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Molecular Targets for the Formation and Treatment of Nonalcoholic Fatty Liver Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 August 2023) | Viewed by 15059

Special Issue Editor

Dr. Evangelos Cholongitas

E-Mail Website
Guest Editor
1st Department of Internal Medicine, General Hospital of Athens “Laiko”, Medical School of National and Kapodistrian University of Athens, 11527 Athens, Greece
Interests: non alcoholic liver disease; liver transplantation; cirrhosis; viral hepatitis; liver diseases; hepatitis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Non-alcoholic fatty liver disease (NAFLD) has emerged as the predominant cause of chronic liver injury worldwide, while it is projected to become the leading cause of liver transplantation by 2030. Obesity due to type 2 diabetes and aging is becoming more common and is receiving worldwide attention. NAFLD can progress to non-alcoholic steatohepatitis (NASH), characterized by the presence of liver steatosis and inflammation, with or without fibrosis, and in some fewer cases to liver cirrhosis and hepatocellular carcinoma. Despite the vast scientific effort made globally, until now, no medication for NAFLD has been approved and the current management of patients mostly focuses on lifestyle interventions.

This Special Issue of the International Journal of Molecular Sciences focuses on the recent findings derived from both animal and human studies concerning the pathways involved in the pathogenesis of NAFLD and NAFLD-related hepatocellular carcinoma and the future perspectives for the development of NAFLD-specific treatment.

Dr. Evangelos Cholongitas
Guest Editor

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • non-alcoholic fatty liver disease
  • hepatocellular carcinoma
  • pathogenesis
  • molecular targets
  • molecular pathways

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Published Papers (4 papers)

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Research

Jump to: Review

17 pages, 9244 KiB  
Article
Pharmacological Prevention of Ectopic Erythrophagocytosis by Cilostazol Mitigates Ferroptosis in NASH
by Joon Beom Park, Kangeun Ko, Yang Hyun Baek, Woo Young Kwon, Sunghwan Suh, Song-Hee Han, Yun Hak Kim, Hye Young Kim and Young Hyun Yoo
Int. J. Mol. Sci. 2023, 24(16), 12862; https://doi.org/10.3390/ijms241612862 - 16 Aug 2023
Cited by 3 | Viewed by 2052
Abstract
Hepatic iron overload (HIO) is a hallmark of nonalcoholic fatty liver disease (NAFLD) with a poor prognosis. Recently, the role of hepatic erythrophagocytosis in NAFLD is emerging as a cause of HIO. We undertook various assays using human NAFLD patient pathology samples and [...] Read more.
Hepatic iron overload (HIO) is a hallmark of nonalcoholic fatty liver disease (NAFLD) with a poor prognosis. Recently, the role of hepatic erythrophagocytosis in NAFLD is emerging as a cause of HIO. We undertook various assays using human NAFLD patient pathology samples and an in vivo nonalcoholic steatohepatitis (NASH) mouse model named STAMTM. To make the in vitro conditions comparable to those of the in vivo NASH model, red blood cells (RBCs) and platelets were suspended and subjected to metabolic and inflammatory stresses. An insert-coculture system, in which activated THP-1 cells and RBCs are separated from HepG2 cells by a porous membrane, was also employed. Through various analyses in this study, the effect of cilostazol was examined. The NAFLD activity score, including steatosis, ballooning degeneration, inflammation, and fibrosis, was increased in STAMTM mice. Importantly, hemolysis occurred in the serum of STAMTM mice. Although cilostazol did not improve lipid or glucose profiles, it ameliorated hepatic steatosis and inflammation in STAMTM mice. Platelets (PLTs) played an important role in increasing erythrophagocytosis in the NASH liver. Upregulated erythrophagocytosis drives cells into ferroptosis, resulting in liver cell death. Cilostazol inhibited the augmentation of PLT and RBC accumulation. Cilostazol prevented the PLT-induced increase in ectopic erythrophagocytosis in in vivo and in vitro NASH models. Cilostazol attenuated ferroptosis of hepatocytes and phagocytosis of RBCs by THP-1 cells. Augmentation of hepatic erythrophagocytosis by activated platelets in NASH exacerbates HIO. Cilostazol prevents ectopic erythrophagocytosis, mitigating HIO-mediated ferroptosis in NASH models. Full article
(This article belongs to the Special Issue Molecular Targets for the Formation and Treatment of Nonalcoholic Fatty Liver Disease)
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Figure 1

Figure 1
<p>NASH was induced in the STAM<sup>TM</sup> model. (<b>A</b>) The gross phenotype of the liver. (<b>B</b>) Liver weight (upper) and liver weight/body weight (lower). (<b>C</b>) Masson’s trichrome staining of liver tissue. (<b>D</b>) Scores indicating NAFLD activity. (<b>E</b>) Western blot data showing the expression levels of the inflammatory factors IL-6 and F4/80. (<b>F</b>) Assays showing that insulin resistance was induced in the STAM<sup>TM</sup> model. GTT (<b>upper</b>) and ITT (<b>lower</b>). (<b>G</b>) Assays showing that hemolysis occurred in the serum of NASH mice. Photograph of serum showing hemolysis, quantification of hemoglobin, heme assay, and hemopexin ELISA. ** <span class="html-italic">p</span> &lt; 0.01, Mann–Whitney U test.</p> Full article ">Figure 2
<p>Cilostazol ameliorates ballooning degeneration and inflammation in the STAM<sup>TM</sup> model. (<b>A</b>) Design of the NASH studies using the STAM<sup>TM</sup> model. (<b>B</b>) Masson’s trichrome staining of liver tissue. (<b>C</b>–<b>G</b>) Score according to Kleiner’s NAS system. (<b>C</b>) Ballooning degeneration score. (<b>D</b>) Inflammation score. (<b>E</b>) Fibrosis score. (<b>F</b>) Author-scored NAS value; sum of ballooning degeneration score, inflammation score, steatosis score, and fibrosis score. (<b>G</b>) NAS value determined by the deep learning module developed by Heinemann et al. (<b>H</b>) Western blot data showing that inflammatory factors (IL-6 and F4/80) were reversed in the cilostazol group. ** <span class="html-italic">p</span> &lt; 0.01, Mann–Whitney U test.</p> Full article ">Figure 3
<p>Cilostazol resolved the augmentation of PLT and RBC accumulation in NASH livers and prevented the PLT-induced increase in erythrophagocytosis in vitro. (<b>A</b>) H&amp;E staining (upper) and immunohistochemistry of CD61 (lower) in liver tissue from human NASH patients. (<b>B</b>) Immunohistochemistry and (<b>C</b>) Western blotting data of CD61 in liver tissue from the STAM<sup>TM</sup> model. * <span class="html-italic">p</span> &lt; 0.05 and ** <span class="html-italic">p</span> &lt; 0.01. (<b>D</b>) Immunohistochemistry of hemoglobin alpha in liver tissue from the STAM<sup>TM</sup> model. (<b>E</b>–<b>G</b>) Detection of CD68-FITC-labeled THP-1 cells phagocytosing PKH26-labeled RBCs. (<b>E</b>) Microplate fluorescence photometry. * <span class="html-italic">p</span> &lt; 0.05 and ** <span class="html-italic">p</span> &lt; 0.01. (<b>F</b>) Flow cytometry and (<b>G</b>) confocal microscopy. Green: CD68, Red: PKH26.</p> Full article ">Figure 4
<p>Cilostazol inhibited PLT-RBC contact-induced phosphatidylserine exposure and hemolysis. (<b>A</b>–<b>D</b>) Analysis of serum from STAM<sup>TM</sup> mice. (<b>A</b>) Photograph of serum. (<b>B</b>) Quantification of hemoglobin. (<b>C</b>) Heme assay. (<b>D</b>,<b>E</b>) In vitro simulation of NASH and RBC-PLT interaction assay. (<b>D</b>) Photograph of suspension. (<b>E</b>) Quantification of hemoglobin. The mean ± S.D. of three independent experiments performed in triplicate is presented. *** <span class="html-italic">p</span> &lt; 0.01 according to Scheffe’s test. (<b>F</b>) Schematic diagram of the experiment (<b>left</b>) and western blotting data (<b>right</b>). (<b>G</b>) RBC-PLT binding. (<b>H</b>,<b>I</b>) Flow cytometry using PKH26-labeled RBCs and PKH67-labeled PLTs. (<b>H</b>) PLT-Annexin-V. (<b>I</b>) RBC-Annexin-V. * <span class="html-italic">p</span> &lt; 0.05 and ** <span class="html-italic">p</span> &lt; 0.01, Mann–Whitney U test. The values in (<b>E</b>) represent the mean ± S.D. of three independent experiments performed in triplicate. *** <span class="html-italic">p</span> &lt; 0.01 according to Scheffe’s test.</p> Full article ">Figure 5
<p>Cilostazol rehabilitated the upregulation of erythrophagocytosis-induced HIO in NASH models. (<b>A</b>) Prussian blue staining of liver tissue from the STAM<sup>TM</sup> model. (<b>B</b>) Western blotting data of liver tissue from the STAM<sup>TM</sup> model. (<b>C</b>) Heme and iron assay using liver tissue lysate. (<b>D</b>) Heme and iron assay using spleen tissue lysate. Data in (<b>C</b>,<b>D</b>). ** <span class="html-italic">p</span> &lt; 0.01, Mann–Whitney U test. (<b>E</b>–<b>G</b>) Insert coculture study. (<b>E</b>) Schematic illustration. (<b>F</b>,<b>G</b>) Western blotting data showing the ratio of the corresponding protein to Erk1/2. ** <span class="html-italic">p</span> &lt; 0.01 according to Scheffe’s test.</p> Full article ">Figure 6
<p>Cilostazol attenuated RBC-induced ferroptosis in THP-1 and HepG2 cells. (<b>A</b>–<b>D</b>) Coculture experimental system. (<b>A</b>) Cell viability assay. (<b>B</b>) Quantification of the ratio of cleaved caspase-3 to procaspase-3. (<b>C</b>,<b>D</b>) Quantification of western blotting for the ratio of AIFM2 (<b>C</b>) and GPX4 (<b>D</b>) to the loading control. (<b>E</b>) Immunohistochemistry of AIFM2 in liver tissue from human NASH patients. (<b>F</b>,<b>G</b>) Flow cytometry assay and confocal microscopy of THP-1 (<b>F</b>) and HepG2 (<b>G</b>) cells stained with BODIPY<sup>TM</sup> 581/591 C11. Confocal microscopy stained with BODIPY<sup>TM</sup> 581/591 C11 (red) and counterstained with Hoechst 33342 (blue). ** <span class="html-italic">p</span> &lt; 0.01 according to Scheffe’s test.</p> Full article ">Figure 7
<p>GEO data analysis of human, rat, and mouse NASH. (<b>A</b>) Heatmap plot of the factors classified by GO terms related to heme and iron metabolism, showing upward mRNA expression of most factors in NAFLD compared to healthy controls in humans, rats, and mice. Green indicates an above-average increase, red indicates a below-average decrease, and black indicates no difference from the average. The intensity of a color is proportional to the base 2 logarithm. (<b>B</b>–<b>D</b>) Volcano plots showing that most factors related to heme and iron metabolism are statistically significant. Gray dots are not significant. (<b>E</b>) Gene ontology enrichment plot comparing NASH to normal controls.</p> Full article ">

Review

Jump to: Research

28 pages, 1138 KiB  
Review
Glucagon-like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide, and Glucagon Receptor Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Medication in New Liver Disease Nomenclature
by Lampros G. Chrysavgis, Spyridon Kazanas, Konstantina Bafa, Sophia Rozani, Maria-Evangelia Koloutsou and Evangelos Cholongitas
Int. J. Mol. Sci. 2024, 25(7), 3832; https://doi.org/10.3390/ijms25073832 - 29 Mar 2024
Cited by 1 | Viewed by 4963
Abstract
Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that regulate postprandial glucose regulation, stimulating insulin secretion from pancreatic β-cells in response to food ingestion. Modified GLP-1 receptor agonists (GLP-1RAs) are being administered for the treatment of obesity and type 2 [...] Read more.
Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that regulate postprandial glucose regulation, stimulating insulin secretion from pancreatic β-cells in response to food ingestion. Modified GLP-1 receptor agonists (GLP-1RAs) are being administered for the treatment of obesity and type 2 diabetes mellitus (T2DM). Strongly related to those disorders, metabolic dysfunction-associated steatotic liver disease (MASLD), especially its aggressive form, defined as metabolic dysfunction-associated steatohepatitis (MASH), is a major healthcare burden associated with high morbidity and extrahepatic complications. GLP-1RAs have been explored in MASH patients with evident improvement in liver dysfunction enzymes, glycemic control, and weight loss. Importantly, the combination of GLP-1RAs with GIP and/or glucagon RAs may be even more effective via synergistic mechanisms in amelioration of metabolic, biochemical, and histological parameters of MASLD but also has a beneficial impact on MASLD-related complications. In this current review, we aim to provide an overview of incretins’ physiology, action, and signaling. Furthermore, we provide insight into the key pathophysiological mechanisms through which they impact MASLD aspects, as well as we analyze clinical data from human interventional studies. Finally, we discuss the current challenges and future perspectives pertinent to this growing area of research and clinical medicine. Full article
(This article belongs to the Special Issue Molecular Targets for the Formation and Treatment of Nonalcoholic Fatty Liver Disease)
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Figure 1

Figure 1
<p>Pleiotropic effects and actions of glucagon-like peptide-1 (GLP-1) (on the left side in gradient red) and glucose-dependent insulinotropic polypeptide (GIP) (on the right side in gradient blue) in different tissues and organs. GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1.</p> Full article ">Figure 2
<p>Schematic representation of hepatic glucose and lipid metabolism, along with the impact of insulin and endogenous incretin hormones on the triangle interaction between liver, pancreas, and intestine, key tissues influencing metabolic dysfunction-associated steatotic liver disease (MASLD). DAG, diacylglycerol; DNL, de novo lipogenesis; ER, endoplasmic reticulum; GIP, glucose-dependent insulinotropic peptide; GLP-1: Glucagon-like peptide-1; GLP-1RA, Glucagon-like peptide-1 receptor agonist; LD, lipid droplet NEFA, non-esterified fatty acids; TAG, triacylglycerol; VLDL, very low-density lipoprotein.</p> Full article ">
19 pages, 984 KiB  
Review
Faecal Microbiota Transplantation, Paving the Way to Treat Non-Alcoholic Fatty Liver Disease
by María Del Barrio, Lucía Lavín, Álvaro Santos-Laso, Maria Teresa Arias-Loste, Aitor Odriozola, Juan Carlos Rodriguez-Duque, Coral Rivas, Paula Iruzubieta and Javier Crespo
Int. J. Mol. Sci. 2023, 24(7), 6123; https://doi.org/10.3390/ijms24076123 - 24 Mar 2023
Cited by 14 | Viewed by 3619
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent cause of chronic liver disease (CLD). Currently, the only therapeutic recommendation available is a lifestyle change. However, adherence to this approach is often difficult to guarantee. Alteration of the microbiota and an increase [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent cause of chronic liver disease (CLD). Currently, the only therapeutic recommendation available is a lifestyle change. However, adherence to this approach is often difficult to guarantee. Alteration of the microbiota and an increase in intestinal permeability seem to be key in the development and progression of NAFLD. Therefore, the manipulation of microbiota seems to provide a promising therapeutic strategy. One way to do so is through faecal microbiota transplantation (FMT). Here, we summarize the key aspects of FMT, detail its current indications and highlight the most recent advances in NAFLD. Full article
(This article belongs to the Special Issue Molecular Targets for the Formation and Treatment of Nonalcoholic Fatty Liver Disease)
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Figure 1

Figure 1
<p>Different ways to manipulate gut microbiota.</p> Full article ">Figure 2
<p>Non-alcoholic-fatty-liver-disease (NAFLD)-related dysbiosis and increased intestinal permeability and the utility of faecal microbiota transplantation (FMT). The increase in intestinal permeability enables bacteria and their metabolites to reach the liver through the portal system. In FMT, a stool sample is taken from a healthy donor. After processing, it will be administered to the receptor subject with NAFLD. The FMT can be performed in different ways, either orally or by endoscopy or enemas. FMT is intended to reverse existing dysbiosis and restore the intestinal barrier, and consequently improve the severity of the disease.</p> Full article ">
16 pages, 606 KiB  
Review
Microsomal Prostaglandin E Synthase-1 and -2: Emerging Targets in Non-Alcoholic Fatty Liver Disease
by Dimitrios Kotsos and Konstantinos Tziomalos
Int. J. Mol. Sci. 2023, 24(3), 3049; https://doi.org/10.3390/ijms24033049 - 3 Feb 2023
Cited by 3 | Viewed by 3505
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects a substantial proportion of the general population and is even more prevalent in obese and diabetic patients. NAFLD, and particularly the more advanced manifestation of the disease, nonalcoholic steatohepatitis (NASH), increases the risk for both liver-related and [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) affects a substantial proportion of the general population and is even more prevalent in obese and diabetic patients. NAFLD, and particularly the more advanced manifestation of the disease, nonalcoholic steatohepatitis (NASH), increases the risk for both liver-related and cardiovascular morbidity. The pathogenesis of NAFLD is complex and multifactorial, with many molecular pathways implicated. Emerging data suggest that microsomal prostaglandin E synthase-1 and -2 might participate in the development and progression of NAFLD. It also appears that targeting these enzymes might represent a novel therapeutic approach for NAFLD. In the present review, we discuss the association between microsomal prostaglandin E synthase-1 and -2 and NAFLD. Full article
(This article belongs to the Special Issue Molecular Targets for the Formation and Treatment of Nonalcoholic Fatty Liver Disease)
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Figure 1

Figure 1
<p>Schematic representation of the reaction catalyzed by microsomal prostaglandin E synthase-1 and -2. Their downstream position in the molecular pathway as terminal regulators of the prostaglandin E<sub>2</sub> synthesis renders them ideal pharmacological targets. Figure has been created with BioRender.com (<a href="http://www.biorender.com" target="_blank">www.biorender.com</a>, accessed on 5 January 2023).</p> Full article ">
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