Metabolomic Study of High-Fat Diet-Induced Obese (DIO) and DIO Plus CCl4-Induced NASH Mice and the Effect of Obeticholic Acid

The pathophysiology of nonalcoholic fatty liver disease (NAFLD) is a complex process involving metabolic and inflammatory changes in livers and other organs, but the pathogenesis is still not well clarified. Two mouse models were established to study metabolic alteration of nonalcoholic fatty liver and nonalcoholic steatohepatitis, respectively. The concentrations of metabolites in serum, liver and intestine content were measured by the AbsoluteIDQ® p180 Kit (Biocrates Life Sciences, Innsbruck, Austria). Multivariate statistical methods, pathway analysis, enrichment analysis and correlation analysis were performed to analyze metabolomic data. The metabolic characteristics of liver, serum and intestine content could be distinctly distinguished from each group, indicating the occurrence of metabolic disturbance. Among them, metabolic alteration of liver and intestine content was more significant. Based on the metabolic data of liver, 19 differential metabolites were discovered between DIO and control, 12 between DIO-CCl4 and DIO, and 47 between DIO-CCl4 and normal. These metabolites were mainly associated with aminoacyl-tRNA biosynthesis, nitrogen metabolism, lipid metabolism, glyoxylate and dicarboxylate metabolism, and amino metabolism. Further study revealed that the intervention of obeticholic acid (OCA) could partly reverse the damage of CCl4. The correlation analysis of metabolite levels and clinical parameters showed that phosphatidylcholines were negatively associated with serum alanine aminotransferase, aspartate aminotransferase, NAFLD activity score, and fibrosis score, while lysophosphatidylcholines, sphingomyelins, amino acids, and acylcarnitines shared the reverse pattern. Our study investigated metabolic alteration among control, NAFLD model, and OCA treatment groups, providing preclinical information to understand the mechanism of NAFLD and amelioration of OCA.

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Emerging role of obeticholic acid in the management of nonalcoholic fatty liver disease

World Journal of Gastroenterology ◽

10.3748/wjg.v22.i41.9039 ◽

2016 ◽

Vol 22 (41) ◽

pp. 9039 ◽

Cited By ~ 19

Author(s):

Evangelia Makri ◽

Evangelos Cholongitas ◽

Konstantinos Tziomalos

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Obeticholic Acid ◽

Nonalcoholic Fatty Liver

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Obeticholic acid and resveratrol in nonalcoholic fatty liver disease: All that is gold does not glitter, not all those who wander are lost

Hepatology ◽

10.1002/hep.27772 ◽

2015 ◽

Vol 61 (6) ◽

pp. 2104-2106 ◽

Cited By ~ 7

Author(s):

Giovanni Musso

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Obeticholic Acid ◽

Nonalcoholic Fatty Liver

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Distinguishing NASH Histological Severity Using a Multiplatform Metabolomics Approach

Metabolites ◽

10.3390/metabo10040168 ◽

2020 ◽

Vol 10 (4) ◽

pp. 168 ◽

Cited By ~ 2

Author(s):

George N. Ioannou ◽

G. A. Nagana Gowda ◽

Danijel Djukovic ◽

Daniel Raftery

Keyword(s):

Nmr Spectroscopy ◽

Fatty Liver ◽

Metabolic Pathways ◽

Metabolite Profile ◽

Protective Effects ◽

Serum Samples ◽

Multivariate Statistical ◽

Nonalcoholic Fatty Liver ◽

Early Fibrosis ◽

Analytical Platforms

Nonalcoholic fatty liver disease (NAFLD) is categorized based on histological severity into nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH). We used a multiplatform metabolomics approach to identify metabolite markers and metabolic pathways that distinguish NAFL from early NASH and advanced NASH. We analyzed fasting serum samples from 57 prospectively-recruited patients with histologically-proven NAFLD, including 12 with NAFL, 31 with early NASH and 14 with advanced NASH. Metabolite profiling was performed using a combination of liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy analyzed with multivariate statistical and pathway analysis tools. We targeted 237 metabolites of which 158 were quantified. Multivariate analysis uncovered metabolite profile clusters for patients with NAFL, early NASH, and advanced NASH. Also, multiple individual metabolites were associated with histological severity, most notably spermidine which was more than 2-fold lower in advanced fibrosis vs. early fibrosis, in advanced NASH vs. NAFL and in advanced NASH vs. early NASH, suggesting that spermidine exercises a protective effect against development of fibrosing NASH. Furthermore, the results also showed metabolic pathway perturbations between early-NASH and advanced-NASH. In conclusion, using a combination of two reliable analytical platforms (LC-MS and NMR spectroscopy) we identified individual metabolites, metabolite clusters and metabolic pathways that were significantly different between NAFL, early-NASH, and advanced-NASH. These differences provide mechanistic insights as well as potentially important metabolic biomarker candidates that may noninvasively distinguish patients with NAFL, early-NASH, and advanced-NASH. The associations of spermidine levels with less advanced histology merit further assessment of the potential protective effects of spermidine in NAFLD.

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Obeticholic Acid: A New Era in the Treatment of Nonalcoholic Fatty Liver Disease

Pharmaceuticals ◽

10.3390/ph11040104 ◽

2018 ◽

Vol 11 (4) ◽

pp. 104 ◽

Cited By ~ 22

Author(s):

Ludovico Abenavoli ◽

Tetyana Falalyeyeva ◽

Luigi Boccuto ◽

Olena Tsyryuk ◽

Nazarii Kobyliak

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Hepatic Metabolism ◽

Lifestyle Changes ◽

Farnesoid X Receptor ◽

Primary Biliary Cholangitis ◽

Obeticholic Acid ◽

Nonalcoholic Fatty Liver

The main treatments for patients with nonalcoholic fatty liver disease (NAFLD) are currently based on lifestyle changes, including ponderal decrease and dietary management. However, a subgroup of patients with nonalcoholic steatohepatitis (NASH), who are unable to modify their lifestyle successfully, may benefit from pharmaceutical support. Several drugs targeting pathogenic mechanisms of NAFLD have been evaluated in clinical trials for the treatment of NASH. Farnesoid X receptor (FXR) is a nuclear key regulator controlling several processes of the hepatic metabolism. NAFLD has been proven to be associated with abnormal FXR activity. Obeticholic acid (OCA) is a first-in-class selective FXR agonist with anticholestatic and hepato-protective properties. Currently, OCA is registered for the treatment of primary biliary cholangitis. However, promising effects of OCA on NASH and its metabolic features have been reported in several studies.

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Investigating the deregulation of metabolic tasks via Minimum Network Enrichment Analysis (MiNEA) as applied to nonalcoholic fatty liver disease using mouse and human omics data

10.1101/402222 ◽

2018 ◽

Cited By ~ 1

Author(s):

Vikash Pandey ◽

Vassily Hatzimanikatis

Keyword(s):

Fatty Liver ◽

Metabolic Networks ◽

Enrichment Analysis ◽

Minimal Size ◽

Metabolic Processes ◽

Nonalcoholic Fatty Liver ◽

Gene Annotations ◽

Transcriptomics Data ◽

Context Specific ◽

Minimal Networks

AbstractNonalcoholic fatty liver disease (NAFLD) is associated with metabolic syndromes spanning a wide spectrum of diseases, from simple steatosis to the more complex nonalcoholic steatohepatitis. To identify the deregulation that occurs in metabolic processes at the molecular level that give rise to these various NAFLD phenotypes, algorithms such as pathway enrichment analysis (PEA) can be used. These analyses require the use of predefined pathway maps, which are composed of reactions describing metabolic processes/subsystems. Unfortunately, the annotation of the metabolic subsystems can differ depending on the pathway database used, making these approaches subject to biases associated with different pathway annotations, and these methods cannot capture the balancing of cofactors and byproducts through the complex nature and interactions of genome-scale metabolic networks (GEMs). Here, we introduce a framework entitled Minimum Network Enrichment Analysis (MiNEA) that is applied to GEMs to generate all possible alternative minimal networks (MiNs), which are possible and feasible networks composed of all the reactions pertaining to various metabolic subsystems that can synthesize a target metabolite. We applied MiNEA to investigate deregulated MiNs and to identify key regulators in different NAFLD phenotypes, such as a fatty liver and liver inflammation, in both humans and mice by integrating condition-specific transcriptomics data from liver samples. We identified key deregulations in the synthesis of cholesteryl esters, cholesterol, and hexadecanoate in both humans and mice, and we found that key regulators of the hydrogen peroxide synthesis network were regulated differently in humans and mice. We further identified which MiNs demonstrate the general and specific characteristics of the different NAFLD phenotypes. MiNEA is applicable to any GEM and to any desired target metabolite, making MiNEA flexible enough to study condition-specific metabolism for any given disease or organism.Author SummaryThis work aims to introduce a network-based enrichment analysis using metabolic networks and transcriptomics data. Previous pathways/subsystems enrichment methods use predefined gene annotations of metabolic processes and gene annotations can differ based on different resources and can produce bias in pathways definitions. Thus, we introduce a framework, Minimum Network Enrichment Analysis (MiNEA), which first finds all possible minimal-size networks for a given metabolic process/task and then identifies deregulated minimal networks using deregulated genes between two conditions. MiNEA also identifies the deregulation in key reactions that are overlapped across all possible minimal-size networks. We applied MiNEA to identify deregulated metabolic tasks and their synthesis networks in the steatosis and nonalcoholic steatohepatitis (NASH) disease using a metabolic network and transcriptomics data of mouse and human liver samples. We identified key regulators of NASH form the synthesis networks of hydrogen peroxide and ceramide in both humans and mice. We also identified opposite deregulation in NASH for the phosphatidylserine synthesis network between humans and mice. MiNEA finds synthesis networks for a given target metabolite and due to this it is flexible to study deregulation in different phenotypes. MiNEA can be widely applicable for studying context-specific metabolism for any organism because the metabolic networks and context-specific gene expression data are now available for many organisms.

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