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Metabolites
Special Issues
Hepatic Metabolism in Fatty Liver Disease
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Hepatic Metabolism in Fatty Liver Disease

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 11123

Special Issue Editors

Dr. Sander Lefere

E-Mail Website
Guest Editor
Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
Interests: hepatology; NAFLD; metabolism; liver cell biology
Prof. Dr. Walter Wahli

E-Mail Website
Guest Editor
1. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
2. 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, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. The recently suggested nomenclature change to metabolic-associated fatty liver disease (MAFLD) draws attention to metabolic dysregulation as the root cause of the disease. Obesity and adipose tissue insulin resistance cause ectopic fat accumulation in the liver, thereby impairing hepatic insulin signaling, provoking endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress, and inducing inflammation. Metabolites produced by gut bacteria and genetic factors that impact lipid handling further modify these pathophysiological networks.

Novel findings in this field could refine the non-invasive patient stratification and are an optimal starting point to identify treatment options for NAFLD, for which there are no approved pharmacological treatments at present.

In this Special Issue of Metabolites, we invite original research articles, reviews, and shorter perspective articles on all aspects related to the role of hepatic as well as whole body metabolic alterations in fatty liver disease. Articles describing mechanistic, functional, cellular, and clinical aspects are therefore highly welcome.

Potential topics could include, but are not limited to, the following:

  • Adipose tissue–liver crosstalk;
  • Whole body insulin resistance;
  • Liver metabolomic analysis;
  • Mitochondrial dysfunction;
  • Hepatic immune activation by metabolic factors;
  • Clinical impact of NAFLD on metabolic disease;
  • Lifestyle therapy and bariatric surgery;
  • Drugs targeting hepatic metabolism, including PPARs, FXR agonists, GLP-1 analogues, and thyroid receptor agonists.

Dr. Sander Lefere
Prof. Dr. Walter Wahli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (3 papers)

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Research

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16 pages, 4415 KiB  
Article
Fetuin-A in Activated Liver Macrophages Is a Key Feature of Non-Alcoholic Steatohepatitis
by Quentin Etienne, Valérie Lebrun, Mina Komuta, Benoît Navez, Jean-Paul Thissen, Isabelle A. Leclercq and Nicolas Lanthier
Metabolites 2022, 12(7), 625; https://doi.org/10.3390/metabo12070625 - 07 Jul 2022
Cited by 10 | Viewed by 1938
Abstract
Fetuin-A, a plasma multifunctional protein known to play a role in insulin resistance, is usually presented as a liver secreted protein. However, fetuin-A adipose tissue production has been also described. Here, we evaluated fetuin-A production by the liver and the adipose tissue during [...] Read more.
Fetuin-A, a plasma multifunctional protein known to play a role in insulin resistance, is usually presented as a liver secreted protein. However, fetuin-A adipose tissue production has been also described. Here, we evaluated fetuin-A production by the liver and the adipose tissue during metabolic dysfunction-associated fatty liver disease (MAFLD)-non-alcoholic steatohepatitis (NASH) development. Fetuin-A was evaluated by enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), Western blot, and immunofluorescence in male foz−/− mice fed a normal diet (ND) or a high fat diet (HFD) at various timepoints and in MAFLD-NASH patients. Foz−/− mice fed a short-term HFD developed liver steatosis, insulin resistance, and increased circulating levels of fetuin-A compared to ND-fed mice. In mice and patients with NASH, fetuin-A was located not only in healthy or steatotic hepatocytes but also in some macrophages forming lipogranulomas. In both mice and humans, a significant amount of fetuin-A was present in the adipose tissue compared to the liver. However, messenger ribonucleic acid levels and cell culture experiments indicate that fetuin-A is produced by the liver but not by the adipose tissue. In conclusion, fetuin-A is produced by steatotic hepatocytes at early timepoints in MAFLD and correlates with insulin resistance both in mice and humans. In NASH, fetuin-A also co-localizes with activated liver macrophages and could be interpreted as a signal released by damaged hepatocytes. Full article
(This article belongs to the Special Issue Hepatic Metabolism in Fatty Liver Disease)
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31 pages, 7544 KiB  
Article
A Quantitative Systems Pharmacology Platform Reveals NAFLD Pathophysiological States and Targeting Strategies
by Daniel E. Lefever, Mark T. Miedel, Fen Pei, Johanna K. DiStefano, Richard Debiasio, Tong Ying Shun, Manush Saydmohammed, Maria Chikina, Lawrence A. Vernetti, Alejandro Soto-Gutierrez, Satdarshan P. Monga, Ramon Bataller, Jaideep Behari, Vijay K. Yechoor, Ivet Bahar, Albert Gough, Andrew M. Stern and D. Lansing Taylor
Metabolites 2022, 12(6), 528; https://doi.org/10.3390/metabo12060528 - 07 Jun 2022
Cited by 3 | Viewed by 3281
Abstract
Non-alcoholic fatty liver disease (NAFLD) has a high global prevalence with a heterogeneous and complex pathophysiology that presents barriers to traditional targeted therapeutic approaches. We describe an integrated quantitative systems pharmacology (QSP) platform that comprehensively and unbiasedly defines disease states, in contrast to [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) has a high global prevalence with a heterogeneous and complex pathophysiology that presents barriers to traditional targeted therapeutic approaches. We describe an integrated quantitative systems pharmacology (QSP) platform that comprehensively and unbiasedly defines disease states, in contrast to just individual genes or pathways, that promote NAFLD progression. The QSP platform can be used to predict drugs that normalize these disease states and experimentally test predictions in a human liver acinus microphysiology system (LAMPS) that recapitulates key aspects of NAFLD. Analysis of a 182 patient-derived hepatic RNA-sequencing dataset generated 12 gene signatures mirroring these states. Screening against the LINCS L1000 database led to the identification of drugs predicted to revert these signatures and corresponding disease states. A proof-of-concept study in LAMPS demonstrated mitigation of steatosis, inflammation, and fibrosis, especially with drug combinations. Mechanistically, several structurally diverse drugs were predicted to interact with a subnetwork of nuclear receptors, including pregnane X receptor (PXR; NR1I2), that has evolved to respond to both xenobiotic and endogenous ligands and is intrinsic to NAFLD-associated transcription dysregulation. In conjunction with iPSC-derived cells, this platform has the potential for developing personalized NAFLD therapeutic strategies, informing disease mechanisms, and defining optimal cohorts of patients for clinical trials. Full article
(This article belongs to the Special Issue Hepatic Metabolism in Fatty Liver Disease)
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Review

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28 pages, 3035 KiB  
Review
Emerging Role of Nuclear Receptors for the Treatment of NAFLD and NASH
by Ryan D. Welch, Cyrielle Billon, McKenna Losby, Gonzalo Bedia-Diaz, Yuanying Fang, Amer Avdagic, Bahaa Elgendy, Thomas P. Burris and Kristine Griffett
Metabolites 2022, 12(3), 238; https://doi.org/10.3390/metabo12030238 - 11 Mar 2022
Cited by 11 | Viewed by 4863
Abstract
Non-alcoholic fatty liver (NAFLD) over the past years has become a metabolic pandemic linked to a collection of metabolic diseases. The nuclear receptors ERRs, REV-ERBs, RORs, FXR, PPARs, and LXR are master regulators of metabolism and liver physiology. The characterization of these nuclear [...] Read more.
Non-alcoholic fatty liver (NAFLD) over the past years has become a metabolic pandemic linked to a collection of metabolic diseases. The nuclear receptors ERRs, REV-ERBs, RORs, FXR, PPARs, and LXR are master regulators of metabolism and liver physiology. The characterization of these nuclear receptors and their biology has promoted the development of synthetic ligands. The possibility of targeting these receptors to treat NAFLD is promising, as several compounds including Cilofexor, thiazolidinediones, and Saroglitazar are currently undergoing clinical trials. This review focuses on the latest development of the pharmacology of these metabolic nuclear receptors and how they may be utilized to treat NAFLD and subsequent comorbidities. Full article
(This article belongs to the Special Issue Hepatic Metabolism in Fatty Liver Disease)
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