new factors involved in the "multiple hits" theory. In particular, omics determinants have been highlighted as potential innovative markers for NAFLD diagnosis and treatment. In fact, different branches of omics including metabolomics, lipidomics (in particular sphingolipids and ceramides), transcriptomics (including micro RNAs), epigenomics (such as DNA methylation), proteomics, and glycomics represent the most attractive pathogenic elements in NAFLD development, by providing insightful perspectives in this field. In this perspective, we aimed to provide a comprehensive overview of NAFLD pathophysiology in children, from the oldest pathogenic elements (including genetics) to the newest intriguing perspectives (such as omics branches).
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Affiliation(s)
- Simona Riccio
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Rosa Melone
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Caterina Vitulano
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Pierfrancesco Guida
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Ivan Maddaluno
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Stefano Guarino
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Emanuele Miraglia del Giudice
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Anna Di Sessa
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
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26
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Liver Steatosis: A Marker of Metabolic Risk in Children. Int J Mol Sci 2022; 23:ijms23094822. [PMID: 35563210 PMCID: PMC9100068 DOI: 10.3390/ijms23094822] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/24/2022] [Accepted: 04/24/2022] [Indexed: 11/16/2022] Open
Abstract
Obesity is one of the greatest health challenges affecting children of all ages and ethnicities. Almost 19% of children and adolescents worldwide are overweight or obese, with an upward trend in the last decades. These reports imply an increased risk of fat accumulation in hepatic cells leading to a series of histological hepatic damages gathered under the acronym NAFLD (Non-Alcoholic Fatty Liver Disease). Due to the complex dynamics underlying this condition, it has been recently renamed as 'Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)', supporting the hypothesis that hepatic steatosis is a key component of the large group of clinical and laboratory abnormalities of Metabolic Syndrome (MetS). This review aims to share the latest scientific knowledge on MAFLD in children in an attempt to offer novel insights into the complex dynamics underlying this condition, focusing on the novel molecular aspects. Although there is still no treatment with a proven efficacy for this condition, starting from the molecular basis of the disease, MAFLD's therapeutic landscape is rapidly expanding, and different medications seem to act as modifiers of liver steatosis, inflammation, and fibrosis.
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27
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Maternal polyunsaturated fatty acid concentrations during pregnancy and childhood liver fat accumulation. Clin Nutr 2022; 41:847-854. [DOI: 10.1016/j.clnu.2022.02.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/01/2021] [Accepted: 02/14/2022] [Indexed: 11/21/2022]
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28
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Panda C, Varadharaj S, Voruganti VS. PUFA, genotypes and risk for cardiovascular disease. Prostaglandins Leukot Essent Fatty Acids 2022; 176:102377. [PMID: 34915303 DOI: 10.1016/j.plefa.2021.102377] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 11/15/2021] [Accepted: 11/18/2021] [Indexed: 12/18/2022]
Abstract
Polyunsaturated fatty acids (PUFAs) are long chain fatty acids that are characterized by the presence of more than one double bond. These include fatty acids such as ꞷ-3-α-linolenic acid (ALA) and ꞷ-6 -linoleic acid (LA) which can only be obtained from dietary sources and are therefore termed essential fatty acids. They contain the building blocks for dihomo-γ-linolenic acid and arachidonic acid in the ꞷ-6 family as well as eicosapentaenoic acid and docosahexaenoic acid in the ꞷ-3 family. Both ALA and LA are important constituents of animal and plant cell membranes and are important components of anti-inflammatory and pro-inflammatory hormones and therefore, often modulate cellular immunity under chronic inflammatory states. The variation in physiological PUFA levels is under significant genetic influence, the fatty acid desaturase (FADS) genes being key regulators of PUFA metabolism. These genetic variants have been shown to alter fatty acid metabolism and influence the onset and progression of various metabolic conditions. This detailed review discusses the role of PUFAs, diet and genotypes in risk for cardiovascular diseases.
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Affiliation(s)
- Chinmayee Panda
- Department of Nutrition and Nutrition Research Institute, University of North Carolina at Chapel Hill, United States; Standard Process Inc, United States
| | | | - Venkata Saroja Voruganti
- Department of Nutrition and Nutrition Research Institute, University of North Carolina at Chapel Hill, United States.
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29
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Martínez-Montoro JI, Cornejo-Pareja I, Gómez-Pérez AM, Tinahones FJ. Impact of Genetic Polymorphism on Response to Therapy in Non-Alcoholic Fatty Liver Disease. Nutrients 2021; 13:4077. [PMID: 34836332 PMCID: PMC8625016 DOI: 10.3390/nu13114077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 12/13/2022] Open
Abstract
In the last decades, the global prevalence of non-alcoholic fatty liver disease (NAFLD) has reached pandemic proportions with derived major health and socioeconomic consequences; this tendency is expected to be further aggravated in the coming years. Obesity, insulin resistance/type 2 diabetes mellitus, sedentary lifestyle, increased caloric intake and genetic predisposition constitute the main risk factors associated with the development and progression of the disease. Importantly, the interaction between the inherited genetic background and some unhealthy dietary patterns has been postulated to have an essential role in the pathogenesis of NAFLD. Weight loss through lifestyle modifications is considered the cornerstone of the treatment for NAFLD and the inter-individual variability in the response to some dietary approaches may be conditioned by the presence of different single nucleotide polymorphisms. In this review, we summarize the current evidence on the influence of the association between genetic susceptibility and dietary habits in NAFLD pathophysiology, as well as the role of gene polymorphism in the response to lifestyle interventions and the potential interaction between nutritional genomics and other emerging therapies for NAFLD, such as bariatric surgery and several pharmacologic agents.
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Affiliation(s)
- José Ignacio Martínez-Montoro
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.I.M.-M.); (F.J.T.)
- Faculty of Medicine, University of Málaga, 29071 Málaga, Spain
| | - Isabel Cornejo-Pareja
- Instituto de Investigación Biomédica de Málaga (IBIMA), Virgen de la Victoria University Hospital, 29010 Málaga, Spain
- Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ana María Gómez-Pérez
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.I.M.-M.); (F.J.T.)
| | - Francisco J. Tinahones
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; (J.I.M.-M.); (F.J.T.)
- Faculty of Medicine, University of Málaga, 29071 Málaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Virgen de la Victoria University Hospital, 29010 Málaga, Spain
- Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBERObn), Instituto de Salud Carlos III, 28029 Madrid, Spain
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30
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Assessing Interactions between PNPLA3 and Dietary Intake on Liver Steatosis in Mexican-Origin Adults. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18137055. [PMID: 34280991 PMCID: PMC8296936 DOI: 10.3390/ijerph18137055] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/25/2021] [Accepted: 06/26/2021] [Indexed: 12/16/2022]
Abstract
Mexican-origin (MO) adults have among the highest rates of nonalcoholic fatty liver disease (NAFLD) placing them at increased risk of liver cancer. Evidence suggests that a single nucleotide polymorphism (SNP) in the PNPLA3 gene, rs738409, increases the risk and progression of NAFLD and may modify the relationship between certain dietary factors and liver steatosis. The purpose of this study was to identify whether interactions exist between specific dietary factors and rs738409 genotype status among MO adults in relation to levels of liver steatosis. We analyzed cross-sectional data from a sample of 288 MO adults. Participants completed at least two 24-h dietary recalls. Multiple linear regression was performed assuming an additive genetic model to test the main effects of several dietary variables on levels of hepatic steatosis, adjusting for covariates. To test for effect modification, the product of the genotype and the dietary variable was included as a covariate in the model. No significant association between dietary intake and level of hepatic steatosis was observed, nor any significant gene-diet interactions. Our findings suggest that dietary intake may have the same magnitude of protective or deleterious effect even among MO adults with high genetic risk for NAFLD and NAFLD progression.
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31
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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: 48] [Impact Index Per Article: 12.0] [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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Dallio M, Romeo M, Gravina AG, Masarone M, Larussa T, Abenavoli L, Persico M, Loguercio C, Federico A. Nutrigenomics and Nutrigenetics in Metabolic- (Dysfunction) Associated Fatty Liver Disease: Novel Insights and Future Perspectives. Nutrients 2021; 13:1679. [PMID: 34063372 PMCID: PMC8156164 DOI: 10.3390/nu13051679] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/12/2021] [Accepted: 05/13/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic- (dysfunction) associated fatty liver disease (MAFLD) represents the predominant hepatopathy and one of the most important systemic, metabolic-related disorders all over the world associated with severe medical and socio-economic repercussions due to its growing prevalence, clinical course (steatohepatitis and/or hepatocellular-carcinoma), and related extra-hepatic comorbidities. To date, no specific medications for the treatment of this condition exist, and the most valid recommendation for patients remains lifestyle change. MAFLD has been associated with metabolic syndrome; its development and progression are widely influenced by the interplay between genetic, environmental, and nutritional factors. Nutrigenetics and nutrigenomics findings suggest nutrition's capability, by acting on the individual genetic background and modifying the specific epigenetic expression as well, to influence patients' clinical outcome. Besides, immunity response is emerging as pivotal in this multifactorial scenario, suggesting the interaction between diet, genetics, and immunity as another tangled network that needs to be explored. The present review describes the genetic background contribution to MAFLD onset and worsening, its possibility to be influenced by nutritional habits, and the interplay between nutrients and immunity as one of the most promising research fields of the future in this context.
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Affiliation(s)
- Marcello Dallio
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Naples, Italy; (M.R.); (A.G.G.); (C.L.); (A.F.)
| | - Mario Romeo
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Naples, Italy; (M.R.); (A.G.G.); (C.L.); (A.F.)
| | - Antonietta Gerarda Gravina
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Naples, Italy; (M.R.); (A.G.G.); (C.L.); (A.F.)
| | - Mario Masarone
- Department of Medicine and Surgery, University of Salerno, Via Allende, 84081 Baronissi, Italy; (M.M.); (M.P.)
| | - Tiziana Larussa
- Department of Health Sciences, University Magna Graecia, viale Europa, 88100 Catanzaro, Italy; (T.L.); (L.A.)
| | - Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, viale Europa, 88100 Catanzaro, Italy; (T.L.); (L.A.)
| | - Marcello Persico
- Department of Medicine and Surgery, University of Salerno, Via Allende, 84081 Baronissi, Italy; (M.M.); (M.P.)
| | - Carmelina Loguercio
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Naples, Italy; (M.R.); (A.G.G.); (C.L.); (A.F.)
| | - Alessandro Federico
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Naples, Italy; (M.R.); (A.G.G.); (C.L.); (A.F.)
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Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD. Am J Gastroenterol 2021; 116:994-1006. [PMID: 33306506 PMCID: PMC8087619 DOI: 10.14309/ajg.0000000000001072] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 10/23/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION This study explored the relationship between patatin-like phospholipase domain-containing 3 gene (PNPLA3 rs738409), nutrient intake, and liver histology severity in patients with nonalcoholic fatty liver disease (NAFLD). METHODS PNPLA3-rs738409 variant was genotyped in 452 non-Hispanic whites with histologically confirmed NAFLD who completed Food Frequency Questionnaire within 6 months of their liver biopsy. The fibrosis severity on liver histology was the outcome of interest. RESULTS The distribution of PNPLA3 genotypes was CC: 28%, CG: 46%, and GG: 25%. High-carbohydrate (% of energy/d) intake was positively associated (adjusted [Adj] odds ratio [OR]: 1.03, P < 0.01), whereas higher n-3 polyunsaturated fatty acids (n-3 PUFAs) (g/d) (Adj. OR: 0.17, P < 0.01), isoflavones (mg/d) (Adj. OR: 0.74, P = 0.049), methionine (mg/d) (Adj. OR: 0.32, P < 0.01), and choline (mg/d) (Adj. OR: 0.32, P < 0.01) intakes were inversely associated with increased risk of significant fibrosis (stage of fibrosis ≥2). By using an additive model of inheritance, our moderation analysis showed that PNPLA3 rs738409 significantly modulates the relationship between carbohydrate (%), n-3 PUFAs, total isoflavones, methionine, and choline intakes and fibrosis severity in a dose-dependent, genotype manner. These dietary factors tended to have a larger and significant effect on fibrosis severity among rs738409 G-allele carriers. Associations between significant fibrosis and carbohydrates (Adj. OR: 1.04, P = 0.019), n-3 PUFAs (Adj. OR: 0.16, P < 0.01), isoflavones (Adj. OR: 0.65, P = 0.025), methionine (Adj. OR: 0.30, P < 0.01), and total choline (Adj. OR: 0.29, P < 0.01) intakes remained significant only among rs738409 G-allele carriers. DISCUSSION This gene-diet interaction study suggests that PNPLA3 rs738409 G-allele might modulate the effect of specific dietary nutrients on risk of fibrosis in patients with NAFLD.
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Perez-Diaz-Del-Campo N, Marin-Alejandre BA, Cantero I, Monreal JI, Elorz M, Herrero JI, Benito-Boillos A, Riezu-Boj JI, Milagro FI, Tur JA, Martinez JA, Abete I, Zulet MA. Differential response to a 6-month energy-restricted treatment depending on SH2B1 rs7359397 variant in NAFLD subjects: Fatty Liver in Obesity (FLiO) Study. Eur J Nutr 2021; 60:3043-3057. [PMID: 33474638 DOI: 10.1007/s00394-020-02476-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Non-alcoholic fatty liver disease (NAFLD) is worldwide recognized as the most common cause of chronic liver disease. Current NAFLD clinical management relies on lifestyle change, nevertheless, the importance of the genetic make-up on liver damage and the possible interactions with diet are still poorly understood. The aim of the study was to evaluate the influence of the SH2B1 rs7359397 genetic variant on changes in body composition, metabolic status and liver health after 6-month energy-restricted treatment in overweight/obese subjects with NAFLD. In addition, gene-treatment interactions over the course of the intervention were examined. METHODS The SH2B1 genetic variant was genotyped in 86 overweight/obese subjects with NAFLD from the FLiO study (Fatty Liver in Obesity study). Subjects were metabolically evaluated at baseline and at 6-months. Liver assessment included ultrasonography, Magnetic Resonance Imaging, elastography, a lipidomic test (OWL®-test) and specific blood liver biomarkers. Additionally, body composition, general biochemical markers and dietary intake were determined. RESULTS Both genotypes significantly improved their body composition, general metabolic status and liver health after following an energy-restricted strategy. Liver imaging techniques showed a greater decrease in liver fat content (- 44.3%, p < 0.001) and in serum ferritin levels (p < 0.001) in the carriers of the T allele after the intervention. Moreover, lipidomic analysis, revealed a higher improvement in liver status when comparing risk vs. no-risk genotype (p = 0.006 vs. p = 0.926, respectively). Gene-treatment interactions showed an increase in fiber intake and omega-3 fatty acid in risk genotype (p interaction = 0.056 and p interaction = 0.053, respectively), while a significant increase in MedDiet score was observed in both genotype groups (p = 0.020). Moreover, no-risk genotype presented a relevant decrease in hepatic iron as well as in MUFA intake (p = 0.047 and p = 0.034, respectively). CONCLUSION Subjects carrying the T allele of the rs7359397 polymorphism may benefit more in terms of hepatic health and liver status when prescribed an energy-restricted treatment, where a Mediterranean dietary pattern rich in fiber and other components such as omega-3 fatty acids might boost the benefits. TRIAL REGISTRATION The Fatty Liver in Obesity was approved by the Research Ethics Committee of the University of Navarra and retrospectively registered (NCT03183193; www.clinicaltrials.gov ); June 2017.
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Affiliation(s)
- Nuria Perez-Diaz-Del-Campo
- Department of Nutrition, Food Sciences and Physiology, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
| | - Bertha Araceli Marin-Alejandre
- Department of Nutrition, Food Sciences and Physiology, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
| | - Irene Cantero
- Department of Nutrition, Food Sciences and Physiology, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
| | - J Ignacio Monreal
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
- Clinical Chemistry Department, Clínica Universidad de Navarra, 31008, Pamplona, Spain
| | - Mariana Elorz
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
- Department of Radiology, Clínica Universidad de Navarra, 31008, Pamplona, Spain
| | - José Ignacio Herrero
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
- Liver Unit, Clínica Universidad de Navarra, 31008, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029, Madrid, Spain
| | - Alberto Benito-Boillos
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
- Department of Radiology, Clínica Universidad de Navarra, 31008, Pamplona, Spain
| | - Jose I Riezu-Boj
- Department of Nutrition, Food Sciences and Physiology, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
| | - Fermín I Milagro
- Department of Nutrition, Food Sciences and Physiology, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
- Biochemical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Josep A Tur
- Biochemical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain
- Research Group on Community Nutrition and Oxidative Stress, University of Balearic Islands & Balearic Islands Institute for Health Research (IDISBA), 07122, Palma, Spain
| | - J Alfredo Martinez
- Department of Nutrition, Food Sciences and Physiology, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
- Biochemical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Itziar Abete
- Department of Nutrition, Food Sciences and Physiology, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain.
- Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain.
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain.
- Biochemical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain.
| | - M Angeles Zulet
- Department of Nutrition, Food Sciences and Physiology, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain.
- Centre for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain.
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain.
- Biochemical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, 28029, Madrid, Spain.
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Nutrients, Genetic Factors, and Their Interaction in Non-Alcoholic Fatty Liver Disease and Cardiovascular Disease. Int J Mol Sci 2020; 21:ijms21228761. [PMID: 33228237 PMCID: PMC7699550 DOI: 10.3390/ijms21228761] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/15/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and expose patients to increased risk of hepatic and cardiovascular (CV) morbidity and mortality. Both environmental factors and genetic predisposition contribute to the risk. An inappropriate diet, rich in refined carbohydrates, especially fructose, and saturated fats, and poor in fibers, polyunsaturated fats, and vitamins is one of the main key factors, as well as the polymorphism of patatin-like phospholipase domain containing 3 (PNPLA3 gene) for NAFLD and the apolipoproteins and the peroxisome proliferator-activated receptor (PPAR) family for the cardiovascular damage. Beyond genetic influence, also epigenetics modifications are responsible for various clinical manifestations of both hepatic and CV disease. Interestingly, data are accumulating on the interplay between diet and genetic and epigenetic modifications, modulating pathogenetic pathways in NAFLD and CV disease. We report the main evidence from literature on the influence of both macro and micronutrients in NAFLD and CV damage and the role of genetics either alone or combined with diet in increasing the risk of developing both diseases. Understanding the interaction between metabolic alterations, genetics and diet are essential to treat the diseases and tailoring nutritional therapy to control NAFLD and CV risk.
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Van Name MA, Savoye M, Chick JM, Galuppo BT, Feldstein AE, Pierpont B, Johnson C, Shabanova V, Ekong U, Valentino PL, Kim G, Caprio S, Santoro N. A Low ω-6 to ω-3 PUFA Ratio (n-6:n-3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth. J Nutr 2020; 150:2314-2321. [PMID: 32652034 PMCID: PMC7467848 DOI: 10.1093/jn/nxaa183] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 02/28/2020] [Accepted: 06/08/2020] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Recent literature suggests that the Western diet's imbalance between high ω-6 (n-6) and low ω-3 (n-3) PUFA intake contributes to fatty liver disease in obese youth. OBJECTIVES We tested whether 12 wk of a low n-6:n-3 PUFA ratio (4:1) normocaloric diet mitigates fatty liver and whether the patatin-like containing domain phospholipase 3 (PNPLA3) rs738409 variant affects the response. METHODS In a single-arm unblinded study, obese youth 9-19 y of age with nonalcoholic fatty liver disease were treated with a normocaloric low n-6:n-3 PUFA ratio diet for 12 wk. The primary outcome was change in hepatic fat fraction (HFF%), measured by abdominal MRI. Metabolic parameters included alanine aminotransferase (ALT), lipids, measures of insulin sensitivity, and plasma oxidized linoleic acid metabolites (OXLAMs). Outcomes were also analyzed by PNPLA3 rs738409 genotype. Wilcoxon's signed rank test, the Mann-Whitney U test, and covariance pattern modeling were used. RESULTS Twenty obese adolescents (median age: 13.3 y; IQR: 10.5-16.4 y) were enrolled and 17 completed the study. After 12 wk of dietary intervention, HFF% decreased by 25.8% (P = 0.009) despite stable weight. We observed a 34.4% reduction in ALT (P = 0.001), 21.9% reduction in triglycerides (P = 0.046), 3.28% reduction in LDL cholesterol (P = 0.071), and a 26.3% improvement in whole body insulin sensitivity (P = 0.032). The OXLAMs 9-hydroxy-octadecandienoic acid (9-HODE) (P = 0.011), 13-HODE (P = 0.007), and 9-oxo-octadecadienoic acid (9-oxoODE) (P = 0.024) decreased after 12 wk. HFF% declined in both the not-at-risk (CC/CG) and at-risk (GG) PNPLA3 rs738409 genotype groups, with significant (P = 0.016) HFF% reduction in the GG group. Changes in 9-HODE (P = 0.023), 9-oxoODE (P = 0.009), and 13-oxoODE (P = 0.003) differed between the 2 genotype groups over time. CONCLUSIONS These data suggest that, independently of weight loss, a low n-6:n-3 PUFA diet ameliorates the metabolic phenotype of adolescents with fatty liver disease and that response to this diet is modulated by the PNPLA3 rs738409 genotype.This trial was registered at clinicaltrials.gov as NCT01556113.
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Affiliation(s)
| | - Mary Savoye
- Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA
| | - Jennifer M Chick
- Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA
| | | | - Ariel E Feldstein
- Division of Pediatric Gastrointestinal Diseases, Hepatology, and Nutrition, University of California San Diego, San Diego, CA, USA
| | - Bridget Pierpont
- Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA
| | - Casey Johnson
- Division of Pediatric Gastrointestinal Diseases, Hepatology, and Nutrition, University of California San Diego, San Diego, CA, USA
| | | | - Udeme Ekong
- Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA
| | | | - Grace Kim
- Seattle Children's Hospital, Seattle, WA, USA
| | - Sonia Caprio
- Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA
| | - Nicola Santoro
- Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA
- Department of Medicine and Health Sciences, “V. Tiberio,” University of Molise, Campobasso, Italy
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Li J, Hua W, Ji C, Rui J, Zhao Y, Xie C, Shi B, Yang X. Effect of the patatin-like phospholipase domain containing 3 gene (PNPLA3) I148M polymorphism on the risk and severity of nonalcoholic fatty liver disease and metabolic syndromes: A meta-analysis of paediatric and adolescent individuals. Pediatr Obes 2020; 15:e12615. [PMID: 32020770 DOI: 10.1111/ijpo.12615] [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: 09/24/2019] [Revised: 12/06/2019] [Accepted: 12/19/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND The effect of the patatin-like phospholipase domain containing 3 gene (PNPLA3) I148M polymorphism on the risk and severity of paediatric and adolescent nonalcoholic fatty liver disease (NAFLD) remains inconclusive. OBJECTIVES We aimed to estimate the effect of this polymorphism not only on early-onset NAFLD risk and severity but also on metabolic syndromes susceptibility. METHODS A systematic literature search was performed to identify relevant datasets. The odds ratio of the dichotomic variables and the standardized mean difference of quantitative variables with corresponding 95% confidence intervals were calculated to assess the strength of the associations. RESULTS Twenty-seven studies comprising 10 070 subjects were eligible. The summary effect showed that this polymorphism increased susceptibility to NAFLD development. Furthermore, it also indicated that nonalcoholic steatohepatitis (NASH) was more frequently observed in G allele carriers among paediatric and adolescent NAFLD patients. Moreover, the meta-analysis suggested that the variant was significantly associated with elevated liver damage indexes, including serum alanine transaminase, aspartate transaminase, gamma-glutamyltransferase concentrations, and liver fat content. However, the summary estimates for insulin resistance, lipid metabolism, and adiposity showed no significant associations. CONCLUSIONS The PNPLA3 I148M polymorphism is associated with elevated early-onset NAFLD risk, severity, and liver damage but not with related metabolic syndromes.
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Affiliation(s)
- Jiaying Li
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China.,Medical College, Soochow University, Suzhou, China
| | - Wenxi Hua
- Medical College, Soochow University, Suzhou, China
| | - Cheng Ji
- School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China
| | - Jingwen Rui
- Medical College, Soochow University, Suzhou, China
| | - Yuening Zhao
- Medical College, Soochow University, Suzhou, China
| | - Chenyao Xie
- Medical College, Soochow University, Suzhou, China
| | - Bimin Shi
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaoqin Yang
- School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China
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Carlsson B, Lindén D, Brolén G, Liljeblad M, Bjursell M, Romeo S, Loomba R. Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2020; 51:1305-1320. [PMID: 32383295 PMCID: PMC7318322 DOI: 10.1111/apt.15738] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/13/2020] [Accepted: 03/29/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) characterised by liver fat accumulation, inflammation and progressive fibrosis. Emerging data indicate that genetic susceptibility increases risks of NAFLD, NASH and NASH-related cirrhosis. AIMS To review NASH genetics and discuss the potential for precision medicine approaches to treatment. METHOD PubMed search and inclusion of relevant literature. RESULTS Single-nucleotide polymorphisms in PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 are clearly associated with NASH development or progression. These genetic variants are common and have moderate-to-large effect sizes for development of NAFLD, NASH and hepatocellular carcinoma (HCC). The genes play roles in lipid remodelling in lipid droplets, hepatic very low-density lipoprotein (VLDL) secretion and de novo lipogenesis. The PNPLA3 I148M variant (rs738409) has large effects, with approximately twofold increased odds of NAFLD and threefold increased odds of NASH and HCC per allele. Obesity interacts with PNPLA3 I148M to elevate liver fat content and increase rates of NASH. Although the isoleucine-to-methionine substitution at amino acid position 148 of the PNPLA3 enzyme inactivates its lipid remodelling activity, the effect of PNPLA3 I148M results from trans-repression of another lipase (ATGL/PNPLA2) by sequestration of a shared cofactor (CGI-58/ABHD5), leading to decreased hepatic lipolysis and VLDL secretion. In homozygous Pnpla3 I148M knock-in rodent models of NAFLD, targeted PNPLA3 mRNA knockdown reduces hepatic steatosis, inflammation and fibrosis. CONCLUSION The emerging genetic and molecular understanding of NASH paves the way for novel interventions, including precision medicines that can modulate the activity of specific genes associated with NASH.
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Affiliation(s)
- Björn Carlsson
- Research and Early DevelopmentCardiovascular, Renal and MetabolismBioPharmaceuticals R&DAstraZenecaGothenburgSweden
| | - Daniel Lindén
- Research and Early DevelopmentCardiovascular, Renal and MetabolismBioPharmaceuticals R&DAstraZenecaGothenburgSweden,Division of EndocrinologyDepartment of Neuroscience and PhysiologySahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Gabriella Brolén
- Precision MedicineCardiovascular, Renal and MetabolismR&DAstraZenecaGothenburgSweden
| | - Mathias Liljeblad
- Research and Early DevelopmentCardiovascular, Renal and MetabolismBioPharmaceuticals R&DAstraZenecaGothenburgSweden
| | - Mikael Bjursell
- Research and Early DevelopmentCardiovascular, Renal and MetabolismBioPharmaceuticals R&DAstraZenecaGothenburgSweden
| | - Stefano Romeo
- Department of Molecular and Clinical MedicineUniversity of GothenburgGothenburgSweden,Clinical Nutrition UnitDepartment of Medical and Surgical SciencesMagna Graecia UniversityCatanzaroItaly,Cardiology DepartmentSahlgrenska University HospitalGothenburgSweden
| | - Rohit Loomba
- NAFLD Research CenterDivision of GastroenterologyUniversity of California San DiegoSan DiegoCAUSA
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Eslam M, Sanyal AJ, George J. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology 2020; 158:1999-2014.e1. [PMID: 32044314 DOI: 10.1053/j.gastro.2019.11.312] [Citation(s) in RCA: 2155] [Impact Index Per Article: 431.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/27/2019] [Accepted: 11/05/2019] [Indexed: 12/02/2022]
Abstract
Fatty liver associated with metabolic dysfunction is common, affects a quarter of the population, and has no approved drug therapy. Although pharmacotherapies are in development, response rates appear modest. The heterogeneous pathogenesis of metabolic fatty liver diseases and inaccuracies in terminology and definitions necessitate a reappraisal of nomenclature to inform clinical trial design and drug development. A group of experts sought to integrate current understanding of patient heterogeneity captured under the acronym nonalcoholic fatty liver disease (NAFLD) and provide suggestions on terminology that more accurately reflects pathogenesis and can help in patient stratification for management. Experts reached consensus that NAFLD does not reflect current knowledge, and metabolic (dysfunction) associated fatty liver disease "MAFLD" was suggested as a more appropriate overarching term. This opens the door for efforts from the research community to update the nomenclature and subphenotype the disease to accelerate the translational path to new treatments.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
| | - Arun J Sanyal
- Virginia Commonwealth University School of Medicine, Richmond, Virginia.
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
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Meroni M, Longo M, Rustichelli A, Dongiovanni P. Nutrition and Genetics in NAFLD: The Perfect Binomium. Int J Mol Sci 2020; 21:ijms21082986. [PMID: 32340286 PMCID: PMC7215858 DOI: 10.3390/ijms21082986] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/19/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents a global healthcare burden since it is epidemiologically related to obesity, type 2 diabetes (T2D) and Metabolic Syndrome (MetS). It embraces a wide spectrum of hepatic injuries, which include simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The susceptibility to develop NAFLD is highly variable and it is influenced by several cues including environmental (i.e., dietary habits and physical activity) and inherited (i.e., genetic/epigenetic) risk factors. Nonetheless, even intestinal microbiota and its by-products play a crucial role in NAFLD pathophysiology. The interaction of dietary exposure with the genome is referred to as 'nutritional genomics,' which encompasses both 'nutrigenetics' and 'nutriepigenomics.' It is focused on revealing the biological mechanisms that entail both the acute and persistent genome-nutrient interactions that influence health and it may represent a promising field of study to improve both clinical and health nutrition practices. Thus, the premise of this review is to discuss the relevance of personalized nutritional advices as a novel therapeutic approach in NAFLD tailored management.
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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.); (A.R.)
- 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, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (A.R.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milano, Italy
| | - Alice Rustichelli
- 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.); (A.R.)
| | - 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.); (A.R.)
- Correspondence: ; Tel.: +39-02-5503-3467; Fax: +39-02-5503-4229
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41
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Abstract
Nonalcoholic fatty liver disease is strongly associated with obesity and the metabolic syndrome, but genetic factors also contribute to disease susceptibility. Human genetic studies have identified several common genetic variants contributing to nonalcoholic fatty liver disease initiation and progression. These findings have provided new insights into the pathogenesis of nonalcoholic fatty liver disease and opened up new avenues for the development of therapeutic interventions. In this review, we summarize the current state of knowledge about the genetic determinants of nonalcoholic fatty liver disease, focusing on the most robustly validated genetic risk factors and on recently discovered modifiers of disease progression.
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Affiliation(s)
- Julia Kozlitina
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8591, USA.
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42
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Quesada-Vázquez S, Aragonès G, Del Bas JM, Escoté X. Diet, Gut Microbiota and Non-Alcoholic Fatty Liver Disease: Three Parts of the Same Axis. Cells 2020; 9:E176. [PMID: 31936799 PMCID: PMC7016763 DOI: 10.3390/cells9010176] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/04/2020] [Accepted: 01/07/2020] [Indexed: 01/30/2023] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common liver disease in the world. NAFLD is principally characterized by an excessive fat accumulation in the hepatocytes. Diet is considered as one of the main drivers to modulate the composition of gut microbiota, which participate in different processes, affecting human metabolism. A disruption in the homeostasis of gut microbiota may lead to dysbiosis, which is commonly reflected by a reduction of the beneficial species and an increment in pathogenic microbiota. Gut and liver are in close relation due to the anatomical and functional interactions led by the portal vein, thus altered intestinal microbiota might affect liver functions, promoting inflammation, insulin resistance and steatosis, which is translated into NAFLD. This review will highlight the association between diet, gut microbiota and liver, and how this axis may promote the development of NAFLD progression, discussing potential mechanisms and alterations due to the dysbiosis of gut microbiota. Finally, it will revise the variations in gut microbiota composition in NAFLD, and it will focus in specific species, which directly affect NAFLD progression.
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Affiliation(s)
- Sergio Quesada-Vázquez
- Unitat de Nutrició i Salut, Centre Tecnològic de Catalunya, Eurecat, 43204 Reus, Spain; (S.Q.-V.); (J.M.D.B.)
| | - Gerard Aragonès
- Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, Nutrigenomics Research Group, 43007 Tarragona, Spain;
| | - Josep M Del Bas
- Unitat de Nutrició i Salut, Centre Tecnològic de Catalunya, Eurecat, 43204 Reus, Spain; (S.Q.-V.); (J.M.D.B.)
| | - Xavier Escoté
- Unitat de Nutrició i Salut, Centre Tecnològic de Catalunya, Eurecat, 43204 Reus, Spain; (S.Q.-V.); (J.M.D.B.)
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43
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Huang T, Wang T, Heianza Y, Zheng Y, Sun D, Kang JH, Pasquale LR, Rimm EB, Manson JE, Hu FB, Qi L. Habitual consumption of long-chain n-3 PUFAs and fish attenuates genetically associated long-term weight gain. Am J Clin Nutr 2019; 109:665-673. [PMID: 30629107 PMCID: PMC6408206 DOI: 10.1093/ajcn/nqy238] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 07/25/2018] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND A growing amount of data suggests that n-3 (ω-3) polyunsaturated fatty acid (PUFA) intake may modify the genetic association with weight change. OBJECTIVES We aimed to prospectively test interactions of habitual consumption of n-3 PUFAs or fish, the major food source, with overall genetic susceptibility on long-term weight change. DESIGN Gene-diet interactions were examined in 11,330 women from the Nurses' Health Study (NHS), 6773 men from the Health Professionals Follow-Up Study (HPFS), and 6254 women from the Women's Health Initiative (WHI). RESULTS In the NHS and HPFS cohorts, food-sourced long-chain n-3 PUFA intake showed directionally consistent interactions with genetic risk score on long-term changes in BMI (P-interaction = 0.01 in the HPFS, 0.15 in the NHS, and 0.01 in both cohorts combined). Such interactions were successfully replicated in the WHI, an independent cohort (P-interaction = 0.02 in the WHI and 0.01 in the combined 3 cohorts). The genetic associations with changes in BMI (in kg/m2) consistently decreased (0.15, 0.10, 0.07, and -0.14 per 10 BMI-increasing alleles) across the quartiles of long-chain n-3 PUFAs in the combined cohorts. In addition, high fish intake also attenuated the genetic associations with long-term changes in BMI in the HPFS (P-interaction = 0.01), NHS (P-interaction = 0.03), WHI (P-interaction = 0.10), and the combined cohorts (P-interaction = 0.01); and the differences in BMI changes per 10 BMI-increasing alleles were 0.16, 0.06, -0.08, and -0.18, respectively, across the categories (≤1, 1∼4, 4∼6, and ≥7 servings/wk) of total fish intake. Similar interactions on body weight were observed for fish intake (P-interaction = 0.003) and long-chain n-3 PUFA intake (P-interaction = 0.12). CONCLUSION Our study provides replicable evidence to show that high intakes of fish and long-chain n-3 PUFAs are associated with an attenuation of the genetic association with long-term weight gain based on results from 3 prospective cohorts of Caucasians.
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Affiliation(s)
- Tao Huang
- Department of Epidemiology and Biostatistics, Beijing, China,Department of Global Health, School of Public Health, Beijing, China,Global Health Institute, Peking University, Beijing, China,Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
| | - Tiange Wang
- Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Yoriko Heianza
- Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA
| | - Yan Zheng
- State Key Laboratory of Genetic Engineering, Human Phenome Institute and School of Life Sciences, Fudan University, Shanghai, China
| | - Dianjianyi Sun
- Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA
| | - Jae H Kang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Louis R Pasquale
- Department of Nutrition, Boston, MA,Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA
| | - Eric B Rimm
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA,Department of Nutrition, Boston, MA,Department of Epidemiology, Harvard School of Public Health, Boston, MA
| | - JoAnn E Manson
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA,Department of Nutrition, Boston, MA,Department of Epidemiology, Harvard School of Public Health, Boston, MA
| | - Frank B Hu
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA,Department of Nutrition, Boston, MA,Department of Epidemiology, Harvard School of Public Health, Boston, MA
| | - Lu Qi
- Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA,Department of Nutrition, Boston, MA,Address correspondence to LQ (e-mail: )
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44
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Kovalic AJ, Banerjee P, Tran QT, Singal AK, Satapathy SK. Genetic and Epigenetic Culprits in the Pathogenesis of Nonalcoholic Fatty Liver Disease. J Clin Exp Hepatol 2018; 8:390-402. [PMID: 30564000 PMCID: PMC6286466 DOI: 10.1016/j.jceh.2018.04.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 04/18/2018] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) constitutes a wide spectrum of liver pathology with hepatic steatosis at the core of this pathogenesis. Variations of certain genetic components have demonstrated increased susceptibility for hepatic steatosis. Therefore, these inciting variants must be further characterized in order to ultimately provide effective, targeted therapies for NAFLD and will be the focus of this review. Several genetic variants revealed an association with NAFLD through Genome-wide Association Study, meta-analyses, and retrospective case-control studies. PNPLA3 rs738409 and TM6SF2 rs58542926 are the two genetic variants providing the strongest evidence for association with NAFLD. However, it remains to be determined if these genetic variants serve as the primary culprit which induces the pathogenesis of NAFLD. Prospective and intervention studies are urgently needed to firmly establish a cause-and-effect relationship between the presence of certain genetic variants and risk of NAFLD development and progression.
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Key Words
- 1H-MRS, Proton Magnetic Resonance Spectroscopy
- ACC2, Acetyl-CoA Carboxylase 2
- ACLY, ATP Citrate Lyase
- BMI, Body Mass Index
- CK-18, Cytokeratin 18
- CT, Computed Tomography
- FASN, Fatty Acid Synthase
- GWAS, Genome-wide Association Study
- HCC, Hepatocellular Carcinoma
- LT, Liver Transplantation
- NAFLD, Nonalcoholic Fatty Liver Disease
- NASH, Nonalcoholic Steatohepatitis
- SCD1, Stearoyl-CoA Desaturase 1
- SNP, Single Nucleotide Polymorphism
- US, Ultrasonography
- epigenetics
- genetic polymorphisms
- genetic variants
- miRNA, MicroRNA
- nonalcoholic fatty liver disease
- single nucleotide polymorphisms
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Affiliation(s)
- Alexander J. Kovalic
- Wake Forest Baptist Medical Center, Department of Internal Medicine, Winston-Salem, NC, United States
| | - Pratik Banerjee
- University of Memphis, School of Public Health, Division of Epidemiology, Biostatistics, and Environmental Health, Memphis, TN, United States
| | - Quynh T. Tran
- University of Tennessee Health Science Center, Department of Preventive Medicine, Memphis, TN, United States
| | - Ashwani K. Singal
- University of Alabama at Birmingham, Department of Medicine, Division of Gastroenterology and Hepatology, Birmingham, AL, United States
| | - Sanjaya K. Satapathy
- University of Tennessee Health Science Center, Methodist University Hospital Transplant Institute, Memphis, TN, United States
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45
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Tricò D, Caprio S, Rosaria Umano G, Pierpont B, Nouws J, Galderisi A, Kim G, Mata MM, Santoro N. Metabolic Features of Nonalcoholic Fatty Liver (NAFL) in Obese Adolescents: Findings From a Multiethnic Cohort. Hepatology 2018; 68:1376-1390. [PMID: 29665034 PMCID: PMC6173637 DOI: 10.1002/hep.30035] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 04/06/2018] [Indexed: 12/28/2022]
Abstract
UNLABELLED We conducted a prospective study in a large, multiethnic cohort of obese adolescents to characterize clinical and genetic features associated with pediatric nonalcoholic fatty liver (NAFL), the most common cause of chronic liver disease in youth. A total of 503 obese adolescents were enrolled, including 191 (38.0%) whites, 134 (26.6%) blacks, and 178 (35.4%) Hispanics. Participants underwent abdominal magnetic resonance imaging (MRI) to quantify hepatic fat fraction (HFF), an oral glucose tolerance test (OGTT) to assess glucose tolerance and insulin sensitivity, and the genotyping of three single-nucleotide polymorphisms (SNPs) associated with nonalcoholic fatty liver disease (NAFLD) (patatin-like phospholipase domain-containing protein 3 [PNPLA3] rs738409, glucokinase regulatory protein [GCKR] rs1260326, and transmembrane 6 superfamily member 2 [TM6SF2] rs58542926). Assessments were repeated in 133 subjects after a 2-year follow-up. Prevalence of nonalcoholic fatty liver (NAFL) was 41.6% (209 patients) and ranged widely among ethnicities, being 42.9% in whites, 15.7% in blacks, and 59.6% in Hispanics (P < 0.0001). Among adolescents with NAFL, blacks showed the highest prevalence of altered glucose homeostasis (66%; P = 0.0003). Risk factors for NAFL incidence were white or Hispanic ethnicity (P = 0.021), high fasting C-peptide levels (P = 0.0006), and weight gain (P = 0.0006), whereas baseline HFF (P = 0.004) and weight loss (P = 0.032) predicted resolution of NAFL at follow-up. Adding either gene variant to these variables improved significantly the model predictive performance. CONCLUSION Black obese adolescents are relatively protected from liver steatosis, but are more susceptible to the deleterious effects of NAFL on glucose metabolism. The combination of ethnicity/race with markers of insulin resistance and genetic factors might help identify obese youth at risk for developing NAFL.
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Affiliation(s)
- Domenico Tricò
- Department of Internal MedicineYale University School of MedicineNew HavenCT,Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Sonia Caprio
- Department of PediatricsYale University School of MedicineNew HavenCT
| | - Giuseppina Rosaria Umano
- Department of PediatricsYale University School of MedicineNew HavenCT,Department of PediatricsUniversity of Campania “L. Vanvitelli”NapoliItaly
| | - Bridget Pierpont
- Department of PediatricsYale University School of MedicineNew HavenCT
| | - Jessica Nouws
- Department of PediatricsYale University School of MedicineNew HavenCT
| | - Alfonso Galderisi
- Department of PediatricsYale University School of MedicineNew HavenCT
| | - Grace Kim
- Seattle Children’s HospitalSeattleWA
| | - Mariana M. Mata
- Department of PediatricsYale University School of MedicineNew HavenCT
| | - Nicola Santoro
- Department of PediatricsYale University School of MedicineNew HavenCT
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46
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Body composition and insulin resistance in children. Eur J Clin Nutr 2018; 72:1239-1245. [DOI: 10.1038/s41430-018-0239-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 05/14/2018] [Indexed: 12/21/2022]
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47
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Wang JZ, Cao HX, Chen JN, Pan Q. PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease. World J Clin Cases 2018; 6:167-175. [PMID: 30148144 PMCID: PMC6107533 DOI: 10.12998/wjcc.v6.i8.167] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 05/16/2018] [Accepted: 06/08/2018] [Indexed: 02/05/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has now become the leading cause of chronic liver disease with its growing incidence worldwide. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C > G reflects one of the critical genetic factors that confers high-risk to NAFLD. However, the role of PNPLA3 polymorphism in NAFLD treatment remains uncertain. Here, the present review reveals that NAFLD patients with G-allele at PNPLA3 rs738409 (PNPLA3 148M variant) are sensitive to therapies of lifestyle modification, dipeptidyl peptidase-4 inhibitors, and bariatric surgery. They exhibit much significant reduction of liver fat content, in concurrence with weigh loss and abolished insulin resistance, as compared to those of C-allele carriers. In contrast, patients bearing PNPLA3 rs738409 C-allele (PNPLA3 148I variant), instead of G-allele, demonstrate greater beneficial effects by omega-3 poly-unsaturated fatty acids and statin intervention. Improved adipose tissue-liver interaction and decrease in intrahepatic triglyceride efflux may contribute to the PNPLA3 rs738409 related diversities in therapeutic efficacy. Therefore, PNPLA3 rs738409 underlies the response to a variety of treatments, which warrants a personalized, precise medicine in NAFLD on the basis of genotype stratification.
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Affiliation(s)
- Jin-Zhi Wang
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Hai-Xia Cao
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Jian-Neng Chen
- Department of Hepatology, Zhengxing Hospital, Zhangzhou 363000, Fujian Province, China
| | - Qin Pan
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
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48
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Ma J, Hennein R, Liu C, Long MT, Hoffmann U, Jacques PF, Lichtenstein AH, Hu FB, Levy D. Improved Diet Quality Associates With Reduction in Liver Fat, Particularly in Individuals With High Genetic Risk Scores for Nonalcoholic Fatty Liver Disease. Gastroenterology 2018; 155:107-117. [PMID: 29604292 PMCID: PMC6035111 DOI: 10.1053/j.gastro.2018.03.038] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 03/02/2018] [Accepted: 03/19/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Dietary modification has been recommended for treatment of nonalcoholic fatty liver disease (NAFLD), although it is not clear whether improving diet quality can prevent its development. We performed a prospective study to examine the association between diet quality change and change in liver fat. We also examined the association between genetic risk score and liver fat change in individuals with different levels of diet quality change. METHODS Our study included 1521 participants who attended the seventh and eighth examinations (1998-2001 and 2005-2008) of the second-generation cohort or attended the first and second examinations (2002-2005 and 2008-2011) of the third-generation cohort in the Framingham Heart Study. The self-administered semiquantitative 126-item Harvard food frequency questionnaire was used to determine dietary intake in the year leading up to an examination. We assessed levels of liver fat using liver-phantom ratio (LPR) on computed tomography images from 2002 through 2005 and again from 2008 through 2011. LPR values are inversely related to liver fat: increased LPR indicates decreased liver fat. We examined associations of changes in 2 diet scores, the Mediterranean-style diet score (MDS) and Alternative Healthy Eating Index (AHEI), with changes in liver fat and new-onset fatty liver. We evaluated interactions between diet score change and a weighted genetic risk score for NAFLD, determined based on multiple single-nucleotide polymorphisms identified in genome-wide association studies of NAFLD. The primary outcome was change in LPR between baseline and follow-up measurement. RESULTS For each 1 standard deviation increase in MDS, the LPR increased (meaning liver fat decreased) by 0.57 (95% confidence interval [CI] 0.27-0.86; P < .001) and the odds for incident fatty liver decreased by 26% (95% CI 10%-39%; P = .002). For each 1 standard deviation increase in AHEI, LPR increased by 0.56 (95% CI 0.29-0.84; P < .001) and the odds for incident fatty liver decreased by 21% (95% CI 5%-35%; P = .02). Increased diet scores were also associated with reduced odds of developing more-advanced fatty liver. Higher genetic risk scores were associated with increased liver fat accumulation in participants who had decreased MDS (P < .001) or AHEI scores (P = .001), but not in those with stable or improved diet scores (P for gene-diet interaction <.001). CONCLUSIONS In an analysis of participants in the Framingham Heart Study, increasing diet quality, determined based on MDS and AHEI scores, is associated with less liver fat accumulation and reduced risk for new-onset fatty liver. An improved diet is particularly important for individuals with a high genetic risk for NAFLD.
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Affiliation(s)
- Jiantao Ma
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland and the Framingham Heart Study, Framingham, Massachusetts, USA, 01702
| | - Rachel Hennein
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland and the Framingham Heart Study, Framingham, Massachusetts, USA, 01702
| | - Chunyu Liu
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland and the Framingham Heart Study, Framingham, Massachusetts, USA, 01702
| | - Michelle T. Long
- Section of Gastroenterology, Evans Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA, 02118
| | - Udo Hoffmann
- Radiology Department, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA, 02114
| | - Paul F. Jacques
- Nutrition Epidemiology Program, USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA, 02111
| | - Alice H. Lichtenstein
- Cardiovascular Nutrition Laboratory, USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA, 02111
| | - Frank B. Hu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA, 02115
| | - Daniel Levy
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; Framingham Heart Study, Framingham, Massachusetts.
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Metwally M, Eslam M, George J. Genetic and Epigenetic Associations of NAFLD: Focus on Clinical Decision Making. CURRENT HEPATOLOGY REPORTS 2017; 16:335-345. [DOI: 10.1007/s11901-017-0372-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
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50
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Abstract
A single-nucleotide polymorphism occurring in the sequence of the human patatin-like phospholipase domain-containing 3 gene (PNPLA3), known as I148M variant, is one of the best characterized and deeply investigated variants in several clinical scenarios, because of its tight correlation with increased risk for developing hepatic steatosis and more aggressive part of the disease spectrum, such as nonalcoholic steatohepatitis, advanced fibrosis and cirrhosis. Further, the I148M variant is positively associated with alcoholic liver diseases, chronic hepatitis C-related cirrhosis and hepatocellular carcinoma. The native gene encodes for a protein that has not yet a fully defined role in liver lipid metabolism and, according to recent observations, seems to be divergently regulated among distinct liver cells type, such as hepatic stellate cells. Therefore, the aim of this review is to collect the latest data regarding PNPLA3 expression in human liver and to analyze the impact of its genetic variant in human hepatic pathologies. Moreover, a description of the current biochemical and metabolic data pertaining to PNPLA3 function in both animal models and in vitro studies is summarized to allow a better understanding of the relevant pathophysiological role of this enzyme in the progression of hepatic diseases.
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Affiliation(s)
- Francesca Virginia Bruschi
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Matteo Tardelli
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
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