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Biomedicines
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Metabolic- and Genetic-Associated Fatty Liver Diseases Volume II
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Metabolic- and Genetic-Associated Fatty Liver Diseases Volume II

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Endocrinology and Metabolism Research".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 9619

Special Issue Editors

Dr. Laura D’Erasmo

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Guest Editor
Department of Translational and Precision Medicine, University of Rome Sapienza, Viale del Policlinico 155, 00185 Rome, Italy
Interests: clinical study; molecular biology; NAFLD; cardiovascular risk stratification; atherosclerosis; lipid metabolism; rare disease; hypercholesterolemia; hypertriglyceridemia; precision medicine
Special Issues, Collections and Topics in MDPI journals
Dr. Alessia Di Costanzo

E-Mail Website
Guest Editor
Department of Translational and Precision Medicine, University of Rome Sapienza, 00161 Rome, Italy
Interests: molecular biology; genetic associated fatty liver disease; polygenic risk score for NAFLD; monogenic and polygenic lipid disorders; cardiovascular risk stratification
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue of Biomedicine, entitled “Metabolic- and Genetic-Associated Fatty Liver Diseases”, will include a selection of articles (both original and review) focusing on the role of metabolic and genetic factors in non-alcoholic fatty liver disease (NAFLD) and its clinical consequences (progression to liver diseases as well as atherosclerotic cardiovascular disease—ASCVD).

NAFLD is a highly prevalent disease and is usually accompanied by metabolic, inflammatory, coagulation, and blood pressure disturbances. Increasing evidence is questioning the role of fatty liver per se in causing ASCVD, suggesting that the pathogenesis of NAFLD might be crucial in influencing the different associated clinical consequences. We are seeking basic, clinical, and multi-disciplinary research that will aid in building the knowledge base of this topic and help fully characterize the mechanisms underlying the relationship between NAFLD and severe liver diseases or atherosclerosis processes.

Dr. Laura D’Erasmo
Dr. Alessia Di Costanzo
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. Biomedicines 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 2600 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.

Keywords

  • NAFLD
  • MAFLD
  • NASH
  • fibrosis
  • irrhosis
  • genetics
  • metabolic syndrome
  • pathogenesis
  • atherosclerosis
  • animal models
  • epidemiology

Published Papers (7 papers)

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Research

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13 pages, 4726 KiB  
Article
Different Coactivator Recruitment to Human PPARα/δ/γ Ligand-Binding Domains by Eight PPAR Agonists to Treat Nonalcoholic Fatty Liver Disease
by Shotaro Kamata, Akihiro Honda, Nonoka Kashiwagi, Ayumi Shimamura, Sayaka Yashiro, Yuna Komori, Aoi Hosoda, Noriyuki Akahoshi and Isao Ishii
Biomedicines 2024, 12(3), 624; https://doi.org/10.3390/biomedicines12030624 - 11 Mar 2024
Viewed by 1275
Abstract
Three peroxisome proliferator-activated receptor subtypes, PPARα, PPAR(ß/)δ, and PPARγ, exert ligand-dependent transcriptional control in concert with retinoid X receptors (RXRs) on various gene sets harboring PPAR response elements (PPREs) in their promoter regions. Ligand-bound PPAR/RXR complexes do not directly regulate transcription; instead, they [...] Read more.
Three peroxisome proliferator-activated receptor subtypes, PPARα, PPAR(ß/)δ, and PPARγ, exert ligand-dependent transcriptional control in concert with retinoid X receptors (RXRs) on various gene sets harboring PPAR response elements (PPREs) in their promoter regions. Ligand-bound PPAR/RXR complexes do not directly regulate transcription; instead, they recruit multiprotein coactivator complexes to specific genomic regulatory loci to cooperatively activate gene transcription. Several coactivators are expressed in a single cell; however, a ligand-bound PPAR can be associated with only one coactivator through a consensus LXXLL motif. Therefore, altered gene transcription induced by PPAR subtypes/agonists may be attributed to the recruitment of various coactivator species. Using a time-resolved fluorescence resonance energy transfer assay, we analyzed the recruitment of four coactivator peptides (PGC1α, CBP, SRC1, and TRAP220) to human PPARα/δ/γ-ligand-binding domains (LBDs) using eight PPAR dual/pan agonists (bezafibrate, fenofibric acid, pemafibrate, pioglitazone, elafibranor, lanifibranor, saroglitazar, and seladelpar) that are/were anticipated to treat nonalcoholic fatty liver disease. These agonists all recruited four coactivators to PPARα/γ-LBD with varying potencies and efficacy. Only five agonists (bezafibrate, pemafibrate, elafibranor, lanifibranor, and seladelpar) recruited all four coactivators to PPARδ-LBD, and their concentration-dependent responses differed from those of PPARα/γ-LBD. These results indicate that altered gene expression through consensus PPREs by different PPAR subtypes/agonists may be caused, in part, by different coactivators, which may be responsible for the unique pharmacological properties of these PPAR agonists. Full article
(This article belongs to the Special Issue Metabolic- and Genetic-Associated Fatty Liver Diseases Volume II)
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17 pages, 2416 KiB  
Article
Compensated Advanced Chronic Liver Disease and Steatosis in Patients with Type 2 Diabetes as Assessed through Shear Wave Measurements and Attenuation Measurements
by Mislav Barisic-Jaman, Marko Milosevic, Viktoria Skurla, David Dohoczky, Josip Stojic, Petra Dinjar Kujundzic, Maja Cigrovski Berkovic, Ana Majic-Tengg, Ana Matijaca, Tomo Lucijanic, Mirjana Kardum-Pejic, Vlatka Pandzic Jaksic, Srecko Marusic and Ivica Grgurevic
Biomedicines 2024, 12(2), 323; https://doi.org/10.3390/biomedicines12020323 - 30 Jan 2024
Viewed by 830
Abstract
Patients with type 2 diabetes (T2D) are at risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). We investigated the prevalence of compensated advanced chronic liver disease (cACLD) and steatosis in patients with T2D using the new non-invasive diagnostic methods of shear wave [...] Read more.
Patients with type 2 diabetes (T2D) are at risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). We investigated the prevalence of compensated advanced chronic liver disease (cACLD) and steatosis in patients with T2D using the new non-invasive diagnostic methods of shear wave measurements (SWMs) and attenuation (ATT) measurements in comparison with those of vibration-controlled transient elastography (VCTE) and the controlled attenuation parameter (CAP), which served as the reference methods. Among 214 T2D patients, steatosis at any grade and cACLD were revealed in 134 (62.6%) and 19 (8.9%) patients, respectively. SWMs showed a high correlation with VCTE (Spearman’s ρ = 0.641), whereas SWMs produced lower (mean of −0.7 kPa) liver stiffness measurements (LSMs) overall. At a LSM of >11.0 kPa (Youden), SWMs had an AUROC of 0.951 that was used to diagnose cACLD (defined as a LSM of >15 kPa through VCTE) with 84.2% sensitivity and 96.4% specificity. The performance of ATT measurements in diagnosing liver steatosis at any grade (defined as the CAP of ≥274 dB/m) was suboptimal (AUROC of 0.744 at the ATT measurement cut-off of >0.63 dB/cm/MHz (Youden) with 59% sensitivity and 81.2% specificity). In conclusion, the prevalence of liver steatosis and previously unrecognized cACLD in patients with T2D is high and SWMs appear to be a reliable diagnostic method for this purpose, whereas further investigation is needed to optimize the diagnostic performance of ATT measurements. Full article
(This article belongs to the Special Issue Metabolic- and Genetic-Associated Fatty Liver Diseases Volume II)
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21 pages, 17774 KiB  
Communication
Novel Noninvasive Paraclinical Study Method for Investigation of Liver Diseases
by Nina Gyorfi, Adrian Robert Gal, Andras Fincsur, Karoly Kalmar-Nagy, Kitti Mintal, Edina Hormay, Attila Miseta, Tamas Tornoczky, Anita Katalin Nemeth, Peter Bogner, Tamas Kiss, Zsuzsanna Helyes, Zoltan Sari, Mihaly Klincsik, Vladimir Tadic, Laszlo Lenard, Andras Vereczkei, Zoltan Karadi, Zoltan Vizvari and Attila Toth
Biomedicines 2023, 11(9), 2449; https://doi.org/10.3390/biomedicines11092449 - 3 Sep 2023
Cited by 1 | Viewed by 965
Abstract
Based on a prior university patent, the authors developed a novel type of bioimpedance-based test method to noninvasively detect nonalcoholic fatty liver disease (NAFLD). The development of a new potential NAFLD diagnostic procedure may help to understand the underlying mechanisms between NAFLD and [...] Read more.
Based on a prior university patent, the authors developed a novel type of bioimpedance-based test method to noninvasively detect nonalcoholic fatty liver disease (NAFLD). The development of a new potential NAFLD diagnostic procedure may help to understand the underlying mechanisms between NAFLD and severe liver diseases with a painless and easy-to-use paraclinical examination method, including the additional function to detect even the earlier stages of liver disease. The aim of this study is to present new results and the experiences gathered in relation to NAFLD progress during animal model and human clinical trials. Full article
(This article belongs to the Special Issue Metabolic- and Genetic-Associated Fatty Liver Diseases Volume II)
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15 pages, 1236 KiB  
Article
SAMM50-rs2073082, -rs738491 and -rs3761472 Interactions Enhancement of Susceptibility to Non-Alcoholic Fatty Liver Disease
by Jinhan Zhao, Xiaoyi Xu, Xinhuan Wei, Shuang Zhang, Hangfei Xu, Xiaodie Wei, Yang Zhang and Jing Zhang
Biomedicines 2023, 11(9), 2416; https://doi.org/10.3390/biomedicines11092416 - 29 Aug 2023
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Abstract
Background and aim: Several studies have identified that three SAMM50 polymorphisms (rs2073082, rs738491, rs3761472) are associated with an increased risk of non-alcoholic fatty liver disease (NAFLD). However, the clinical significance of the SAMM50 SNP in relation to NAFLD remains [...] Read more.
Background and aim: Several studies have identified that three SAMM50 polymorphisms (rs2073082, rs738491, rs3761472) are associated with an increased risk of non-alcoholic fatty liver disease (NAFLD). However, the clinical significance of the SAMM50 SNP in relation to NAFLD remains largely unknown. Therefore, we conducted a clinical study and SNP–SNP interaction analysis to further elucidate the effect of the SAMM50 SNP on the progression of NAFLD in the elderly. Methods: A total of 1053 patients over the age of 65 years were recruited. Liver fat and fibrosis were detected by abdominal ultrasound or FibroScan, respectively. Genomic DNA was extracted and then genotyped by Fluidigm 96.96 Dynamic Array. Multivariable logistic regression was used to evaluate the association between NAFLD and SNP. SNP–SNP interactions were analyzed using generalized multivariate dimensionality reduction (GMDR). Results: The risk of NAFLD was substantially higher in people who carried SAMM50-rs2073082 G and -rs738491 T alleles (OR, 1.962; 95% CI, 1.448–2.659; p < 0.001; OR, 1.532; 95% CI, 1.246–1.884; p = 0.021, respectively) compared to noncarriers. Carriers of the rs738491 T and rs3761472 G alleles in the cohort showed a significant increase in liver stiffness measurements (LSM). The combination of the three SNPs showed the highest predictive power for NAFLD. The rs2073082 G allele, rs738491 T allele and rs3761472 G carriers had a two-fold higher risk of NAFLD compared to noncarriers. Conclusions: Our research has demonstrated a strong correlation between the genetic polymorphism of SAMM50 and NAFLD in the elderly, which will contribute to a better understanding of the impact of age and genetics on this condition. Additionally, this study provides a potential predictive model for the early clinical warning of NAFLD. Full article
(This article belongs to the Special Issue Metabolic- and Genetic-Associated Fatty Liver Diseases Volume II)
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Review

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15 pages, 1398 KiB  
Review
Bridging Metabolic-Associated Steatotic Liver Disease and Cardiovascular Risk: A Potential Role for Ketogenesis
by Rafael Suárez del Villar-Carrero, Agustín Blanco, Lidia Daimiel Ruiz, Maria J. García-Blanco, Ramón Costa Segovia, Rocío García de la Garza and Diego Martínez-Urbistondo
Biomedicines 2024, 12(3), 692; https://doi.org/10.3390/biomedicines12030692 - 20 Mar 2024
Viewed by 1262
Abstract
The prevalence of cardiovascular diseases (CVDs) is a growing global health concern. Recent advances have demonstrated significant reductions in acute cardiovascular events through the management of modifiable cardiovascular risk factors. However, these factors are responsible for about 50% of the global cardiovascular disease [...] Read more.
The prevalence of cardiovascular diseases (CVDs) is a growing global health concern. Recent advances have demonstrated significant reductions in acute cardiovascular events through the management of modifiable cardiovascular risk factors. However, these factors are responsible for about 50% of the global cardiovascular disease burden. Considering that CVDs are one of the top mortality causes worldwide, the concept of residual cardiovascular risk is an important emerging area of study. Different factors have been proposed as sources of residual risk markers, including non-HDL particles characterization, as well as inflammation measured by serum and imaging technics. Among these, metabolic-associated steatotic liver disease (MASLD) remains controversial. Two opposing viewpoints contend: one positing that fatty liver disease merely reflects classical risk factors and thus adds no additional risk and another asserting that fatty liver disease independently impacts cardiovascular disease incidence. To address this dilemma, one hypothetical approach is to identify specific hepatic energy-yielding mechanisms and assess their impact on the cardiovascular system. Ketogenesis, a metabolic intermediate process particularly linked to energy homeostasis during fasting, might help to link these concepts. Ketogenic metabolism has been shown to vary through MASLD progression. Additionally, newer evidence supports the significance of circulating ketone bodies in cardiovascular risk prediction. Furthermore, ketogenic metabolism modification seems to have a therapeutic impact on cardiovascular and endothelial damage. Describing the relationship, if any, between steatotic liver disease and cardiovascular disease development through ketogenesis impairment might help to clarify MASLD’s role in cardiovascular risk. Furthermore, this evidence might help to solve the controversy surrounding liver steatosis impact in CVD and might lead to a more accurate risk assessment and therapeutic targets in the pursuit of precision medicine. Full article
(This article belongs to the Special Issue Metabolic- and Genetic-Associated Fatty Liver Diseases Volume II)
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28 pages, 1848 KiB  
Review
Exploring the Multifaceted Landscape of MASLD: A Comprehensive Synthesis of Recent Studies, from Pathophysiology to Organoids and Beyond
by Allison Soto, Colby Spongberg, Alessandro Martinino and Francesco Giovinazzo
Biomedicines 2024, 12(2), 397; https://doi.org/10.3390/biomedicines12020397 - 8 Feb 2024
Viewed by 1685
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a widespread contributor to chronic liver disease globally. A recent consensus on renaming liver disease was established, and metabolic dysfunction-associated steatotic liver disease, MASLD, was chosen as the replacement for NAFLD. The disease’s range extends from the [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a widespread contributor to chronic liver disease globally. A recent consensus on renaming liver disease was established, and metabolic dysfunction-associated steatotic liver disease, MASLD, was chosen as the replacement for NAFLD. The disease’s range extends from the less severe MASLD, previously known as non-alcoholic fatty liver (NAFL), to the more intense metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH), characterized by inflammation and apoptosis. This research project endeavors to comprehensively synthesize the most recent studies on MASLD, encompassing a wide spectrum of topics such as pathophysiology, risk factors, dietary influences, lifestyle management, genetics, epigenetics, therapeutic approaches, and the prospective trajectory of MASLD, particularly exploring its connection with organoids. Full article
(This article belongs to the Special Issue Metabolic- and Genetic-Associated Fatty Liver Diseases Volume II)
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17 pages, 2194 KiB  
Review
SREBP Regulation of Lipid Metabolism in Liver Disease, and Therapeutic Strategies
by Na Li, Xiaodan Li, Yifu Ding, Xiao Liu, Karin Diggle, Tatiana Kisseleva and David A. Brenner
Biomedicines 2023, 11(12), 3280; https://doi.org/10.3390/biomedicines11123280 - 12 Dec 2023
Cited by 1 | Viewed by 2060
Abstract
Sterol regulatory element-binding proteins (SREBPs) are master transcription factors that play a crucial role in regulating genes involved in the biogenesis of cholesterol, fatty acids, and triglycerides. As such, they are implicated in several serious liver diseases, including non-alcoholic fatty liver disease (NAFLD), [...] Read more.
Sterol regulatory element-binding proteins (SREBPs) are master transcription factors that play a crucial role in regulating genes involved in the biogenesis of cholesterol, fatty acids, and triglycerides. As such, they are implicated in several serious liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). SREBPs are subject to regulation by multiple cofactors and critical signaling pathways, making them an important target for therapeutic interventions. In this review, we first introduce the structure and activation of SREBPs, before focusing on their function in liver disease. We examine the mechanisms by which SREBPs regulate lipogenesis, explore how alterations in these processes are associated with liver disease, and evaluate potential therapeutic strategies using small molecules, natural products, or herb extracts that target these pathways. Through this analysis, we provide new insights into the versatility and multitargets of SREBPs as factors in the modulation of different physiological stages of liver disease, highlighting their potential targets for therapeutic treatment. Full article
(This article belongs to the Special Issue Metabolic- and Genetic-Associated Fatty Liver Diseases Volume II)
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