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Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and ranges from isolated steatosis to NASH. To determine whether circulating fatty acids could serve as diagnostic markers of NAFLD severity and whether specific fatty acids could contribute to the pathogenesis of NASH, we analyzed two independent NAFLD patient cohorts and used the methionine- and choline-deficient diet (MCD) NASH mouse model. We identified six fatty acids that could serve as non-invasive markers of NASH in patients with NAFLD. Serum levels of 15:0, 17:0 and 16:1n7t negatively correlated with NAFLD activity scores and hepatocyte ballooning scores, while 18:1n7c serum levels strongly correlated with fibrosis stage and liver inflammation. Serum levels of 15:0 and 17:0 also negatively correlated with fasting glucose and AST, while 16:1n7c and 18:1n7c levels positively correlated with AST and ferritin, respectively. Inclusion of demographic and clinical parameters improved the performance of the fatty acid panels in detecting NASH in NAFLD patients. The panel [15:0, 16:1n7t, 18:1n7c, 22:5n3, age, ferritin and APRI] predicted intermediate or advanced fibrosis in NAFLD patients, with 82% sensitivity at 90% specificity [AUROC = 0.92]. 15:0 and 18:1n7c were further selected for functional studies in vivo. Mice treated with 15:0-supplemented MCD diet showed reduced AST levels and hepatic infiltration of ceroid-laden macrophages compared to MCD-treated mice, suggesting that 15:0 deficiency contributes to liver injury in NASH. In contrast, 18:1n7c-supplemented MCD diet didn't affect liver pathology. In conclusion, 15:0 may serve as a promising biomarker or therapeutic target in NASH, opening avenues for the integration of diagnosis and treatment.

SUBMITTER: Yoo W

PROVIDER: S-EPMC5731750 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid.

Yoo Wonbeak W Gjuka Donjeta D Stevenson Heather L HL Song Xiaoling X Shen Hong H Yoo Suk Young SY Wang Jing J Fallon Michael M Ioannou George N GN Harrison Stephen A SA Beretta Laura L

PloS one 20171215 12

Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and ranges from isolated steatosis to NASH. To determine whether circulating fatty acids could serve as diagnostic markers of NAFLD severity and whether specific fatty acids could contribute to the pathogenesis of NASH, we analyzed two independent NAFLD patient cohorts and used the methionine- and choline-deficient diet (MCD) NASH mouse model. We identified six fatty acids that could serve as non-invasive markers ...[more]

PMID: 29244873

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Project description:This paper is based upon the "Charles Lieber Satellite Symposia" organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human immunodeficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible repair. We aim to (1) determine the immuno-pathology of alcohol-induced liver damage, (2) examine the role of genetics in the development of ASH, (3) propose diagnostic markers of ASH and NASH, (4) examine age differences, (5) develop common research tools to study alcohol-induced effects in clinical and pre-clinical studies, and (6) focus on factors that aggravate severity of organ-damage. The intention of these symposia is to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.

Project description:BackgroundNon-alcoholic fatty liver (NAFL) disease (NAFLD) is the most common chronic liver disease in the world. While most subjects have 'inert' NAFL, a subset will progress to non-alcoholic steatohepatitis (NASH) and its life-threatening complications. A substantial body of literature supports that a low muscle mass, low strength, and/or muscle fatty infiltration (myosteatosis) are associated with NAFLD severity. Here, we evaluated the muscle compartment in NASH preclinical models to decipher the kinetics of muscle alterations in relation with liver disease progression.MethodsWe developed and validated a micro-computed tomography-based methodology to prospectively study skeletal muscle mass and density in muscle and liver (i.e. reflecting fatty infiltration) in a high-throughput and non-invasive manner in three preclinical NAFLD/NASH rodent models: fat aussie (FOZ) mice fed a high-fat diet (FOZ HF), wild-type (WT) mice fed a high-fat high-fructose diet (WT HFF), and WT mice fed a high-fat diet (WT HF). We compared them with WT mice fed a normal diet (WT ND) used as controls.Results-FOZ HF with fibrosing NASH had sarcopenia characterized by a reduced muscle strength when compared with WT HF and WT HFF with early NASH and WT ND controls (165.2 ± 5.2 g vs. 237.4 ± 11.7 g, 256 ± 5.7 g, and 242.9 ± 9.3 g, respectively, P 60; 0.001). Muscle mass or strength was not lower in FOZ HF, WT HF, and WT HFF with early NASH than in controls. Myosteatosis was present in FOZ HF with fibrosing NASH, but also in FOZ HF, WT HF, and WT HFF with early NASH (muscle density = 0.50 ± 0.02, 0.62 ± 0.02, 0.70 ± 0.05, and 0.75 ± 0.03, respectively, with P 60; 0.001 when compared with respective controls). Myosteatosis degree was strongly correlated with NAFLD activity score (r = -0.87, n = 67, P 60; 0.001). In multivariate analysis, the association between myosteatosis and NASH was independent from homeostatic model assessment of insulin resistance and visceral fat area (P 60; 0.05). Myosteatosis degree powerfully discriminated NASH from benign NAFL and normal liver (area under the receiver operating characteristic = 0.96, n = 67, P 60; 0.001).ConclusionsTaken together, our data support that there is no sarcopenia in obese mice with early NASH. In contrast, the severity of myosteatosis reflects on hepatocellular damage and inflammation during early NASH development. This observation prompts us to exploit myosteatosis as a novel non-invasive marker of NASH.

Project description:BackgroundNon-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Autophagy plays a vital role in NAFLD development and progression. We aimed to establish a novel autophagy-related gene (ARG) signature as a therapeutic target in NAFLD patients based on high-throughput sequencing data.MethodsARGs obtained from the HAMdb and high-sequencing data obtained from the Gene Expression Omnibus (GEO) database were analyzed to identify differentially expressed ARGs (DEARGs) between normal and NASH tissues. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to explore potential biological and pathological functions of DEARGs. The protein-protein interaction (PPI) network of the DEARGs was established through the STRING website, and visualized by Cytoscape. In addition, hub genes were validated by an independent dataset GSE89632. Finally, we performed Gene Set Variation Analysis (GSVA) pathway-related analysis to identify the pivotal signaling pathways and genes for the progression of non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH).ResultsA total of 76 DEARGs were identified in the GSE126848 dataset, of which 45 genes were upregulated and 31 genes were downregulated. GO analysis showed that the biological functions of DEARGs focused primarily on autophagy, cellular response to external stimulus, fibroblast proliferation, late endosome, and ubiquitin protein ligase binding. KEGG pathway analysis showed that these DEARGs were mainly involved in the apoptosis, PI3K-Akt signaling pathway, and estrogen signaling pathway. Among DEGs, 9 most closely related genes were identified from the PPI network. Furthermore, NOS3, IGF1, VAMP8, FOS, and HMOX1 were verified in the GSE89632 dataset. At last, the MAPK signal pathway was identified as important pathway, and JUN was identified as a key gene involved in the progression from NAFL to NASH.ConclusionThis study may provide credible molecular biomarkers in terms of screening and diagnosis for NAFLD. Meanwhile, it also serves as a basis for exploring the molecular mechanisms underlying the progression of NAFL to NASH.

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Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid.

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Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid.

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