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Metabolic Syndrome and NASH: From Molecular Basis to Therapy

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 37795

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Special Issue Editors

Dr. Juan Manuel Pericas

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Guest Editor

Vall d'Hebron University Hospital, Vall d'Hebron Institute for Research (VHIR), Hospital Clínic de Barcelona, Johns Hopkins University-Pompeu Fabra University Public Policy Center, Barcelona, Spain
Interests: NAFLD/NASH; infectious diseases; bloodstream infections; platform trials; COVID-19; public health

Dr. Andreea Ciudin

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Co-Guest Editor

Morbid Obesity Unit Coordinator, Endocrinology and Nutrition Department, Vall Hebron Research Institut-VHIR, Vall Hebron University Hospital, Universitat Autonoma de Barcelona, CIBERDEM, 08193 Barcelona, Spain
Interests: complications of type 2 diabetes; neurodegeneration and cognitive impairment; obesity and insulin resistance
Special Issues, Collections and Topics in MDPI journals

Dr. Francisco Javier Cubero

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Co-Guest Editor

Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain
Interests: DILI; ALD; JNK; NASH; gut-liver axis; HCC

Special Issue Information

Dear Colleagues,

The rising incidence of non-alcoholic fatty liver disease (NAFLD) globally goes hand in hand with the current epidemics of obesity. The relationship between body weight, fat accumulation and inflammation is probably the most relevant interaction within the constellation of metabolic syndrome leading to steatohepatitis (NASH), liver fibrosis, cirrhosis, cardiovascular complications and end-stage liver disease, namely, hepatocellular carcinoma. Therefore, much attention has been given to this special and complex link between body weight and the severity of NASH from the mechanistic and therapeutic perspectives, leading to a burgeoning and exciting field of research and drug development. However, the relationships between body weight and liver inflammation in NASH are far from linear, thus leading to relevant caveats and many unanswered questions from the standpoints of physiopathology and clinical management.

We invite investigators to contribute with either original research or review articles focusing on the variety of altered molecular mechanisms that link systemic inflammation, adipose tissue and liver fibrosis and their role in NASH and associated complications, as well as on the strategies for addressing the problem from a clinical and epidemiological perspective. The potential topics of interest include but are not limited to the role of extracellular vesicles, and neddylation or ubiquitination pathways; the impacts of obesity and body weight changes in the adipose tissue–liver axis; the role of the microbiome in NASH’s natural history according to a patient’s body weight; different obesity phenotypes according to impact in liver fibrosis; and the usefulness of new drugs for body weight loss in reducing liver fibrosis.

Dr. Juan Manuel Pericas
Guest Editor
Dr. Andreea Ciudin
Dr. Francisco Javier Cubero
Co-Guest Editors

Manuscript Submission Information

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Keywords

MAFLD
NAFLD
NASH
obesity
liver fibrosis
cirrhosis

Published Papers (7 papers)

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Research

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20 pages, 2053 KiB

Open AccessArticle

A Nine-Strain Bacterial Consortium Improves Portal Hypertension and Insulin Signaling and Delays NAFLD Progression In Vivo

by Iris Pinheiro, Aurora Barberá, Imma Raurell, Federico Estrella, Marcel de Leeuw, Selin Bolca, Davide Gottardi, Nigel Horscroft, Sam Possemiers, María Teresa Salcedo, Joan Genescà, María Martell and Salvador Augustin

Biomedicines 2022, 10(5), 1191; https://doi.org/10.3390/biomedicines10051191 - 20 May 2022

Cited by 3 | Viewed by 5450

Abstract

The gut microbiome has a recognized role in Non-alcoholic fatty liver disease (NAFLD) and associated comorbidities such as Type-2 diabetes and obesity. Stool transplantation has been shown to improve disease by restoring endothelial function and insulin signaling. However, more patient-friendly treatments are required. The present study aimed to test the effect of a defined bacterial consortium of nine gut commensal strains in two in vivo rodent models of Non-alcoholic steatohepatitis (NASH): a rat model of NASH and portal hypertension (PHT), and the Stelic animal (mouse) model (STAM™). In both studies the consortium was administered orally q.d. after disease induction. In the NASH rats, the consortium was administered for 2 weeks and compared to stool transplant. In the STAM™ study administration was performed for 4 weeks, and the effects compared to vehicle or Telmisartan at the stage of NASH/early fibrosis. A second group of animals was followed for another 3 weeks to assess later-stage fibrosis. In the NASH rats, an improvement in PHT and endothelial function was observed. Gut microbial compositional changes also revealed that the consortium achieved a more defined and richer replacement of the gut microbiome than stool transplantation. Moreover, liver transcriptomics suggested a beneficial modulation of pro-fibrogenic pathways. An improvement in liver fibrosis was then confirmed in the STAM™ study. In this study, the bacterial consortium improved the NAFLD activity score, consistent with a decrease in steatosis and ballooning. Serum cytokeratin-18 levels were also reduced. Therefore, administration of a specific bacterial consortium of defined composition can ameliorate NASH, PHT, and fibrosis, and delay disease progression. Full article

(This article belongs to the Special Issue Metabolic Syndrome and NASH: From Molecular Basis to Therapy)

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12 pages, 297 KiB

Open AccessArticle

Influence of Type 2 Diabetes in the Association of PNPLA3 rs738409 and TM6SF2 rs58542926 Polymorphisms in NASH Advanced Liver Fibrosis

by Pablo Gabriel-Medina, Roser Ferrer-Costa, Francisco Rodriguez-Frias, Andreea Ciudin, Salvador Augustin, Jesus Rivera-Esteban, Juan M. Pericàs and David Martinez Selva

Biomedicines 2022, 10(5), 1015; https://doi.org/10.3390/biomedicines10051015 - 28 Apr 2022

Cited by 6 | Viewed by 1901

Abstract

Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis in western countries. Insulin resistance (IR), type 2 diabetes (T2D), and the polymorphisms patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 are independent risk factors of NASH. Nevertheless, little is known about the interaction between IR and T2D with these polymorphisms in the pathogenesis of NASH and the development of advanced fibrosis. Thus, our study aimed to investigate this relationship. This is a cross-sectional study including NASH patients diagnosed by liver biopsy, at the Vall d’Hebron University Hospital. A total of 140 patients were included (93 T2D, 47 non-T2D). T2D (OR = 4.67; 95%CI 2.13–10.20; p < 0.001), PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms (OR = 3.94; 95%CI 1.63–9.54; p = 0.002) were independently related with advanced liver fibrosis. T2D increased the risk of advance fibrosis on top of the two polymorphisms (OR = 14.69; 95%CI 3.03–77.35; p = 0.001 for PNPLA3 rs738409 and OR = 11.45; 95%CI 3.16–41.55; p < 0.001 for TM6SF2 rs58542926). In non-T2D patients, the IR (HOMA-IR ≥ 5.2, OR = 14.33; 95%CI 2.14–18.66; p = 0.014) increased the risk of advanced fibrosis when the polymorphisms were present (OR = 19.04; 95%CI 1.71–650.84; p = 0.042). The T2D and IR status increase the risk of advanced fibrosis in patients with NASH carrying the PNPLA3 rs738409 and/or TM6SF2 rs58542926 polymorphisms, respectively. Full article

(This article belongs to the Special Issue Metabolic Syndrome and NASH: From Molecular Basis to Therapy)

14 pages, 2281 KiB

Open AccessArticle

Fatty Acid Synthase Inhibitor Platensimycin Intervenes the Development of Nonalcoholic Fatty Liver Disease in a Mouse Model

by Meng Su, Danfeng Cao, Zhe Wang, Yanwen Duan and Yong Huang

Biomedicines 2022, 10(1), 5; https://doi.org/10.3390/biomedicines10010005 - 21 Dec 2021

Cited by 9 | Viewed by 3163

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting about 25% of world population, while there are still no approved targeted therapies. Although platensimycin (PTM) was first discovered to be a broad-spectrum antibiotic, it was also effective against type II diabetes in animal models due to its ability to inhibit both bacterial and mammalian fatty acid synthases (FASN). Herein, we report the pharmacological effect and potential mode of action of PTM against NAFLD in a Western diet/CCI₄-induced mouse model and a free fatty acids (FFAs)-induced HepG2 cell model. The proper dose of PTM and its liposome-based nano-formulations not only significantly attenuated the Western diet-induced weight gain and the levels of plasma total triglycerides and glucose, but reduced liver steatosis in mice according to histological analyses. Western blotting analysis showed a reduced protein level of FASN in the mouse liver, suggesting that PTM intervened in the development of NAFLD through FASN inhibition. PTM reduced both the protein and mRNA levels of FASN in FFAs-induced HepG2 cells, as well as the expression of several key proteins in lipogenesis, including sterol regulatory element binding protein-1, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. The expression of lipid oxidation-related genes, including peroxisome proliferator activated receptor α and acyl-CoA oxidase 1, was significantly elevated. In conclusion, our study supports the reposition of PTM to intervene in NAFLD progression, since it could effectively inhibit de novo lipogenesis. Full article

(This article belongs to the Special Issue Metabolic Syndrome and NASH: From Molecular Basis to Therapy)

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17 pages, 3754 KiB

Open AccessArticle

Fat: Quality, or Quantity? What Matters Most for the Progression of Metabolic Associated Fatty Liver Disease (MAFLD)

by Olga Estévez-Vázquez, Raquel Benedé-Ubieto, Feifei Guo, Beatriz Gómez-Santos, Patricia Aspichueta, Johanna Reissing, Tony Bruns, Carlos Sanz-García, Svenja Sydor, Lars P. Bechmann, Eva Maranillo, José Ramón Sañudo, María Teresa Vázquez, Arantza Lamas-Paz, Laura Morán, Marina S. Mazariegos, Andreea Ciudin, Juan M. Pericàs, María Isabel Peligros, Javier Vaquero, Eduardo Martínez-Naves, Christian Liedtke, José R. Regueiro, Christian Trautwein, Rafael Bañares, Francisco Javier Cubero and Yulia A. Nevzorova Show full author list Hide full author list

Biomedicines 2021, 9(10), 1289; https://doi.org/10.3390/biomedicines9101289 - 22 Sep 2021

Cited by 4 | Viewed by 3129

Abstract

Objectives: Lately, many countries have restricted or even banned transfat, and palm oil has become a preferred replacement for food manufacturers. Whether palm oil is potentially an unhealthy food mainly due to its high content of saturated Palmitic Acid (PA) is a matter of debate. The aim of this study was to test whether qualitative aspects of diet such as levels of PA and the fat source are risk factors for Metabolic Syndrome (MS) and Metabolic Associated Fatty Liver Disease (MAFLD). Methods: C57BL/6 male mice were fed for 14 weeks with three types of Western diet (WD): 1. LP-WD—low concentration of PA (main fat source—corn and soybean oils); 2. HP-WD—high concentration of PA (main fat source—palm oil); 3. HP-Trans-WD—high concentration of PA (mainly transfat). Results: All types of WD caused weight gain, adipocyte enlargement, hepatomegaly, lipid metabolism alterations, and steatohepatitis. Feeding with HP diets led to more prominent obesity, hypercholesterolemia, stronger hepatic injury, and fibrosis. Only the feeding with HP-Trans-WD resulted in glucose intolerance and elevation of serum transaminases. Brief withdrawal of WDs reversed MS and signs of MAFLD. However, mild hepatic inflammation was still detectable in HP groups. Conclusions: HP and HP-Trans-WD play a crucial role in the genesis of MS and MAFLD. Full article

(This article belongs to the Special Issue Metabolic Syndrome and NASH: From Molecular Basis to Therapy)

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Review

Jump to: Research

18 pages, 1327 KiB

Open AccessReview

Exploring New Drug Targets for Type 2 Diabetes: Success, Challenges and Opportunities

by Abhinav Kanwal, Navjot Kanwar, Sanjay Bharati, Prateek Srivastava, Shailendra P. Singh and Salomon Amar

Biomedicines 2022, 10(2), 331; https://doi.org/10.3390/biomedicines10020331 - 31 Jan 2022

Cited by 17 | Viewed by 5368

Abstract

There are substantial shortcomings in the drugs currently available for treatment of type 2 diabetes mellitus. The global diabetic crisis has not abated despite the introduction of new types of drugs and targets. Persistent unaddressed patient needs remain a significant factor in the quest for new leads in routine studies. Drug discovery methods in this area have followed developments in the market, contributing to a recent rise in the number of molecules. Nevertheless, troubling developments and fresh challenges are still evident. Recently, metformin, the most widely used first-line drug for diabetes, was found to contain a carcinogenic contaminant known as N-nitroso dimethylamine (NDMA). Therefore, purity and toxicity are also a big challenge for drug discovery and development. Moreover, newer drug classes against SGLT-2 illustrate both progress and difficulties. The same was true previously in the case of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Furthermore, researchers must study the importance of mechanistic characteristics of novel compounds, as well as exposure-related hazardous aspects of current and newly identified protein targets, in order to identify new pharmacological molecules with improved selectivity and specificity. Full article

(This article belongs to the Special Issue Metabolic Syndrome and NASH: From Molecular Basis to Therapy)

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25 pages, 728 KiB

Open AccessReview

Non-Alcoholic Fatty Liver Disease (NAFLD) and Potential Links to Depression, Anxiety, and Chronic Stress

by Sue Shea, Christos Lionis, Chris Kite, Lou Atkinson, Surinderjeet S. Chaggar, Harpal S. Randeva and Ioannis Kyrou

Biomedicines 2021, 9(11), 1697; https://doi.org/10.3390/biomedicines9111697 - 16 Nov 2021

Cited by 33 | Viewed by 8170

Abstract

Non-alcoholic fatty liver disease (NAFLD) constitutes the most common liver disease worldwide, and is frequently linked to the metabolic syndrome. The latter represents a clustering of related cardio-metabolic components, which are often observed in patients with NAFLD and increase the risk of cardiovascular disease. Furthermore, growing evidence suggests a positive association between metabolic syndrome and certain mental health problems (e.g., depression, anxiety, and chronic stress). Given the strong overlap between metabolic syndrome and NAFLD, and the common underlying mechanisms that link the two conditions, it is probable that potentially bidirectional associations are also present between NAFLD and mental health comorbidity. The identification of such links is worthy of further investigation, as this can inform more targeted interventions for patients with NAFLD. Therefore, the present review discusses published evidence in relation to associations of depression, anxiety, stress, and impaired health-related quality of life with NAFLD and metabolic syndrome. Attention is also drawn to the complex nature of affective disorders and potential overlapping symptoms between such conditions and NAFLD, while a focus is also placed on the postulated mechanisms mediating associations between mental health and both NAFLD and metabolic syndrome. Relevant gaps/weaknesses of the available literature are also highlighted, together with future research directions that need to be further explored. Full article

(This article belongs to the Special Issue Metabolic Syndrome and NASH: From Molecular Basis to Therapy)

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21 pages, 1338 KiB

Open AccessReview

Non-Alcoholic Fatty Liver Disease in Lean and Non-Obese Individuals: Current and Future Challenges

by Mohammad Shafi Kuchay, José Ignacio Martínez-Montoro, Narendra Singh Choudhary, José Carlos Fernández-García and Bruno Ramos-Molina

Biomedicines 2021, 9(10), 1346; https://doi.org/10.3390/biomedicines9101346 - 28 Sep 2021

Cited by 51 | Viewed by 9316

Abstract

Non-alcoholic fatty liver disease (NAFLD), which approximately affects a quarter of the world’s population, has become a major public health concern. Although usually associated with excess body weight, it may also affect normal-weight individuals, a condition termed as lean/non-obese NAFLD. The prevalence of lean/non-obese NAFLD is around 20% within the NAFLD population, and 5% within the general population. Recent data suggest that individuals with lean NAFLD, despite the absence of obesity, exhibit similar cardiovascular- and cancer-related mortality compared to obese NAFLD individuals and increased all-cause mortality risk. Lean and obese NAFLD individuals share several metabolic abnormalities, but present dissimilarities in genetic predisposition, body composition, gut microbiota, and susceptibility to environmental factors. Current treatment of lean NAFLD is aimed at improving overall fitness and decreasing visceral adiposity, with weight loss strategies being the cornerstone of treatment. Moreover, several drugs including PPAR agonists, SGLT2 inhibitors, or GLP-1 receptor agonists could also be useful in the management of lean NAFLD. Although there has been an increase in research regarding lean NAFLD, there are still more questions than answers. There are several potential drugs for NAFLD therapy, but clinical trials are needed to evaluate their efficacy in lean individuals. Full article

(This article belongs to the Special Issue Metabolic Syndrome and NASH: From Molecular Basis to Therapy)

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