简介：Nonalcoholicfattyliverdisease(NAFLD),definedasabnormalaccumulation(>5%)ofhepatictriglyceridewithoutexcessalcoholintake,isthemostcommonformofchronicliverdiseaseinadultsandchildrenintheUnitedStates.NAFLDencompassesaspectrumofhistologicfindingsincludinguncomplicatedsteatosis,steatosiswithinflammationandsteatohepatitis[nonalcoholicsteatohepatitis(NASH)];thelattercanadvancetocirrhosisandhepatocellularcarcinoma.NASHiscurrentlyacceptedasthehepaticmanifestationofthesetofcardiovascularriskfactorscollectivelyknownasmetabolicsyndrome.In1999asystemforhistologicgradingandstagingforNASHwasproposed;thiswasrevisedbytheNASHClinicalResearchNetworkin2005fortheentirespectrumoflesionsinNAFLD,includingthelesionsandpatternsofpediatricNAFLD,andforapplicationinclinicalresearchtrials.Diagnosisremainsdistinctfromgradeandstage.ArecentEuropeanproposalseparatessteatosisfromactivitytoderiveanumericdiagnosisofNASH.Eventhoughtherehavebeenpromisingadvancementsinnon-invasivetesting,thesetestsarenotyetdetailedenoughtoreplacethefullrangeoffindingsprovidedbyliverbiopsyevaluation.Limitationsofbiopsyareacknowledged,butliverbiopsyremainsthe'goldstandard'fordiagnosisanddeterminationofamountsofnecroinflammatoryactivity,andlocationoffibrosis,aswellasremodelingoftheparenchymainNASH.ThisreviewfocusesonthespecifichistologiclesionsofNAFLDandNASH,gradingandstaging,differentialdiagnosestobeconsidered,andthecontinuingroleoftheliverbiopsyinthisimportantliverdisease.

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简介：SulfatechitosanderivativeshavegoodsolubilityandtherapeuticeffectonthecellmodelofNAFLD.TheaimofthisstudywastoexaminethetherapeuticeffectofsulfatechitosanderivativesonNAFLD.ThemaleWistarratswereorallyfedhighfatemulsionandreceivedsulfatechitosanderivativesfor5weekstodeterminethepre-treatmenteffectofsulfatechitosanderivativesonNAFLD.ToevaluatethetherapeuticeffectofsulfatechitosanderivativesonNAFLD,theratswereorallyfedwithhighconcentrationemulsionfor5weeks,followedbysulfatechitosanderivativesfor3weeks.Histologicalanalysisandbiomedicalassaysshowedthatsulfatechitosanderivativescandramaticallypreventthedevelopmentofhepaticsteatosisinhepatocytecells.Inanimalstudies,pre-treatmentandtreatmentwithsulfatechitosanderivativessignificantlyprotectedagainsthepaticsteatohepatitisinducedbyhighfatdietaccordingtohistologicalanalysis.Furthermore,increasedTC,ALT,MDA,andLEPinNAFLDweresignificantlyamelioratedbypre-treatmentandtreatmentwithsulfatechitosanderivatives.Furthermore,increasedTG,AST,andTNF-αinNAFLDweresignificantlyamelioratedbytreatmentwithsulfatechitosanderivatives.Sulfatechitosanderivativeshavegoodpre-treatmentandtherapeuticeffectonNAFLD.

简介：AIM:Toinvestigatewhetherliversteatosisreductionduetoasix-monthdietaryinterventionresultsinsignificantchangesintheconcentrationsoffattyacids.METHODS:Agroupof35Caucasianindividualsdiagnosedwithdifferentlevelsofsteatosiswereprospectivelyenrolledinthepresentstudy.Analysisofthefattyacidprofileswasperformedaccordingtochangesinliversteatosis(liversteatosisreductionbyoneortwodegrees)afterasix-monthdietaryintervention.Thediethelpedreducebodymassinobeseandoverweightpatients,andstabilizebothglycemiaanddyslipidemia.FattyacidswereextractedaccordingtotheFolchmethodandanalyzedbygaschromatography.RESULTS:Thisstudyshowedsignificantchangesinfattyacidprofilesinpatientswhohadreducedliversteatosisbyoneaswellastwodegrees.Areductioninliversteatosisbyonedegreecausedasignificantincreaseinthelevelofthen-3family:eicosapentaenoicacid(P<0.055),docosapentaenoicacid-C22:5(P<0.05)anddocosahexaenoicacid(P<0.05).Areductioninliversteatosisbytwodegreescausedasignificantdecreaseinserumpalmitoleicacid-C16:1(P<0.05).CONCLUSION:Liversteatosisreductionisassociatedwithchangesinfattyacidprofiles,andthesechangesmayreflectanalterationinfattyacidsynthesisandmetabolism.Thesefindingsmayhelpbetterunderstandregressionofnonalcoholicfattyliverdisease.

简介：AbstractNonalcoholic fatty liver disease (NAFLD) is becoming increasingly common as the global economy grows and living standards improve. Timely and effective preventions and treatments for NAFLD are urgently needed. Retinol-binding protein-4 (RBP4), the protein that transports retinol through the circulation, was found to be positively related to diabetes, obesity, cardiovascular disease, and other metabolic diseases. Observational studies on the association between serum RBP4 level and the prevalence of NAFLD found contradictory results. Some of the underlying mechanisms responsible for this association have been revealed, and the possible clinical implications of treating NAFLD by targeting RBP4 have been demonstrated. Future studies should focus on the predictive value of RBP4 on NAFLD development and its potential as a therapeutic target in NAFLD.

简介：AbstractBackground:The global prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing. The pathogenesis of NAFLD is multifaceted, and the underlying mechanisms are elusive. We conducted data mining analysis to gain a better insight into the disease and to identify the hub genes associated with the progression of NAFLD.Methods:The dataset GSE49541, containing the profile of 40 samples representing mild stages of NAFLD and 32 samples representing advanced stages of NAFLD, was acquired from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using the R programming language. The Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database were used to perform the enrichment analysis and construct protein-protein interaction (PPI) networks, respectively. Subsequently, transcription factor networks and key modules were identified. The hub genes were validated in a mice model of high fat diet (HFD)-induced NAFLD and in cultured HepG2 cells by real-time quantitative PCR.Results:Based on the GSE49541 dataset, 57 DEGs were selected and enriched in chemokine activity and cellular component, including the extracellular region. Twelve transcription factors associated with DEGs were indicated from PPI analysis. Upregulated expression of five hub genes (SOX9, CCL20, CXCL1, CD24, and CHST4), which were identified from the dataset, was also observed in the livers of HFD-induced NAFLD mice and in HepG2 cells exposed to palmitic acid or advanced glycation end products.Conclusion:The hub genes SOX9, CCL20, CXCL1, CD24, and CHST4 are involved in the aggravation of NAFLD. Our results offer new insights into the underlying mechanism of NAFLD progression.

简介：AIM:Toinvestigatetheproteinexpressionofphosphataseandtensinhomolog(PTEN)inhumanliverbiopsiesofpatientswithalcoholicandnon-alcoholicliverdisease.METHODS:PTENproteinexpressionwasassessedbyimmunohistochemistryinformalin-fixed,paraffinembeddedliversectionsofpatientswithnon-alcoholicfattyliverdisease(NAFLD)(n=44)oralcoholicliverdisease(ALD)(n=25).Liverresectionsobtainedfrom3healthysubjectscandidateforpartialliverdonationservedascontrols.Histologicalevaluationswereperformedbytwoexperiencedpathologists,anddiagnosesestablishedbasedoninternationalcriteria.TheintensityofthePTENstaininginnucleiwascomparedbetweensteatoticandnon-steatoticareasofeachliverfragmentanalyzed.Foreachliverspecimen,theantibody-stainedsectionswereexaminedandscoredblindlybythreeindependentobservers,whowereunawareofthepatients’clinicalhistory.RESULTS:Inhealthyindividuals,PTENimmunostainingwasintenseinboththecytoplasmandnucleiofallhepatocytes.However,PTENwasstronglydownregulatedinboththenucleusandthecytoplasmofhepatocytesfromsteatoticareasinpatientswithNAFLD,independentlyofthediseasestage.Incontrast,nochangesinPTENproteinexpressionwereobservedinpatientswithALD,regardlessofthepresenceofsteatosisorthestageofthedisease.ThedegreeofPTENdownregulationinhepatocytesofpatientswithNAFLDcorrelatedwiththepercentageofsteatosis(r=0.3061,P=0.0459)andtheBMI(r=0.4268,P=0.0043).Hovewer,inpatientswithALD,PTENexpressionwasnotcorrelatedwiththepercentageofsteatosiswithorwithoutobesityasaconfoundingfactor(P=0.5574).Finally,PTENexpressionlevelinsteatoticareasofALDpatientswassignificantlydifferentfromthatseeninsteatoticareasofNAFLDpatients(P<0.0001).CONCLUSION:PTENproteinexpressionisdownregulatedearlyinNAFLD,butnotinALD.PTENimmunohistochemicaldetectioncouldhelpinthedifferentialdiagnosisofN

简介：AIM:Tostudytheformationofintracellularglyceraldehyde-derivedadvancedglycationendproducts(Glycer-AGEs)inthepresenceofhighconcentrationsoffructose.METHODS:CellsofthehumanhepatocytecelllineHep3Bwereincubatedwithorwithoutfructoseforfivedays,andthecorrespondingcelllysateswereseparatedbytwo-dimensionalgradientsodiumdodecylsulfate-polyacrylamidegelelectrophoresis.Glycer-AGEsweredetectedwiththeanti-Glycer-AGEsantibody.Furthermore,theidentificationoftheproteinsthataremodifiedbyglyceraldehydeinthepresenceofhighconcentrationsoffructosewasconductedusingmatrixassistedlaserdesorption/ionizationtime-of-flightmassspectrometry(MALDI-TOF-MS).TheproteinandmRNAlevelsweredeterminedbyWesternblottingandrealtimereversetranscriptionPCR,respectively.RESULTS:Theresultsofthetwo-dimensionalgradientsodiumdodecylsulfate-polyacrylamidegelelectrophoresisindicatedagreateramountofGlycerAGEsinthesampleexposedtohighconcentrationsoffructosethaninthecontrol.ThedetectedGlycerAGEsshowedisoelectricpointsintherangeof8.0-9.0andmolecularweightsintherangeof60-80kDa.TheheterogeneousnuclearribonucleoproteinM(hnRNPM),whichplaysanimportantroleinregulatinggeneexpressionbyprocessingheterogeneousnuclearRNAstoformmaturemRNAs,wasidentifiedasamodifiedproteinusingMALDI-TOF-MS.Increasingtheconcentrationoffructoseinthemediuminducedaconcentration-dependentincreaseinthegeneratedGlycer-AGEs.Furthermore,inanexperimentusingglyceraldehyde,whichisaprecursorofGlycer-AGEs,hnRNPMwasfoundtobemoreeasilyglycatedthantheotherproteins.CONCLUSION:Theresultssuggestthatglyceraldehyde-modifiedhnRNPMaltersgeneexpression.Thischangemaycauseadverseeffectsinhepatocytesandmayserveasatargetfortherapeuticintervention.

简介：AbstractObjective:This study aimed to investigate the association between single-nucleotide polymorphisms (SNPs) of PCSK1 (proprotein convertase subtilisin/kexin type 1) related to obesity and nonalcoholic fatty liver disease (NAFLD).Methods:In this case-control observational study, four candidate SNPs (rs6234, rs155971, rs6232, rs3811951) of PCSK1 were genotyped in 732 NAFLD patients and 823 healthy control participants, all of whom were of ethnic Han Chinese descent. All participants came from Shanghai, China, and joined our study during 2015 to 2016. The frequencies of each allele and genotype, paired linkage disequilibrium, and haplotype were calculated on the SHEsis platform. In addition to SHEsis, five different genetic models (codominant, dominant, recessive, overdominant, and log-additive) were employed to identify the correlation between genotype frequency and NAFLD. This study was approved by the Medical Ethics Committee of Shanghai University of Traditional Chinese Medicine (approved No. 2017LCSY069).Results:In a comparison of NAFLD patients and healthy participants, none of the four PCSK1 SNPs were significantly correlated with the occurrence of NAFLD (P>0.05), in either genotypic or allelic distribution. The recessive model of rs3811951 appeared to show a correlation (odds ratio=1.077; 95% confidence interval=0.924-1.256; P=0.04), but there was no statistical significance after Bonferroni correction (Pcorr>0.0125).Conclusions:Four obesity-related PCSK1 SNPs (rs6234, rs155971, rs6232, rs3811951) showed no significant correlation with the development of NAFLD in a Han Chinese population.

简介：AbstractObjective:Metabolic disorders are markedly common in women with polycystic ovary syndrome (PCOS), and nonalcoholic fatty liver disease (NAFLD) is observed in 30%-55% of all PCOS patients. Many studies have reported that autophagy and apoptosis, which are closely related to mitochondrial function, play important roles in the development of NAFLD. Therefore, in this study, we aimed to explore the role of mitochondrial dysfunction caused by liver apoptosis and autophagy imbalance in the development of NAFLD in a PCOS mouse model.Methods:We used a dihydrotestosterone (DHT)-induced PCOS model to mimic the pathological process of hyperandrogenism. Hematoxylin and eosin and Oil Red O staining assays were used to observe the pathological changes in the liver. Western blotting and quantitative real-time polymerase chain reaction were used to perform mitochondrion-related assays.Results:Hepatic steatosis and different degrees of inflammation were observed in the DHT-treated mice. The expression of molecules involved in the respiratory chain and aerobic respiration process was altered. The levels of the key molecules associated with apoptosis and autophagy were abnormal.Conclusions:Androgens may play a role in the process of hepatic steatosis development by affecting mitochondrial function and subsequently inducing apoptosis and autophagy. Such phenomena might be involved in the pathogenesis of NAFLD in women with PCOS.

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简介：AbstractNon-alcoholic fatty liver disease (NAFLD) is one of the fastest-growing diseases, and its global prevalence is estimated to increase >50% by 2030. NAFLD is comorbid with metabolic syndrome, obesity, type 2 diabetes, and insulin resistance. Despite extensive research efforts, there are no pharmacologic or biological therapeutics for the treatment of NAFLD. Bile acids and sphingolipids are well-characterized signaling molecules. Over the last few decades, researchers have uncovered potential mechanisms by which bile acids and sphingolipids regulate hepatic lipid metabolism. Dysregulation of bile acid and sphingolipid metabolism has been linked to steatosis, inflammation, and fibrosis in patients with NAFLD. This clinical observation has been recapitulated in animal models, which are well-accepted by experts in the hepatology field. Recent transcriptomic and lipidomic studies also show that sphingolipids are important players in the pathogenesis of NAFLD. Moreover, the identification of bile acids as activators of sphingolipid-mediated signaling pathways established a novel theory for bile acid and sphingolipid biology. In this review, we summarize the recent advances in the understanding of bile acid and sphingolipid-mediated signaling pathways as potential contributors to NAFLD. A better understanding of the pathologic effects mediated by bile acids and sphingolipids will facilitate the development of new diagnostic and therapeutic strategies for NAFLD.

简介：AbstractFor the detection of steatosis, quantitative ultrasound imaging techniques have achieved great progress in past years. Magnetic resonance imaging proton density fat fraction is currently the most accurate test to detect hepatic steatosis. Some blood biomarkers correlate with non-alcoholic steatohepatitis, but the accuracy is modest. Regarding liver fibrosis, liver stiffness measurement by transient elastography (TE) has high accuracy and is widely used across the world. Magnetic resonance elastography is marginally better than TE but is limited by its cost and availability. Several blood biomarkers of fibrosis have been used in clinical trials and hold promise for selecting patients for treatment and monitoring treatment response. This article reviews new developments in the non-invasive assessment of non-alcoholic fatty liver disease (NAFLD). Accumulating evidence suggests that various non-invasive tests can be used to diagnose NAFLD, assess its severity, and predict the prognosis. Further studies are needed to determine the role of the tests as monitoring tools. We cannot overemphasize the importance of context in selecting appropriate tests.

简介：AbstractNon-alcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver disease worldwide. It refers to a range of liver conditions affecting people who drink little or no alcohol. NAFLD comprises non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH), the more aggressive form of NAFLD. NASH is featured by steatosis, lobular inflammation, hepatocyte injury, and various degrees of fibrosis. Although much progress has been made over the past decades, the pathogenic mechanism of NAFLD remains to be fully elucidated. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear hormone receptor that is highly expressed in hepatocytes. Hepatic HNF4α expression is markedly reduced in NAFLD patients and mouse models of NASH. HNF4α has been shown to regulate bile acid, lipid, glucose, and drug metabolism. In this review, we summarize the recent advances in the understanding of the pathogenesis of NAFLD with a focus on the regulation of HNF4α and the role of hepatic HNF4α in NAFLD. Several lines of evidence have shown that hepatic HNF4α plays a key role in the initiation and progression of NAFLD. Recent data suggest that hepatic HNF4α may be a promising target for treatment of NAFLD.

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简介：Weprovideaconcisereviewofthemainepidemiologicalliteratureonfattyliver(FL)publishedbetweenJanuary2011andOctober2013.Thefindingsfromtheliteraturewillbeconsideredinlightofthealreadyavailableknowledge.WediscussthelimitationsinherentinthecategorizationofFLintonon-alcoholicandalcoholicFL,thepotentialrelevanceofFLasanindependentpredictorofcardiometabolicdisease,andrecentresearchaddressingtheroleofFLasanindependentpredictorofmortality.ThisreviewisorganizedasaseriesofanswerstorelevantquestionsabouttheepidemiologyofFL.

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简介：AbstractNon-alcoholic fatty liver disease (NAFLD) is a disorder of lipid metabolism. The lipotoxic intermediates of lipid metabolism cause mitochondrial dysfunction and endoplasmic reticulum stress. Organelle-specific autophagy is responsible for the removal of dysfunctional organelles to maintain intracellular homeostasis. Lipophagy contributes to lipid turnover by degrading lipid droplets. The level of autophagy changes during the course of NAFLD, and the activation of hepatocyte autophagy might represent a method of treating NAFLD.

简介：AbstractChronic hepatitis B (CHB) virus infection is an important threat to global health despite the administration of vaccines and the use of antiviral treatments. In recent years, as the prevalence of obesity and metabolic syndrome has increased, non-alcoholic fatty liver disease (NAFLD) in patients with CHB has become more common. Both diseases can lead to liver fibrosis and even hepatocellular carcinoma, but the risk of dual etiology, outcome, and CHB combined with NAFLD is not fully elucidated. In this review, we assess the overlapping prevalence of NAFLD and CHB, summarize recent studies of clinical and basic research related to potential interactions, and evaluate the progressive changes of treatments for CHB patients with NAFLD. This review increases the understanding of the relationship and mechanisms of interaction between steatosis and hepatitis B virus infection, and it provides new strategies for the future clinical management and treatment of CHB combined with NAFLD.