Multi-omic profiles of human non-alcoholic fatty liver disease tissue highlight heterogenic phenotypes (original) (raw)
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Nutritional Genomics in Nonalcoholic Fatty Liver Disease
Biomedicines
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-associat...
Genetic Factors in the Pathogenesis of Nonalcoholic Fatty Liver and Steatohepatitis
BioMed Research International, 2015
Liver fat accumulation generally related to systemic insulin resistance characterizes nonalcoholic fatty liver disease (NAFLD), which in the presence of nonalcoholic steatohepatitis (NASH) can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease in Western countries. Epidemiological, familial, and twin studies provide evidence for a strong genetic component of NAFLD susceptibility. Recently, genome-wide association studies led to the identification of the major inherited determinants of hepatic fat accumulation:patatin-like phospholipase domain-containing 3 (PNPLA3)I148M gene andtransmembrane 6 superfamily member 2 (TM6SF2)E167K gene variants, involved in lipid droplets remodelling and very low-density lipoproteins secretion, are the major determinants of interindividual differences in liver steatosis, and susceptibility to progressive NASH. In this review, we aimed to provide an overview of recent insi...
Non-alcoholic Fatty Liver Disease: What We Learn from Omics Studies
Non-Alcoholic Fatty Liver Disease - Molecular Bases, Prevention and Treatment, 2018
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver diseases with 10-30% prevalence in western countries. The severity of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). However, the wide range of clinical staging of the disease prevents the clear understanding of its pathogenesis. Recently, high-throughput genomic, transcriptomic, and proteomic studies focus on enlightening the complex mechanisms responsible for NAFLD and NASH development. All together these Omics studies, in different cohorts once again, proved that NAFLD and NASH are linked with many complex mechanisms such as accumulation and traffic of various lipids in the liver and activation of inflammation responses. Moreover, some of these studies may have identified potential biomarkers and candidate risky or protective alleles that can be a valuable tool for the assessment of susceptibility and histological severity of NAFLD. Nonetheless, confirmation of these potential biomarkers and candidate genes by multiple Omics tools is required for their clinical application in the diagnosis and treatment of NASH and NAFLD.
A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures
Nature metabolism, 2023
Non-alcoholic fatty liver disease (NAFLD) is a common, progressive liver disease strongly associated with the metabolic syndrome. It is unclear how progression of NAFLD towards cirrhosis translates into systematic changes in circulating proteins. Here, we provide a detailed proteo-transcriptomic map of steatohepatitis and fibrosis during progressive NAFLD. In this multicentre proteomic study, we characterize 4,730 circulating proteins in 306 patients with histologically characterized NAFLD and integrate this with transcriptomic analysis in paired liver tissue. We identify circulating proteomic signatures for active steatohepatitis and advanced fibrosis, and correlate these with hepatic transcriptomics to develop a proteo-transcriptomic signature of 31 markers. Deconvolution of this signature by single-cell RNA sequencing reveals the hepatic cell types likely to contribute to proteomic changes with disease progression. As an exemplar of use as a non-invasive diagnostic, logistic regression establishes a composite model comprising four proteins (ADAMTSL2, AKR1B10, CFHR4 and TREM2), body mass index and type 2 diabetes mellitus status, to identify at-risk steatohepatitis. Non-alcoholic fatty liver disease (NAFLD) is a chronic, progressive condition affecting about 25% of the global population that is strongly associated with features of the metabolic syndrome, including obesity and type 2 diabetes mellitus (T2DM) 1. NAFLD is characterized by excessive accumulation of hepatic triglyceride and encompasses a range of disease states: from steatosis (non-alcoholic fatty liver, NAFL) through non-alcoholic steatohepatitis (NASH), defined by the presence of hepatocyte ballooning and lobular inflammation with increasing fibrosis stage, to cirrhosis and hepatocellular carcinoma 1. Not every patient diagnosed with NAFL will develop NASH or progress to cirrhosis and end-stage liver disease, meaning that there is substantial interindividual variation in disease severity. Patients with greater steatohepatitic disease activity, defined by a histological NAFLD Activity Score (NAS, the sum of steatosis, hepatocyte ballooning and lobular inflammation) more than or equal to 4 with fibrosis stage of 2 or more (F ≥ 2) are considered to show 'at-risk NASH' that indicates a high likelihood of progressive disease 2,3 .
A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease
Hepatology, 2005
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and some of its forms are progressive. This study describes the profiling of hepatic gene expression and serum protein content in patients with different subtypes of NAFLD. Liver biopsy specimens from 98 bariatric surgery patients were classified as normal, steatosis alone, steatosis with nonspecific inflammation, and nonalcoholic steatohepatitis (NASH). Microarray hybridizations were performed in triplicate and the microarray expression levels of a selected group of genes were confirmed using real-time quantitative reverse-transcriptase polymerase chain reaction. Serum protein profiles of the same patients were determined by SELDI-TOF mass spectrometry. Of 98 obese patients, 91 were diagnosed with NAFLD (12 steatosis alone, 52 steatosis with nonspecific inflammation, and 27 NASH), and 7 patients without NAFLD served as obese controls. Each group of NAFLD patients was compared with the obese controls, and 22 genes with more than twofold differences in expression levels were revealed. Proteomics analyses were performed for the same group comparisons and revealed twelve significantly different protein peaks. In conclusion, this genomic/proteomic analysis suggests differential expression of several genes and protein peaks in patients within and across the forms of NAFLD. These findings may help clarify the pathogenesis of NAFLD and identify potential targets for therapeutic intervention. (HEPATOLOGY 2005;42:665-674.) Abbreviations: NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; SELDI-TOF, surface-enhanced laser desorption ionization time of flight; cDNA, complementary DNA; RT-PCR, reverse-transcriptase polymerase chain reaction.
Stem Cells, 2016
Considered a feature of the metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), is associated with insulin resistance, type 2 diabetes, obesity and drug toxicity. Its prevalence is estimated at about 30% in western countries mainly due to sedentary life styles and high fat diets. Genome-wide association studies have identified polymorphisms in several genes, for example, PNPLA3, and TM6SF2 which confer susceptibility to NAFLD. Here, we review recent findings in the NAFLD field with a particular focus on published transcriptomics datasets which we subject to a meta-analysis. We reveal a common gene signature correlating with the progression of the disease from steatosis and steatohepatitis and reveal that lipogenic and cholesterol metabolic pathways are main actors in this signature. We propose the use of disease-in-a-dish models based on hepatocyte-like cells derived from patient-specific induced pluripotent stem cells (iPSC). These will enable investigations into the cont...
Iranian Biomedical Journal
List of Abbreviations: AGTR1, angiotensin receptor type 1; AST, aspartate aminotransferase; CD82, cluster of Differentiation 82; COL13A1, collagen Type XIII alpha 1 chain; FFA, free fatty acid; FNDC5, fibronectin type III domain-containing protein 5; GATAD2A, GATA zinc finger domain containing 2A; GWAS, genome-wide association studies; HSC, hepatic stellate cell; HSD11B1, hydroxysteroid 11-beta dehydrogenase 1; MBOAT7, membrane bound O-acyltransferase domain containing 7; NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NNMT, nicotinamide N-methyltransferase; PGC-1α, peroxisome proliferatoractivated receptor gamma coactivator 1-alpha; PNPLA3, patatin-like phospholipase domain-containing protein 3; PPARGC1A, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PTPRD, protein tyrosine phosphatase receptor type D; ROS, reactive oxygen species; SAMM50, sorting and assembly machinery component 50; SNP, single nucleotide polymorphism; STAT3, signal transducer and activator of transcription 3; TCF7L-2, transcription factor 7 like 2; TG, triglyceride; TGF-β1, transforming growth factor beta 1; TLL1, tolloid-like 1; TM6SF2, transmembrane 6 superfamily member 2; TNF-α, tumor Necrosis Factor α; UCP2, uncoupling protein-2; VLDL, very low-density lipoprotein
Scientific reports, 2017
A longitudinal molecular model of the development and progression of nonalcoholic fatty liver disease (NAFLD) over time is lacking. We have recently validated a high fat/sugar water-induced animal (an isogenic strain of C57BL/6 J:129S1/SvImJ mice) model of NAFLD that closely mimics most aspects of human disease. The hepatic transcriptome of such mice with fatty liver (8 weeks), steatohepatitis with early fibrosis (16-24 weeks) and advanced fibrosis (52 weeks) after initiation of the diet was evaluated and compared to mice on chow diet. Fatty liver development was associated with transcriptional activation of lipogenesis, FXR-RXR, PPAR-α mediated lipid oxidation and oxidative stress pathways. With progression to steatohepatitis, metabolic pathway activation persisted with additional activation of IL-1/inhibition of RXR, granulocyte diapedesis/adhesion, Fc macrophage activation, prothrombin activation and hepatic stellate cell activation. Progression to advanced fibrosis was associate...
Genetic and metabolic aspects of non-alcoholic fatty liver disease (NAFLD) pathogenicity
Egyptian Journal of Medical Human Genetics
Background Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease showing a rising prevalence globally. Genetic predisposition plays a key role in the development and progression of the disease pathogenicity. Main body This paper summarizes genetic associations based on their influence on several metabolic aspects such as lipid metabolism, glucose metabolism, hepatic iron accumulation and cholesterol metabolism toward the NAFLD pathogenicity. Furthermore, we present variations in some epigenetic characters and the microRNA profile with regard to NAFLD. Conclusion As reported in many studies, the PNPLA3 rs738409 variant seems to be significantly associated with NAFLD susceptibility. Other gene variants like TM6SF2 rs58542926, MBOAT7 rs641738 and GCKR variants also appear to be more prevalent among NAFLD patients. We believe these genetic variants may provide insights into new trends in developing noninvasive biomarkers and identify their suitability in cli...