Special Issue "Metabolism and Metabolomics of Liver in Health and Disease"

A special issue of Metabolites (ISSN 2218-1989).

Deadline for manuscript submissions: 30 April 2020.

Special Issue Editors

Prof. Dr. Walter Wahli
E-Mail Website1 Website2
Guest Editor
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, and Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland
Interests: nuclear receptor superfamily, gene regulation and gene expression profiling, metabolic regulations, development, skin and wound healing, cancer, liver physiology, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), adipose tissue, muscle and exercise, gut, microbiota, inter-organ cross-talk, nutrition, nutrigenetics and nutrigenomics
Special Issues and Collections in MDPI journals
Dr. Hervé Guillou
E-Mail Website
Guest Editor
INRA ToxAlim, UMR1331, 180 Chemin de Tournefeuille, BP93173, 31027 Toulouse cedex3, France
Interests: metabolism, lipidomic, nuclear receptor superfamily, gene regulation and gene expression profiling, metabolic regulations, liver physiology, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), microbiota, inter-organ cross-talk, toxicology, nutrition, endocrinology, nutrigenetics and nutrigenomics

Special Issue Information

Dear Colleagues,

In this Issue, we will explore the use of targeted and untargeted metabolome analysis to investigate liver function in health (physiology) and diseases such as viral hepatitis, alcoholic liver disease (ADL), non-alcoholic fatty liver diseases (NAFLD), drug-induced liver injury (DILI), and autoimmune liver diseases.

Our aim is to underscore, through research and review articles, the broad prospects of systems biology and metabolomics for a better understanding of liver function in basic research and possible clinical applications of drug discovery, toxicology, and biomarker identification.

Prof. Dr. Walter Wahli
Dr. Hervé Guillou
Guest Editors

Manuscript Submission Information

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Keywords

  • Liver functions
  • Fatty liver
  • Liver diseases
  • Molecular mechanisms and biomarkers

Published Papers (9 papers)

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Research

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Open AccessArticle
Targeted Analysis of 46 Bile Acids to Study the Effect of Acetaminophen in Rat by LC-MS/MS
Metabolites 2020, 10(1), 26; https://doi.org/10.3390/metabo10010026 - 07 Jan 2020
Abstract
Bile acids represent a large class of steroid acids synthesized in the liver and further metabolized by many bacterial and mammalian enzymes. Variations in bile acid levels can be used as a measure of liver function. There still exists, however, a need to [...] Read more.
Bile acids represent a large class of steroid acids synthesized in the liver and further metabolized by many bacterial and mammalian enzymes. Variations in bile acid levels can be used as a measure of liver function. There still exists, however, a need to study the variation of individual circulating bile acids in the context of hepatotoxity or liver disease. Acetaminophen (APAP), a drug commonly taken to relieve pain and decrease fever, is known to cause acute liver failure at high doses. We have developed a targeted liquid chromatography-tandem mass spectrometry method to monitor the effects of different doses of APAP on the bile acid plasma profile in a rat model. The analysis method was optimized to ensure chromatographic resolution of isomeric species using a mixture of 46 standard bile acids, and 14 isotopically-labeled internal standard (IS) compounds detected in multiple reaction monitoring (MRM) mode on a triple quadrupole mass spectrometer. Four doses of acetaminophen were studied, the highest of which shows signs of hepatotoxicity in rats. This targeted method revealed that high dose APAP has an important effect on bile acid profiles. Changes were seen in several unconjugated bile acids as well as glycine conjugates; however, no obvious changes were apparent for taurine-conjugated species. Full article
(This article belongs to the Special Issue Metabolism and Metabolomics of Liver in Health and Disease)
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Open AccessArticle
Proton NMR Enables the Absolute Quantification of Aqueous Metabolites and Lipid Classes in Unique Mouse Liver Samples
Metabolites 2020, 10(1), 9; https://doi.org/10.3390/metabo10010009 - 21 Dec 2019
Abstract
Hepatic metabolites provide valuable information on the physiological state of an organism, and thus, they are monitored in many clinical situations. Typically, monitoring requires several analyses for each class of targeted metabolite, which is time consuming. The present study aimed to evaluate a [...] Read more.
Hepatic metabolites provide valuable information on the physiological state of an organism, and thus, they are monitored in many clinical situations. Typically, monitoring requires several analyses for each class of targeted metabolite, which is time consuming. The present study aimed to evaluate a proton nuclear magnetic resonance (1H-NMR) method for obtaining quantitative measurements of aqueous and lipidic metabolites. We optimized the extraction protocol, the standard samples, and the organic solvents for the absolute quantification of lipid species. To validate the method, we analyzed metabolic profiles in livers of mice fed three different diets. We compared our results with values obtained with conventional methods and found strong correlations. The 1H-NMR protocol enabled the absolute quantification of 29 aqueous metabolites and eight lipid classes. Results showed that mice fed a diet enriched in saturated fatty acids had higher levels of triglycerides, cholesterol ester, monounsaturated fatty acids, lactate, 3-hydroxy-butyrate, and alanine and lower levels of glucose, compared to mice fed a control diet. In conclusion, proton NMR provided a rapid overview of the main lipid classes (triglycerides, cholesterol, phospholipids, fatty acids) and the most abundant aqueous metabolites in liver. Full article
(This article belongs to the Special Issue Metabolism and Metabolomics of Liver in Health and Disease)
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Open AccessArticle
Acupuncture on ST36, CV4 and KI1 Suppresses the Progression of Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Fatty Liver Disease in Mice
Metabolites 2019, 9(12), 299; https://doi.org/10.3390/metabo9120299 - 09 Dec 2019
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and its treatment remain a constant challenge. A number of clinical trials have shown that acupuncture treatment has beneficial effects for patients with NAFLD, but the molecular mechanisms [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and its treatment remain a constant challenge. A number of clinical trials have shown that acupuncture treatment has beneficial effects for patients with NAFLD, but the molecular mechanisms underlying its action are still largely unknown. In this study, we established a mouse model of NAFLD by administering a methionine- and choline-deficient (MCD) diet and selected three acupoints (ST36, CV4, and KI1) or nonacupoints (sham) for needling. We then investigated the effects of acupuncture treatment on the progression of NAFLD and the underlying mechanisms. After two weeks of acupuncture treatment, the liver in the needling-nonapcupoint group (NG) mice appeared pale and yellowish in color, while that in the needling-acupoint group (AG) showed a bright red color. Histologically, fewer lipid droplets and inflammatory foci were observed in the AG liver than in the NG liver. Furthermore, the expression of proinflammatory signaling factors was significantly downregulated in the AG liver. A lipid analysis showed that the levels of triglyceride (TG) and free fatty acid (FFA) were lower in the AG liver than in the NG liver, with an altered expression of lipid metabolism-related factors as well. Moreover, the numbers of 8-hydroxy-2′-deoxyguanosine (8-OHdG)-positive hepatocytes and levels of hepatic thiobarbituric acid reactive substances (TBARS) were significantly lower in AG mice than in NG mice. In line with these results, a higher expressions of antioxidant factors was found in the AG liver than in the NG liver. Our results indicate that acupuncture repressed the progression of NAFLD by inhibiting inflammatory reactions, reducing oxidative stress, and promoting lipid metabolism of hepatocytes, suggesting that this approach might be an important complementary treatment for NAFLD. Full article
(This article belongs to the Special Issue Metabolism and Metabolomics of Liver in Health and Disease)
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Open AccessArticle
Exposure of HepaRG Cells to Sodium Saccharin Underpins the Importance of Including Non-Hepatotoxic Compounds When Investigating Toxicological Modes of Action Using Metabolomics
Metabolites 2019, 9(11), 265; https://doi.org/10.3390/metabo9110265 - 04 Nov 2019
Abstract
Metabolites represent the most downstream information of the cellular organisation. Hence, metabolomics experiments are extremely valuable to unravel the endogenous pathways involved in a toxicological mode of action. However, every external stimulus can introduce alterations in the cell homeostasis, thereby obscuring the involved [...] Read more.
Metabolites represent the most downstream information of the cellular organisation. Hence, metabolomics experiments are extremely valuable to unravel the endogenous pathways involved in a toxicological mode of action. However, every external stimulus can introduce alterations in the cell homeostasis, thereby obscuring the involved endogenous pathways, biasing the interpretation of the results. Here we report on sodium saccharin, which is considered to be not hepatotoxic and therefore can serve as a reference compound to detect metabolic alterations that are not related to liver toxicity. Exposure of HepaRG cells to high levels of sodium saccharin (>10 mM) induced cell death, probably due to an increase in the osmotic pressure. Yet, a low number (n = 15) of significantly altered metabolites were also observed in the lipidome, including a slight decrease in phospholipids and an increase in triacylglycerols, upon daily exposure to 5 mM sodium saccharin for 72 h. The observation that a non-hepatotoxic compound can affect the metabolome underpins the importance of correct experimental design and data interpretation when investigating toxicological modes of action via metabolomics. Full article
(This article belongs to the Special Issue Metabolism and Metabolomics of Liver in Health and Disease)
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Open AccessArticle
A Lipidomic Analysis of Docosahexaenoic Acid (22:6, ω3) Mediated Attenuation of Western Diet Induced Nonalcoholic Steatohepatitis in Male Ldlr -/- Mice
Metabolites 2019, 9(11), 252; https://doi.org/10.3390/metabo9110252 - 28 Oct 2019
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major public health problem worldwide. NAFLD ranges in severity from benign steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and primary hepatocellular cancer (HCC). Obesity and type 2 diabetes mellitus (T2DM) are strongly associated with NAFLD, and the [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is a major public health problem worldwide. NAFLD ranges in severity from benign steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and primary hepatocellular cancer (HCC). Obesity and type 2 diabetes mellitus (T2DM) are strongly associated with NAFLD, and the western diet (WD) is a major contributor to the onset and progression of these chronic diseases. Our aim was to use a lipidomic approach to identify potential lipid mediators of diet-induced NASH. We previously used a preclinical mouse (low density lipoprotein receptor null mouse, Ldlr -/-) model to assess transcriptomic mechanisms linked to WD-induced NASH and docosahexaenoic acid (DHA, 22:6, ω3)-mediated remission of NASH. This report used livers from the previous study to carry out ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatography coupled with dynamic multi-reaction monitoring (HPLC-dMRM) to assess the impact of the WD and DHA on hepatic membrane lipid and oxylipin composition, respectively. Feeding mice the WD increased hepatic saturated and monounsaturated fatty acids and arachidonic acid (ARA, 20:4, ω6) in membrane lipids and suppressed ω3 polyunsaturated fatty acids (PUFA) in membrane lipids and ω3 PUFA-derived anti-inflammatory oxylipins. Supplementing the WD with DHA lowered hepatic ARA in membrane lipids and ARA-derived oxylipins and significantly increased hepatic DHA and its metabolites in membrane lipids, as well as C20–22 ω3 PUFA-derived oxylipins. NASH markers of inflammation and fibrosis were inversely associated with hepatic C20–22 ω3 PUFA-derived Cyp2C- and Cyp2J-generated anti-inflammatory oxylipins (false discovery rate adjusted p-value; q ≤ 0.026). Our findings suggest that dietary DHA promoted partial remission of WD-induced NASH, at least in part, by lowering hepatic pro-inflammatory oxylipins derived from ARA and increasing hepatic anti-inflammatory oxylipins derived from C20–22 ω3 PUFA. Full article
(This article belongs to the Special Issue Metabolism and Metabolomics of Liver in Health and Disease)
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Open AccessArticle
Hepatic Metabolic Derangements Triggered by Hyperthermia: An In Vitro Metabolomic Study
Metabolites 2019, 9(10), 228; https://doi.org/10.3390/metabo9100228 - 15 Oct 2019
Abstract
Background and aims: Liver toxicity is a well-documented and potentially fatal adverse complication of hyperthermia. However, the impact of hyperthermia on the hepatic metabolome has hitherto not been investigated. Methods: In this study, gas chromatography-mass spectrometry (GC-MS)-based metabolomics was applied to assess the [...] Read more.
Background and aims: Liver toxicity is a well-documented and potentially fatal adverse complication of hyperthermia. However, the impact of hyperthermia on the hepatic metabolome has hitherto not been investigated. Methods: In this study, gas chromatography-mass spectrometry (GC-MS)-based metabolomics was applied to assess the in vitro metabolic response of primary mouse hepatocytes (PMH, n = 10) to a heat stress stimulus, i.e., after 24 h exposure to 40.5 °C. Metabolomic profiling of both intracellular metabolites and volatile metabolites in the extracellular medium of PMH was performed. Results: Multivariate analysis showed alterations in levels of 22 intra- and 59 extracellular metabolites, unveiling the capability of the metabolic pattern to discriminate cells exposed to heat stress from cells incubated at normothermic conditions (37 °C). Hyperthermia caused a considerable loss of cell viability that was accompanied by significant alterations in the tricarboxylic acid cycle, amino acids metabolism, urea cycle, glutamate metabolism, pentose phosphate pathway, and in the volatile signature associated with the lipid peroxidation process. Conclusion: These results provide novel insights into the mechanisms underlying hyperthermia-induced hepatocellular damage. Full article
(This article belongs to the Special Issue Metabolism and Metabolomics of Liver in Health and Disease)
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Review

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Open AccessReview
Glucose-6 Phosphate, a Central Hub for Liver Carbohydrate Metabolism
Metabolites 2019, 9(12), 282; https://doi.org/10.3390/metabo9120282 - 20 Nov 2019
Abstract
Cells efficiently adjust their metabolism according to the abundance of nutrients and energy. The ability to switch cellular metabolism between anabolic and catabolic processes is critical for cell growth. Glucose-6 phosphate is the first intermediate of glucose metabolism and plays a central role [...] Read more.
Cells efficiently adjust their metabolism according to the abundance of nutrients and energy. The ability to switch cellular metabolism between anabolic and catabolic processes is critical for cell growth. Glucose-6 phosphate is the first intermediate of glucose metabolism and plays a central role in the energy metabolism of the liver. It acts as a hub to metabolically connect glycolysis, the pentose phosphate pathway, glycogen synthesis, de novo lipogenesis, and the hexosamine pathway. In this review, we describe the metabolic fate of glucose-6 phosphate in a healthy liver and the metabolic reprogramming occurring in two pathologies characterized by a deregulation of glucose homeostasis, namely type 2 diabetes, which is characterized by fasting hyperglycemia; and glycogen storage disease type I, where patients develop severe hypoglycemia during short fasting periods. In these two conditions, dysfunction of glucose metabolism results in non-alcoholic fatty liver disease, which may possibly lead to the development of hepatic tumors. Moreover, we also emphasize the role of the transcription factor carbohydrate response element-binding protein (ChREBP), known to link glucose and lipid metabolisms. In this regard, comparing these two metabolic diseases is a fruitful approach to better understand the key role of glucose-6 phosphate in liver metabolism in health and disease. Full article
(This article belongs to the Special Issue Metabolism and Metabolomics of Liver in Health and Disease)
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Open AccessReview
Nicotinamide and NAFLD: Is There Nothing New Under the Sun?
Metabolites 2019, 9(9), 180; https://doi.org/10.3390/metabo9090180 - 10 Sep 2019
Abstract
Nicotinamide adenine dinucleotide (NAD) has a critical role in cellular metabolism and energy homeostasis. Its importance has been established early with the discovery of NAD’s therapeutic role for pellagra. This review addresses some of the recent findings on NAD physiopathology and their effects [...] Read more.
Nicotinamide adenine dinucleotide (NAD) has a critical role in cellular metabolism and energy homeostasis. Its importance has been established early with the discovery of NAD’s therapeutic role for pellagra. This review addresses some of the recent findings on NAD physiopathology and their effects on nonalcoholic fatty liver disease (NAFLD) pathogenesis, which need to be considered in the search for a better therapeutic approach. Reduced NAD concentrations contribute to the dysmetabolic imbalance and consequently to the pathogenesis of NAFLD. In this perspective, the dietary supplementation or the pharmacological modulation of NAD levels appear to be an attractive strategy. These reviewed studies open the doors to growing interest in NAD metabolism for NAFLD diagnosis, prevention, and treatment. Future rigorous clinical studies in humans will be necessary to validate these preliminary but promising results. Full article
(This article belongs to the Special Issue Metabolism and Metabolomics of Liver in Health and Disease)
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Open AccessReview
The OMICs Window into Nonalcoholic Fatty Liver Disease (NAFLD)
Metabolites 2019, 9(2), 25; https://doi.org/10.3390/metabo9020025 - 01 Feb 2019
Cited by 3Retraction
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common cause of hepatic abnormalities worldwide. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD and leads to progressive liver disease, such as cirrhosis and hepatocellular carcinoma. In NASH patient, fibrosis represents the major predictor [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is a common cause of hepatic abnormalities worldwide. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD and leads to progressive liver disease, such as cirrhosis and hepatocellular carcinoma. In NASH patient, fibrosis represents the major predictor of liver-related mortality; therefore, it is important to have an early and accurate diagnosis of NASH. The current gold standard for the diagnosis of NASH is still liver biopsy. The development of biomarkers able to predict disease severity, prognosis, as well as response to therapy without the need for a biopsy is the focus of most up-to-date genomic, transcriptomic, proteomic, and metabolomic research. In the future, patients might be diagnosed and treated according to their molecular signatures. In this short review, we discuss how information from genomics, proteomics, and metabolomics contribute to the understanding of NAFLD pathogenesis. Full article
(This article belongs to the Special Issue Metabolism and Metabolomics of Liver in Health and Disease)
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