Non-alcoholic fatty liver disease (NAFLD) is a multisystem disease with complications related to the metabolic syndrome and with a diverse histopathological spectrum ranging from simple steatosis, also termed fatty liver (NAFL) without significant inflammation to steatohepatitis (NASH) with varying stages of fibrosis and, ultimately, cirrhosis, and hepatocellular carcinoma. Since NAFLD is the most common chronic liver disease worldwide, causing a considerable health burden, there is an increasing number of research groups that are deeply interested in the identification of risk factors involved in the progression of the liver damage, the characterization of new biomarkers with utility for its non-invasive diagnosis and the recognition of novel molecular targets for its treatment.Fil: Escribano, Óscar. Universidad Complutense de Madrid; EspañaFil: Frances, Daniel Eleazar Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Otero, Yolanda F.. Valbiotis; FranciaFil: Egea, Javier. Universidad Autonoma de Madrid. Hospital Universitario de la Princesa; EspañaFil: González Rodríguez, Águeda. Centro de Investigación Biomédica En Red de Diabetes y Enfermedades Metabólicas Asociadas; Argentina. Instituto de Salud Carlos III; Españ

Daniel E. Francés

Javier Egea

Yolanda F. Otero

Águeda González-Rodríguez

Óscar Escribano

Frontiers in Medicine

English

PubMed

Escribano, Óscar

Frances, Daniel Eleazar Antonio

Otero, Yolanda F.

Egea, Javier

González Rodríguez, Águeda

LAReferencia - Red Federada de Repositorios Institucionales de Publicaciones Científicas Latinoamericanas

EDITORIALpublished: 12 November 2021doi: 10.3389/fmed.2021.777740Frontiers in Medicine | www.frontiersin.org 1 November 2021 | Volume 8 | Article 777740Edited and reviewed by:Angel Lanas,University of Zaragoza, Spain*Correspondence:Águeda González-Rodríguezaguedagr.phd@gmail.comorcid.org/0000-0003-2851-2318†These authors have contributedequally to this workSpecialty section:This article was submitted toGastroenterology,a section of the journalFrontiers in MedicineReceived: 15 September 2021Accepted: 04 October 2021Published: 12 November 2021Citation:Escribano Ó, Francés DE, Otero YF,Egea J and González-Rodríguez Á(2021) Editorial: New Insights IntoUnderstanding and Managing NAFLD.Front. Med. 8:777740.doi: 10.3389/fmed.2021.777740Editorial: New Insights IntoUnderstanding and Managing NAFLDÓscar Escribano 1†, Daniel E. Francés 2†, Yolanda F. Otero 3†, Javier Egea 4† andÁgueda González-Rodríguez 5,6*†1 Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy,Complutense University of Madrid, Madrid, Spain, 2 Instituto de Fisiología Experimental (IFISE-CONICET), Rosario, Argentina,3 Valbiotis, Riom, France, 4Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Research Unit,Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain,5Metabolic Syndrome and Vascular Risk Research Laboratory, Research Unit, Hospital Universitario Santa Cristina, Institutode Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain, 6Centro de Investigación Biomédica en Redde Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, SpainKeywords: NAFLD (non-alcoholic fatty liver disease), biomarkers, therapeutical approaches, liver pathophysiology,steatohepatitisEditorial on the Research TopicNew Insights Into Understanding and Managing NAFLDNon-alcoholic fatty liver disease (NAFLD) is a multisystem disease with complications relatedto the metabolic syndrome and with a diverse histopathological spectrum ranging from simplesteatosis, also termed fatty liver (NAFL) without significant inflammation to steatohepatitis(NASH) with varying stages of fibrosis and, ultimately, cirrhosis, and hepatocellular carcinoma.Since NAFLD is the most common chronic liver disease worldwide, causing a considerablehealth burden, there is an increasing number of research groups that are deeply interested in theidentification of risk factors involved in the progression of the liver damage, the characterization ofnew biomarkers with utility for its non-invasive diagnosis and the recognition of novel moleculartargets for its treatment.This special issue contains 18 papers, including 10 original research articles and 8 reviews,reporting important data about novel perspectives regarding pathogenesis and managementof NAFLD.Although NAFLD has been conceived as a different entity from alcohol-related fatty liver disease(ALD), both diseases have an overlap in the pathophysiology, share genetic-epigenetic factors,and frequently coexist. In this sense, Idalsoaga et al. reviewed the overlapping pathophysiology ofNAFLD and ALD, and also the effects of metabolic dysfunction and overweight in ALD (Idalsoagaet al.).The identification of risk factors involved in NAFLD progression is important to developpreventive interventions. In this context, Charatcharoenwitthaya et al. described a detrimentaleffect of cigarette smoking on all-cause mortality in the study cohort (19,181 persons), with asimilar but more robust association in women than in men with NAFLD (Charatcharoenwitthayaet al.). In another article, Rim et al. suggested that early screening strategies for people with abruptchronological changes in serum triglycerides might be useful to predict NAFLD development (Rimet al.). Indeed, a better understanding of the different factors linked to NAFLD progression will alsoprovide insight into preventive strategies to reduce the incidence of NAFLD-associated disorders.In this regard, Abdel-Razik et al. attempted to identify risk factors for portal vein thrombosis (PVT)in NAFLD patients, finding that among all PVT-associated factors studied only an increased centralobesity and an elevated leptin/adiponectin ratio in these patients are independently associated withPVT development (Abdel-Razik et al.).Escribano et al. Editorial: Update of NAFLD ManagementPsychological disorders such as depression and anxiety arefrequently present in patients with NAFLD. However, the linkbetween mood disorders and NAFLD is still poorly understood.In this special issue, different studies have provided new insightsabout the association between NAFLD and mental disturbancesthat may have clinical implications for reducing the prevalenceof comorbidities. In this sense, Choi et al. concluded that in aKorean group of study of more than 25,000 subjects, womenwith NAFLD show a higher tendency to suffer from depressionand anxiety compared to non-NAFLD (Choi et al.). In the sameway, the meta-analysis and systematic review performed by Xiaoet al. suggested a strong association between depression andNAFLD. Indeed, they conclude that the worsening of NAFLD toNASH implies a higher risk of suffering depression (Xiao et al.).Moreover, it is still barely unstated how perceived social supportand NAFLD development and progression alter the psychosocialprofile of these patients, and which are relevant risk factors. Inthis special issue, Funuyet-Salas et al. demonstrated that lowperceived social support, significant fibrosis, and female sex areindependently associated with a higher-risk psychosocial profilein NAFLD. Therefore, a psychological intervention in NAFLDpatients could be of great interest (Funuyet-Salas et al.).The underlying mechanism for the setup and progressionof NAFLD is complex and multifactorial, involving multipleparallel factors and signaling pathways. In this sense, microRNAs(miRNAs) function as critical post-transcriptional negativeregulators involved not only in many biological processes butalso in the development of many diseases such as NAFLD.López-Pastor et al. reviewed the latest advances in knowledgeabout the miRNAs involved in the development of NAFLDand related diseases, and examined how this knowledgecould be used to identify new non-invasive biomarkersand new pharmacological interventions for this liver disease(López-Pastor et al.). Moreover, in an updated mini-review,Delli Bovi et al. summarized the current knowledge on therole of oxidative stress in the pathogenesis and progressionof NAFLD, as well as on the preventive and therapeuticstrategies available. The authors reviewed the participation ofthe intestinal microbiota in this process, and highlighted theuse of probiotics as enhancers of antioxidant defenses, aswell as focused on other antioxidant therapeutic interventions,particularly, the use of vitamin E (Delli Bovi et al.). Sinceseveral studies have reported that complement system, aninnate immune system, plays an important role in thepathogenesis of NAFLD, in another review, the authorsexplored the role and molecular mechanism of complementcomponent 3, a protein of the innate immune system,in NASH development as well as its implication in thediagnosis and treatment of this stage of the disease (Hanand Zhang).Likewise, clinical and preclinical studies have revealed thathypoxia may play an important role in the pathophysiologyand progression of NAFLD, which have been included ina mini-review by Isaza et al. Interestingly, the article byRey et al. described for the first time that intermittenthypoxia modulates free fatty acid (FFA) uptake byupregulating the hepatic expression of the FFA translocaseCD36, and partly contributes to the NAFLD setup (Reyet al.).The diagnosis of NAFLD is actually very difficult by non-invasive methods and usually requires a liver biopsy. For thisreason, many researchers and clinicians are making strongefforts to find non-invasive and accurate methods to improvethe diagnosis of this prevalent disease. Bearing this in mind,the study performed by Hokkanen et al. demonstrated thatlow-dose computed tomography (CT) scans could be a usefultool for liver fat quantification and NAFLD diagnosis. Theirresults suggest that low-dose CT is a feasible and well repeatablemethod but amount of liver fat contributes to repeatability.The assessment of liver fat content can be used as additionalinformation in studies where a CT scan has been done forother medical reasons (Hokkanen et al.). In this search fornon-invasive NAFLD biomarkers for diagnosis and prognosis ofNAFLD, another article showed that serum leptin discriminatesNAFLD, and adiponectin combined with specific lipids mightbe useful for the NASH stratification. Moreover, insulin-likegrowth factor 1 (IGF1), international normalized ratio (INR),and ferritin distinguish advanced fibrosis (Marques et al.). Inanother review submitted to this special issue, Garcia-Martinezet al. performed an exhaustive analysis on the literatureregarding the extracellular vesicles (EV) link with hepatocytesstress which is one of the early steps leading to liver disease.Importantly, this review highlighted the potential use of EVas a new biomarker for NAFLD management (Garcia-Martinezet al.).Due to the high prevalence of NAFLD and the absenceof a specific treatment, many attempts are being done tofind new therapeutic targets. In this sense, the discovery ofdietary supplements is a great opportunity. Li and Zhao haveanalyzed the literature supporting the potential of carnitine, anamino acid-derived molecule, as a therapeutic agent for differentliver diseases, particularly NAFLD. Regarding NAFLD, carnitineinhibits β-oxidation, improves mitochondrial dysfunction, andreduces insulin resistance. Therefore, carnitine supplementationmay improve liver diseases including NAFLD (Li and Zhao).Yao et al. in their manuscript described the beneficial effects ofmyricetin, a polyphenolic flavonoid, in a murine dietary modelof NASH, and even help to elucidate the underlying mechanisms:treatment with myricetin favors M2 polarity switch of livermacrophages, attenuating the activation of hepatic stellate cellsand the consequent liver fibrosis (Yao et al.). Based on all this,they propose myricetin as a potential new therapeutic agent forthe treatment of inflammation in NAFLD. In another article,authors explored the effect of crocetin, a bioactive ingredientof saffron, on this liver disease in a mouse model of NAFLDand revealed that crocetin ameliorates obesity-induced NAFLDby suppressing of oxidative stress and decreasing inflammation,demonstrating its therapeutic potential (Xu et al.).In summary, this special issue will help to understandimportant aspects of NAFLD setup and progression.The articles published in this special issue show novelperspectives about pathogenesis and diagnosis of NAFLDas well as possible therapeutic approaches to ameliorateliver injury.Frontiers in Medicine | www.frontiersin.org 2 November 2021 | Volume 8 | Article 777740Escribano et al. Editorial: Update of NAFLD ManagementAUTHOR CONTRIBUTIONSÓE, DF, YO, JE, and AG-R wrote the manuscript. Allauthors critically revised the manuscript for importantintellectual content.FUNDINGThis work was supported by grants RTI-2018-095098-B100 fromMinisterio de Ciencia, Innovación y Universidades (Spain) andPR75/18-21572 from Santander-UCM (Spain) to OE; grantsCPII19/00005 and PI19/00082 from Instituto de Salud CarlosIII (ISCIII, Spain) and Fondo Europeo para el DesarrolloRegional (FEDER) to JE; grants CPII19/00032, PI19/00123, andCIBERDEM from ISCIII/FEDER to AG-R.Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Publisher’s Note: All claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations, or those ofthe publisher, the editors and the reviewers. Any product that may be evaluated inthis article, or claim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Copyright © 2021 Escribano, Francés, Otero, Egea and González-Rodríguez. Thisis an open-access article distributed under the terms of the Creative CommonsAttribution License (CC BY). The use, distribution or reproduction in other forumsis permitted, provided the original author(s) and the copyright owner(s) are creditedand that the original publication in this journal is cited, in accordance with acceptedacademic practice. No use, distribution or reproduction is permitted which does notcomply with these terms.Frontiers in Medicine | www.frontiersin.org 3 November 2021 | Volume 8 | Article 777740

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