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Non-Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of chronic liver disease in the Western world, probably due to the growing prevalence of obesity, metabolic diseases, and exposure to some environmental agents. In certain patients, simple hepatic steatosis can progress to non-alcoholic steatohepatitis (NASH), which can sometimes lead to liver cirrhosis and its complications including hepatocellular carcinoma. Understanding the mechanisms that cause the progression of NAFLD to NASH is crucial to be able to control the advancement of the disease. The main hypothesis considers that it is due to multiple factors that act together on genetically predisposed subjects to suffer from NAFLD including insulin resistance, nutritional factors, gut microbiota, and genetic and epigenetic factors. In this article, we will discuss the epidemiology of NAFLD, and we overview several topics that influence the development of the disease from simple steatosis to liver cirrhosis and its possible complications.

SUBMITTER: Juanola O

PROVIDER: S-EPMC8155932 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Non-Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors.

Juanola Oriol O Martínez-López Sebastián S Francés Rubén R Gómez-Hurtado Isabel I

International journal of environmental research and public health 20210514 10

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of chronic liver disease in the Western world, probably due to the growing prevalence of obesity, metabolic diseases, and exposure to some environmental agents. In certain patients, simple hepatic steatosis can progress to non-alcoholic steatohepatitis (NASH), which can sometimes lead to liver cirrhosis and its complications including hepatocellular carcinoma. Understanding the mechanisms that cause the progression of N ...[more]

PMID: 34069012

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Project description: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 D5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61).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 summaryThe 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.

Project description:BackgroundAlthough many studies on non-alcoholic fatty liver disease (NAFLD) are underway worldwide, and several existing studies have investigated the association between NAFLD and cardiovascular risk factors, studies comparing NAFLD and alcoholic fatty liver disease (AFLD) are scarce. This study aimed to evaluate differences between the incidence of cardiovascular risk factors and metabolic syndrome in NAFLD and AFLD.MethodsA retrospective analysis of 913 patients who underwent abdominal computed tomography (CT) was performed to compare the incidence of cardiovascular risk factors and metabolic syndrome between NAFLD and AFLD. Subjects were divided into three groups based on criteria: healthy (n = 572), NAFLD (n = 295), and AFLD (n = 46). The healthy group had no liver disease. NAFLD was defined as fatty liver diagnosed on CT and drinking less than 140 g/week for men or 70 g/week for women. AFLD was defined as fatty liver diagnosed on CT and drinking more than 140 g/week for men or 70 g/week for women. We compared the incidence of cardiovascular risk factors and metabolic syndrome between the three groups. The relationship between each group and the metabolic syndrome risk was analyzed through multivariate logistic regression analysis.ResultsNo significant differences in several cardiovascular risk factors were observed between the NAFLD and AFLD groups. Upon analyzing the metabolic syndrome status in each group after making appropriate adjustments, the odds ratios (ORs) in the NAFLD (OR = 2.397, P = 0.002) and AFLD groups (OR = 4.445, P = 0.001) were found to be significantly higher than that in the healthy group; the incidence rate of metabolic syndrome was similar in the NAFLD and AFLD groups.ConclusionsBoth the NAFLD and AFLD groups had more cardiovascular risk factors and higher metabolic syndrome risk than the healthy group. Thus, the prevention of fatty liver disease, regardless of the specific type, should involve the identification of cardiovascular and metabolic syndrome risk factors. If abdominal CT reveals a fatty liver, whether NAFLD or AFLD, the risk of cardiovascular disease and metabolic syndrome should be assessed.

Dataset Information

Non-Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors.

Publications

Non-Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors.

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