ArticleJournal of hepatology2022
Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease.
Article in Journal of hepatology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers, 1 of them a synthesis that pooled it.
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Who cites it
91 citing papers in PubMed, 1 synthesis or guideline pooled it, 156 citations in OpenAlex.
- The association of metabolic dysfunction-associated steatotic liver disease (MASLD) with the risk of myocardial infarction: a systematic review and meta-analysis.Annals of medicine · 2024Pooled it
- Trial
- Subtyping metabolic dysfunction-associated steatotic liver disease using electronic health record-linked genomic cohorts reveals diverse etiologies and progression.Nature communications · 2026Article
- Genetic and genomic insights across the steatotic liver disease spectrum.Clinical and molecular hepatology · 2026Review
- Hepatic Lipoprotein Production, Cardiometabolic Phenotypes, and Subtypes of Steatotic Liver Disease.Circulation research · 2026Review
- Lactobacillaceae in Acute and Chronic Liver Diseases: From Microbiota Modulation to Therapeutic Potential.Probiotics and antimicrobial proteins · 2026Review
- [Precise clinical classification of metabolic associated fatty liver disease].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2026Review
- B4GALT1 deficiency attenuates steatohepatitis by regulating the PPARγ/ACSL4 axis.Hepatology communications · 2026Article
- Incretin and Glucagon Signalling in MASLD and MASH: Integrating Metabolic Pathways With Disease Progression.Diabetes, obesity & metabolism · 2026Review
- NMR metabolomic signatures of healthy lifestyle and incident MASLD.Scientific reports · 2026Article
- Genome-wide DNA methylation patterns for indicators of liver steatosis: a longitudinal multiomic study.Clinical epigenetics · 2026Article
- The role of lysine acylation in metabolic dysregulation and inflammatory responses within the hepatic immune microenvironment of MASLD.Frontiers in immunology · 2026Review
- Article
- Global burden of chronic liver disease due to NAFLD from 2012 to 2021: A trend, decomposition, and health inequality analysis.Diabetology & metabolic syndrome · 2025Article
- Dissecting the mechanisms of MASLD fibrosis in the era of single-cell and spatial omics.The Journal of clinical investigation · 2025Review
- Targeted metabolomics reveals bioactive inflammatory mediators from gut into blood circulation in children with NAFLD.NPJ biofilms and microbiomes · 2025Article
- Gene-based therapies for steatotic liver disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Simultaneous in vivo multi-organ fluxomics reveals divergent metabolic adaptations in liver, heart, and skeletal muscle during obesity.Cell reports · 2025Article
- Increased serum β-hydroxybutyrate/acetoacetate ratio and aggravated histological liver inflammation in females with metabolic dysfunction-associated steatotic liver disease and polycystic ovary syndrome.Journal of molecular cell biology · 2025Article
- Plasma Beta-Hydroxybutyrate and All-Cause Mortality in Patients with Liver Cirrhosis.Biomedicines · 2025Article
31 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 5 institutions in 5 countries.
Funding
Abstract
BACKGROUND &
aimsThere is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) ('MetComp') and part by common modifiers of genetic risk ('GenComp'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD.
methodsWe studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D
resultsWe found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the 'MetComp'. In contrast, the 'GenComp' was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum β-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum β-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD.
conclusionsThese data show that the mechanisms underlying 'Metabolic' and 'Genetic' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD. LAY SUMMARY: The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates.
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