Abstract
Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome.
Keywords: Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polymorphism, genetic predisposition.
Current Pharmaceutical Design
Title:Genetic Predisposition in NAFLD and NASH: Impact on Severity of Liver Disease and Response to Treatment
Volume: 19 Issue: 29
Author(s): Paola Dongiovanni, Quentin M. Anstee and Luca Valenti
Affiliation:
Keywords: Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polymorphism, genetic predisposition.
Abstract: Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome.
Export Options
About this article
Cite this article as:
Dongiovanni Paola, Anstee M. Quentin and Valenti Luca, Genetic Predisposition in NAFLD and NASH: Impact on Severity of Liver Disease and Response to Treatment, Current Pharmaceutical Design 2013; 19 (29) . https://dx.doi.org/10.2174/13816128113199990381
DOI https://dx.doi.org/10.2174/13816128113199990381 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Mitophagy and Disease: New Avenues for Pharmacological Intervention
Current Pharmaceutical Design Is Nephrogenic Systemic Fibrosis a Disease of Fibrocytes?
Current Rheumatology Reviews Multiple Sclerosis – Established and Novel Therapeutic Approaches
Central Nervous System Agents in Medicinal Chemistry Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease
Current Drug Targets Evolution and Analysis of Heterogeneity in the Clinical Expression of Aortic Diseases Similar to Marfan’s Syndrome: Challenge and Art in Clinical Diagnosis
Current Rheumatology Reviews Aldehyde Dehydrogenase-2 Roles in Ischemic Cardiovascular Disease
Current Drug Targets Generation of Human Cardiomyocytes for Cardiac Regenerative Therapies: Differentiation and Direct Reprogramming
Current Pharmaceutical Design Persistent Pulmonary Hypertension of the Newborn: Physiology, Hemodynamic Assessment and Novel Therapies
Current Pediatric Reviews Developing Histone Deacetylase Inhibitors as Anti-Cancer Therapeutics
Current Medicinal Chemistry Current Biology of MTP: Implications for Selective Inhibition
Current Topics in Medicinal Chemistry Multiple Drug Resistance Associated with Function of ABC-Transporters in Diabetes Mellitus: Molecular Mechanism and Clinical Relevance
Infectious Disorders - Drug Targets Cardiotoxicity of Molecularly Targeted Agents
Current Cardiology Reviews Alstrom Syndrome: Genetics and Clinical Overview
Current Genomics EDITORIAL [Hot Topic: Diabetes Cardiovascular Complications (Guest Editor: Costanza Emanueli)]
Endocrine, Metabolic & Immune Disorders - Drug Targets Remdesivir and Hydroxychloroquine: A Compassionate Use in Covid-19
Current Drug Targets Extrahepatic Targets and Cellular Reactivity of Drug Metabolites
Current Medicinal Chemistry Biochemical Properties of Indoleamine 2,3-dioxygenase: From Structure to Optimized Design of Inhibitors
Current Medicinal Chemistry Risk Stratification for Sudden Cardiac Death: Current Approaches and Predictive Value
Current Cardiology Reviews T Lymphocytes as Targets of Statins: Molecular Mechanisms and Therapeutic Perspectives
Inflammation & Allergy - Drug Targets (Discontinued) The Effects of Vitamin C on Adriamycin-Induced Hypercholesterolemia in Rat
Current Nutrition & Food Science