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Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH)

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 27240

Special Issue Editors

Dr. Mariapia Vairetti

E-Mail Website
Guest Editor
Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
Interests: liver; NAFLD/NASH; farnesoid X receptor; oxidative stress; metalloproteinases; signal transduction
Special Issues, Collections and Topics in MDPI journals
Dr. Giuseppe Colucci

E-Mail Website
Guest Editor
Department of Medical and Surgical, Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
Interests: chronic hepatitis; NAFLD-NASH; immunopatholoy; liver fibrosis
Special Issues, Collections and Topics in MDPI journals
Dr. Andrea Ferrigno

E-Mail Website
Guest Editor
Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
Interests: liver; ischemia/reperfusion; metabotropic glutamate receptor 5; inflammation; G protein-coupled receptors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nonalcoholic fatty liver disease (NAFLD) is among the most common liver diseases worldwide, affecting up to 20%–30% of the human population. NAFLD is usually associated with the metabolic syndrome that is characterized by increased abdominal fat, insulin resistance, high blood pressure, and high blood triglycerides. In about 10% of individuals, NAFLD progresses to steatohepatitis (NASH), with a long-term risk of cirrhosis and hepatocellular carcinoma, among the most important causes of liver transplantation in US with consequent relevant social and economic impact. Nonetheless, specific pharmacological targets and treatment have not been found yet, leaving important medical needs still to be met. The Special Issue, “Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH)”, of the International Journal of Molecular Sciences, will include a selection of original research papers and reviews on novel molecular and cellular targets to prevent and treat NAFLD. This Special Issue will also include an update on the management of liver steatosis, inflammation, and fibrosis.

Dr. Mariapia Vairetti
Dr. Giuseppe Colucci
Dr. Andrea Ferrigno
Guest Editors

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Keywords

  • fatty liver
  • steatosis
  • steatohepatitis
  • inflammation
  • fibrosis
  • cytochines
  • chemokine receptors
  • insulin sensitizing drugs
  • farnesoid X receptor agonists
  • bile acids
  • oxidative stress
  • mitochondrial function
  • peroxisome proliferator-activated receptors (PPARs)

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Published Papers (6 papers)

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Research

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20 pages, 3119 KiB  
Article
Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the CDK2/4-C/EBPα/DGAT2 Pathway Preventing ER-Stress Induced Lipid Accumulation
by Maddalena Parafati, Sang Hyo Bae, R. Jason Kirby, Martina Fitzek, Preeti Iyer, Ola Engkvist, David M. Smith and Siobhan Malany
Int. J. Mol. Sci. 2020, 21(24), 9557; https://doi.org/10.3390/ijms21249557 - 15 Dec 2020
Cited by 9 | Viewed by 3774
Abstract
Non-alcoholic fatty liver disease (NAFLD) has a large impact on global health. At the onset of disease, NAFLD is characterized by hepatic steatosis defined by the accumulation of triglycerides stored as lipid droplets. Developing therapeutics against NAFLD and progression to non-alcoholic steatohepatitis (NASH) [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) has a large impact on global health. At the onset of disease, NAFLD is characterized by hepatic steatosis defined by the accumulation of triglycerides stored as lipid droplets. Developing therapeutics against NAFLD and progression to non-alcoholic steatohepatitis (NASH) remains a high priority in the medical and scientific community. Drug discovery programs to identify potential therapeutic compounds have supported high throughput/high-content screening of in vitro human-relevant models of NAFLD to accelerate development of efficacious anti-steatotic medicines. Human induced pluripotent stem cell (hiPSC) technology is a powerful platform for disease modeling and therapeutic assessment for cell-based therapy and personalized medicine. In this study, we applied AstraZeneca’s chemogenomic library, hiPSC technology and multiplexed high content screening to identify compounds that significantly reduced intracellular neutral lipid content. Among 13,000 compounds screened, we identified hits that protect against hiPSC-derived hepatic endoplasmic reticulum stress-induced steatosis by a mechanism of action including inhibition of the cyclin D3-cyclin-dependent kinase 2-4 (CDK2-4)/CCAAT-enhancer-binding proteins (C/EBPα)/diacylglycerol acyltransferase 2 (DGAT2) pathway, followed by alteration of the expression of downstream genes related to NAFLD. These findings demonstrate that our phenotypic platform provides a reliable approach in drug discovery, to identify novel drugs for treatment of fatty liver disease as well as to elucidate their underlying mechanisms. Full article
(This article belongs to the Special Issue Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH))
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16 pages, 2721 KiB  
Article
MicroRNA-451 and Genistein Ameliorate Nonalcoholic Steatohepatitis in Mice
by Mailin Gan, Linyuan Shen, Yuan Fan, Ya Tan, Ting Zheng, Guoqing Tang, Lili Niu, Ye Zhao, Lei Chen, Dongmei Jiang, Xuewei Li, Shunhua Zhang and Li Zhu
Int. J. Mol. Sci. 2019, 20(23), 6084; https://doi.org/10.3390/ijms20236084 - 3 Dec 2019
Cited by 14 | Viewed by 3701
Abstract
Effective, targeted therapy for chronic liver disease nonalcoholic steatohepatitis (NASH) is imminent. MicroRNAs (miRNAs) are a potential therapeutic target, and natural products that regulate miRNA expression may be a safe and effective treatment strategy for liver disease. Here, we investigated the functional role [...] Read more.
Effective, targeted therapy for chronic liver disease nonalcoholic steatohepatitis (NASH) is imminent. MicroRNAs (miRNAs) are a potential therapeutic target, and natural products that regulate miRNA expression may be a safe and effective treatment strategy for liver disease. Here, we investigated the functional role of miR-451 and the therapeutic effects of genistein in the NASH mouse model. MiR-451 was downregulated in various types of liver inflammation, and subsequent experiments showed that miR-451 regulates liver inflammation via IL1β. Genistein is a phytoestrogen with anti-inflammatory and anti-oxidant effects. Interestingly, we found that the anti-inflammatory effects of genistein were related to miR-451 and was partially antagonized by the miR-451 inhibitor. MiR-451 overexpression or genistein treatment inhibited IL1β expression and inflammation. Taken together, this study shows that miR-451 has a protective effect on hepatic inflammation, and genistein can be used as a natural promoter of miR-451 to ameliorate NASH. Full article
(This article belongs to the Special Issue Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH))
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22 pages, 4391 KiB  
Article
Cerium Oxide Nanoparticles Protect against Oxidant Injury and Interfere with Oxidative Mediated Kinase Signaling in Human-Derived Hepatocytes
by Silvia Carvajal, Meritxell Perramón, Gregori Casals, Denise Oró, Jordi Ribera, Manuel Morales-Ruiz, Eudald Casals, Pedro Casado, Pedro Melgar-Lesmes, Guillermo Fernández-Varo, Pedro Cutillas, Victor Puntes and Wladimiro Jiménez
Int. J. Mol. Sci. 2019, 20(23), 5959; https://doi.org/10.3390/ijms20235959 - 27 Nov 2019
Cited by 31 | Viewed by 4451
Abstract
Cerium oxide nanoparticles (CeO2NPs) possess powerful antioxidant properties, thus emerging as a potential therapeutic tool in non-alcoholic fatty liver disease (NAFLD) progression, which is characterized by a high presence of reactive oxygen species (ROS). The aim of this study was to [...] Read more.
Cerium oxide nanoparticles (CeO2NPs) possess powerful antioxidant properties, thus emerging as a potential therapeutic tool in non-alcoholic fatty liver disease (NAFLD) progression, which is characterized by a high presence of reactive oxygen species (ROS). The aim of this study was to elucidate whether CeO2NPs can prevent or attenuate oxidant injury in the hepatic human cell line HepG2 and to investigate the mechanisms involved in this phenomenon. The effect of CeO2NPs on cell viability and ROS scavenging was determined, the differential expression of pro-inflammatory and oxidative stress-related genes was analyzed, and a proteomic analysis was performed to assess the impact of CeO2NPs on cell phosphorylation in human hepatic cells under oxidative stress conditions. CeO2NPs did not modify HepG2 cell viability in basal conditions but reduced H2O2- and lipopolysaccharide (LPS)-induced cell death and prevented H2O2-induced overexpression of MPO, PTGS1 and iNOS. Phosphoproteomic analysis showed that CeO2NPs reverted the H2O2-mediated increase in the phosphorylation of peptides related to cellular proliferation, stress response, and gene transcription regulation, and interfered with H2O2 effects on mTOR, MAPK/ERK, CK2A1 and PKACA signaling pathways. In conclusion, CeO2NPs protect HepG2 cells from cell-induced oxidative damage, reducing ROS generation and inflammatory gene expression as well as regulation of kinase-driven cell survival pathways. Full article
(This article belongs to the Special Issue Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH))
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Review

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29 pages, 1548 KiB  
Review
Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: Current Issues and Future Perspectives in Preclinical and Clinical Research
by Clarissa Berardo, Laura Giuseppina Di Pasqua, Marta Cagna, Plinio Richelmi, Mariapia Vairetti and Andrea Ferrigno
Int. J. Mol. Sci. 2020, 21(24), 9646; https://doi.org/10.3390/ijms21249646 - 17 Dec 2020
Cited by 52 | Viewed by 5609
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a continuum of liver abnormalities often starting as simple steatosis and to potentially progress into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Because of its increasing prevalence, NAFLD is becoming a major public health concern, in [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is a continuum of liver abnormalities often starting as simple steatosis and to potentially progress into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Because of its increasing prevalence, NAFLD is becoming a major public health concern, in parallel with a worldwide increase in the recurrence rate of diabetes and metabolic syndrome. It has been estimated that NASH cirrhosis may surpass viral hepatitis C and become the leading indication for liver transplantation in the next decades. The broadening of the knowledge about NASH pathogenesis and progression is of pivotal importance for the discovery of new targeted and more effective therapies; aim of this review is to offer a comprehensive and updated overview on NAFLD and NASH pathogenesis, the most recommended treatments, drugs under development and new drug targets. The most relevant in vitro and in vivo models of NAFLD and NASH will be also reviewed, as well as the main molecular pathways involved in NAFLD and NASH development. Full article
(This article belongs to the Special Issue Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH))
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14 pages, 755 KiB  
Review
Chymase as a Possible Therapeutic Target for Amelioration of Non-Alcoholic Steatohepatitis
by Shinji Takai and Denan Jin
Int. J. Mol. Sci. 2020, 21(20), 7543; https://doi.org/10.3390/ijms21207543 - 13 Oct 2020
Cited by 10 | Viewed by 2945
Abstract
The development and progression of non-alcoholic steatohepatitis (NASH) are linked to oxidative stress, inflammation, and fibrosis of the liver. Chymase, a chymotrypsin-like enzyme produced in mast cells, has various enzymatic actions. These actions include activation of angiotensin II, matrix metalloproteinase (MMP)-9, and transforming [...] Read more.
The development and progression of non-alcoholic steatohepatitis (NASH) are linked to oxidative stress, inflammation, and fibrosis of the liver. Chymase, a chymotrypsin-like enzyme produced in mast cells, has various enzymatic actions. These actions include activation of angiotensin II, matrix metalloproteinase (MMP)-9, and transforming growth factor (TGF)-β, which are associated with oxidative stress, inflammation, and fibrosis, respectively. Augmentation of chymase activity in the liver has been reported in various NASH models. Generation of hepatic angiotensin II and related oxidative stress is upregulated in NASH but attenuated by treatment with a chymase inhibitor. Additionally, increases in MMP-9 and accumulation of inflammatory cells are observed in NASH but are decreased by chymase inhibitor administration. TGF-β and collagen I upregulation in NASH is also attenuated by chymase inhibition. These results in experimental NASH models demonstrate that a chymase inhibitor can effectively ameliorate NASH via the reduction of oxidative stress, inflammation, and fibrosis. Thus, chymase may be a therapeutic target for amelioration of NASH. Full article
(This article belongs to the Special Issue Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH))
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13 pages, 1597 KiB  
Review
Targeting of Secretory Proteins as a Therapeutic Strategy for Treatment of Nonalcoholic Steatohepatitis (NASH)
by Kyeongjin Kim and Kook Hwan Kim
Int. J. Mol. Sci. 2020, 21(7), 2296; https://doi.org/10.3390/ijms21072296 - 26 Mar 2020
Cited by 12 | Viewed by 6018
Abstract
Nonalcoholic steatohepatitis (NASH) is defined as a progressive form of nonalcoholic fatty liver disease (NAFLD) and is a common chronic liver disease that causes significant worldwide morbidity and mortality, and has no approved pharmacotherapy. Nevertheless, growing understanding of the molecular mechanisms underlying the [...] Read more.
Nonalcoholic steatohepatitis (NASH) is defined as a progressive form of nonalcoholic fatty liver disease (NAFLD) and is a common chronic liver disease that causes significant worldwide morbidity and mortality, and has no approved pharmacotherapy. Nevertheless, growing understanding of the molecular mechanisms underlying the development and progression of NASH has suggested multiple potential therapeutic targets and strategies to treat this disease. Here, we review this progress, with emphasis on the functional role of secretory proteins in the development and progression of NASH, in addition to the change of expression of various secretory proteins in mouse NASH models and human NASH subjects. We also highlight secretory protein-based therapeutic approaches that influence obesity-associated insulin resistance, liver steatosis, inflammation, and fibrosis, as well as the gut–liver and adipose–liver axes in the treatment of NASH. Full article
(This article belongs to the Special Issue Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH))
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