Liver cancer is the sixth most commonly diagnosed cancer worldwide,with hepatocellular carcinoma(HCC)comprising most cases.Besides hepatitis B and C viral infections,heavy alcohol use,and nonalcoholic steatohepatitis(...Liver cancer is the sixth most commonly diagnosed cancer worldwide,with hepatocellular carcinoma(HCC)comprising most cases.Besides hepatitis B and C viral infections,heavy alcohol use,and nonalcoholic steatohepatitis(NASH)-associated advanced fibrosis/cirrhosis,several other risk factors for HCC have been identified(i.e.old age,obesity,insulin resistance,type 2 diabetes).These might in fact partially explain the occurrence of HCC in non-cirrhotic patients without viral infection.HCC surveillance through effective screening programs is still an unmet need for many nonalcoholic fatty liver disease(NAFLD)patients,and identification of pre-cirrhotic individuals who progress to HCC represents a substantial challenge in clinical practice at the moment.Patients with NASHcirrhosis should undergo systematic HCC surveillance,while this might be considered in patients with advanced fibrosis based on individual risk assessment.In this context,interventions that potentially prevent NAFLD/NASH-associated HCC are needed.This paper provided an overview of evidence related to lifestyle changes(i.e.weight loss,physical exercise,adherence to healthy dietary patterns,intake of certain dietary components,etc.)and pharmacological interventions that might play a protective role by targeting the underlying causative factors and pathogenetic mechanisms.However,well-designed prospective studies specifically dedicated to NAFLD/NASH patients are still needed to clarify the relationship with HCC risk.展开更多
Distinguishing between nonalcoholic steatohepatitis(NASH) and advanced liver fibrosis is the key for clinical diagnosis of non-alcoholic fatty liver disease(NAFLD). Liver biopsy, which is widely used for diagnosis of ...Distinguishing between nonalcoholic steatohepatitis(NASH) and advanced liver fibrosis is the key for clinical diagnosis of non-alcoholic fatty liver disease(NAFLD). Liver biopsy, which is widely used for diagnosis of liver diseases at present, has many drawbacks, such as being invasive, expensive and unstable. This article compares and summarizes the commonly used non-invasive diagnostic methods, including their diagnostic parameters, advantages and disadvantages, in order to provide a useful reference for the diagnosis of NASH.展开更多
AIM:To investigate whether a noninvasive measurement of tissue strain has a potential usefulness for management of nonalcoholic steatohepatitis(NASH).METHODS:In total 26 patients,23 NASHs and 3 normal controls were en...AIM:To investigate whether a noninvasive measurement of tissue strain has a potential usefulness for management of nonalcoholic steatohepatitis(NASH).METHODS:In total 26 patients,23 NASHs and 3 normal controls were enrolled in this study.NASH was staged based on Brunt criterion.At a region of interest(ROI),a shear wave was evoked by implementing an acoustic radiation force impulse(ARFI),and the propagation velocity was quantif ied.RESULTS:Shear wave velocity(SWV) could be reproducibly quantified at all ROIs in all subjects except for 4 NASH cases,in which a reliable SWV value was not calculated at several ROIs.An average SWV of 1.34 ± 0.26 m/s in fibrous stage 0-1 was significantly slower than 2.20 ± 0.74 m/s and 2.90 ± 1.01 m/s in stages 3 and 4,respectively,but was not significantly different from 1.79 ± 0.78 m/s in stage 2.When a cutoff value was set at 1.47 m/s,receiver operating characteristic analysis showed significance to dissociate stages 3 and 4 from stage 0-1(P=0.0092) with sensitivity,specificity and area under curve of 100%,75% and 94.2%,respectively.In addition,the correlation between SWV and hyaluronic acid was significant(P<0.0001),while a tendency toward negative correlation was observed with serum albumin(P=0.053).CONCLUSION:The clinical implementation of ARFI provides noninvasive repeated evaluations of liver stiffness at an arbitrary position,which has the potential to shed new light on NASH management.展开更多
Recently,nonalcoholic steatohepatitis(NASH) has been considered to be another cause of liver cirrhosis and hepatocellular carcinoma(HCC).The natural history and prognosis of NASH are controversial.Accordingly,we asses...Recently,nonalcoholic steatohepatitis(NASH) has been considered to be another cause of liver cirrhosis and hepatocellular carcinoma(HCC).The natural history and prognosis of NASH are controversial.Accordingly,we assessed the clinicopathological features of NASH-associated HCC in our experience and reviewed the literature of NASH-associated HCC.We experienced 11 patients with NASH-associated HCC(6 male,5 female;mean age 73.8 ± 4.9 years) who received curative treatments.Most(91%) patients had been diagnosed with obesity,diabetes,hypertension,or dyslipidemia.Seven patients(64%) also had a non-cirrhotic liver.The recurrence-free survival rates at 1,3 and 5 years were 72%,60%,and 60%.We also summarized and reviewed 94 cases of NASH-associated HCC which were reported in the literature(64 male;mean age 66 years).The majority of patients(68%) were obese,66% of patients had diabetes,and 24% had dyslipidemia.Furthermore,26% of the HCCs arose from the non-cirrhotic liver.In conclusion,patients with non-cirrhotic NASH may be a high-risk group for HCC,and regular surveillance for HCC is necessary in non-cirrhotic NASH patients as well as cirrhotic patients.展开更多
AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis(NASH) in obese mouse models of biopsy-confirmedNASH.METHODS Male wild-type C57 BL/6 J mice(DIO-NASH) and Lep^(...AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis(NASH) in obese mouse models of biopsy-confirmedNASH.METHODS Male wild-type C57 BL/6 J mice(DIO-NASH) and Lep^(ob/ob)(ob/ob-NASH) mice were fed a diet high in trans-fat(40%), fructose(20%) and cholesterol(2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score(NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide(0.2 mg/kg, SC, BID), obeticholic acid(OCA, 30 mg/kg PO, QD), or elafibranor(30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1 a1.RESULTS Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1 a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression(RNA sequencing) and liver lipid biochemistry.CONCLUSION DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH.展开更多
Background: Nonalcoholic fatty liver disease(NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver(NAFL) and nonalcoholic steatohepatitis(NASH). However, there is no re...Background: Nonalcoholic fatty liver disease(NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver(NAFL) and nonalcoholic steatohepatitis(NASH). However, there is no reliable non-invasive parameter in distinguishing NASH from NAFL in clinical practice. The present study was to find a non-invasive way to differentiate these two categories of NAFLD via lipidomic analysis. Methods: Lipidomic analysis was used to determine the changes of lipid moieties in blood from 20 NAFL and 10 NASH patients with liver biopsy. Liver histology was evaluated after hematoxylin and eosin staining and Masson’s trichrome staining. The profile of lipid metabolites in correlation with steatosis, inflammation, hepatocellular necroptosis, fibrosis, and NAFLD activity score(NAS) was analyzed. Results: Compared with NAFL patients, NASH patients had higher degree of steatosis, ballooning degeneration, lobular inflammation. A total of 434 different lipid molecules were identified, which were mainly composed of various phospholipids and triacylglycerols. Many lipids, such as phosphatidylcholine(PC)(P-22:0/18:1), sphingomyelin(SM)(d14:0/18:0), SM(d14:0/24:0), SM(d14:0/22:0), phosphatidylethanolamine(PE)(18:0/22:5), PC(O-22:2/12:0), and PC(26:1/11:0) were elevated in the NASH group compared to those in the NAFL group. Specific analysis revealed an overall lipidomic profile shift from NAFL to NASH, and identified valuable lipid moieties, such as PCs [PC(14:0/18:2), PE(18:0/22:5) and PC(26:1/11:0)] or plasmalogens [PC(O-22:0/0:0), PC(O-18:0/0:0), PC(O-16:0/0:0)], which were significantly altered in NASH patients. In addition, PC(14:0/18:2), phosphatidic acid(18:2/24:4) were positively correlated with NAS;whereas PC(18:0/0:0) was correlated positively with fibrosis score. Conclusions: The present study revealed overall lipidomic profile shift from NAFL to NASH, identified valuable lipid moieties which may be non-invasive biomarkers in the categorization of NAFLD. The correlations between lipid moieties and NAS and fibrosis scores indicate that these lipid biomarkers may be used to predict the severity of the disease.展开更多
BACKGROUND The association between PPARGC1A rs8192678 and nonalcoholic fatty liver disease(NAFLD)requires further confirmation.In addition,it is still unknown whether PPARGC1A rs8192678 is associated with hepatic hist...BACKGROUND The association between PPARGC1A rs8192678 and nonalcoholic fatty liver disease(NAFLD)requires further confirmation.In addition,it is still unknown whether PPARGC1A rs8192678 is associated with hepatic histological features in NAFLD in the Chinese population.AIM To investigate the interaction between PPARGC1A rs8192678 and nonalcoholic steatohepatitis(NASH),and whether this polymorphism is associated with hepatic histological features.METHODS Fifty-nine patients with liver biopsy-proven NAFLD and 93 healthy controls were recruited to a cohort representing the Chinese Han population.The SAF(steatosis,activity,and fibrosis)scoring system was used for hepatic histopathological evaluation.The polymorphisms of PPARGC1A rs8192678 and patatin-like phospholipase domain-containing protein 3(PNPLA3)rs738409 were genotyped.The intrahepatic mRNA expression of PPARGC1A was evaluated by real-time polymerase chain reaction.RESULTS Thirty-seven patients with NAFLD had NASH,of which 12 were nonobese.The PPARGC1A rs8192678 risk A allele(carrying GA and AA genotypes)had the lowest P value in the dominant model;the odds ratio(OR)for NAFLD was 2.321[95%confidence interval(CI):1.121-4.806].After adjusting for age,sex,and the PNPLA3 rs738409 risk G allele,the PPARGC1A rs8192678 A allele was a risk factor for NAFLD(OR 2.202,95%CI:1.030-4.705,P=0.042).The genetic analysis showed that patients with NAFLD,moderate-to-severe steatosis(S2-3),and Activity 2-4(A≥2)were more likely to carry A in PPARGC1A rs8192678(OR 5.000,95%CI:1.343-18.620,P=0.012;and OR 4.071,95%CI:1.076-15.402,P=0.031).The multivariate logistic regression analysis showed that PPARGC1A rs8192678 risk A allele was also independently associated with S2-3,A≥2,and NASH(OR 6.190,95%CI:1.508-25.410,P=0.011;OR 4.506,95%CI 1.070-18.978,P=0.040;and OR 6.337,95%CI:1.135-35.392,P=0.035,respectively)after adjusting for age,sex,body mass index,and PNPLA3 rs738409 risk G allele.The results also showed that this polymorphism was associated with nonobese NASH(OR 22.000,95%CI:1.540-314.292,P=0.021).The intrahepatic expression of PPARGC1A mRNA was significantly lower in the group of patients who carried the risk A allele(P=0.014).CONCLUSION The PPARGC1A rs8192678 risk A allele is associated with NAFLD,and with S2-3,A≥2 and NASH in NAFLD patients,independent of PNPLA3 rs738409,and may be associated with nonobese NASH.展开更多
AIM To investigate the association of chronic hepatitis B and nonalcoholic steatohepatitis with physical fitness in a Taiwan Residents military male cohort.METHODS We made a cross-sectional examination of this associa...AIM To investigate the association of chronic hepatitis B and nonalcoholic steatohepatitis with physical fitness in a Taiwan Residents military male cohort.METHODS We made a cross-sectional examination of this association using 3669 young adult military males according to cardiorespiratory fitness and hospitalization events recorded in the Taiwan Armed Forces study. Cases of chronic hepatitis B(n = 121) were defined by personal history and positive detection of hepatitis B surface antigen. Cases of nonalcoholic steatohepatitis(n = 129) were defined by alanine transaminase level > 60 U/L, liver ultrasound finding of steatosis, and absence of viral hepatitis A, B or C infection. All other study participants were defined as unaffected(n = 3419). Physical fitness was evaluated by performance in 3000-m run, 2-min sit-ups, and 2-min push-ups exercises, with all the procedures standardized by a computerized scoring system. Multiple linear regression analysis was used to determine the relationship.RESULTS Chronic hepatitis B negatively correlated with 2-min push-up numbers(β =-2.49, P = 0.019) after adjusting for age, service specialty, body mass index, systolic and diastolic blood pressures, current cigarette smoking, alcohol intake status, serum hemoglobin, and average weekly exercise times. Nonalcoholic steatohepatitis was borderline positively correlated with 3000-m running time(β = 11.96, P = 0.084) and negatively correlated with 2-min sit-up numbers(β =-1.47, P = 0.040). CONCLUSION Chronic hepatitis B viral infection and nonalcoholic steatohepatitis affects different physical performances in young adult military males, and future study should determine the underlying mechanism.展开更多
AIM:To characterize development of diet-induced nonalcoholic steatohepatitis(NASH)by performing live biopsy in wild-type and genetically obese mice.METHODS:Male wild-type C57BL/6J(C57)mice(DIO NASH)and male Lep ob/Lep...AIM:To characterize development of diet-induced nonalcoholic steatohepatitis(NASH)by performing live biopsy in wild-type and genetically obese mice.METHODS:Male wild-type C57BL/6J(C57)mice(DIO NASH)and male Lep ob/Lep ob(ob/ob)mice(ob/ob-NASH were maintained on a diet high in trans-fat(40%)fructose(22%)and cholesterol(2%)for 26 and 12 wk respectively.A normal chow diet served as control in C57 mice(lean chow)and ob/ob mice(ob/ob chow)After the diet-induction period,mice were liver biopsied and a blinded histological assessment of steatosis and fibrosis was conducted.Mice were then stratified into groups counterbalanced for steatosis score and fibrosi stage and continued on diet and to receive daily PO dosing of vehicle for 8 wk.Global gene expression in liver tissue was assessed by RNA sequencing and bioin formatics.Metabolic parameters,plasma liver enzyme and lipids(total cholesterol,triglycerides)as well a hepatic lipids and collagen content were measured b biochemical analysis.Non-alcoholic fatty liver disease activity score(NAS)(steatosis/inflammation/ballooningdegeneration)and fibrosis were scored.Steatosis and fibrosis were also quantified using percent fractional area.RESULTS:Diet-induction for 26 and 12 wk in DIONASH and ob/ob-NASH mice,respectively,elicited progressive metabolic perturbations characterized by increased adiposity,total cholesterol and elevated plasma liver enzymes.The diet also induced clear histological features of NASH including hepatosteatosis and fibrosis.Overall,the metabolic NASH phenotype was more pronounced in ob/ob-NASH vs DIO-NASH mice.During the eight week repeated vehicle dosing period,the metabolic phenotype was sustained in DIO-NASH and ob/ob-NASH mice in conjunction with hepatomegaly and increased hepatic lipids and collagen accumulation.Histopathological scoring demonstrated significantly increased NAS of DIO-NASH mice(0 vs4.7±0.4,P<0.001 compared to lean chow)and ob/ob-NASH mice(2.4±0.3 vs 6.3±0.2,P<0.001compared to ob/ob chow),respectively.Furthermore,fibrosis stage was significantly elevated for DIO-NASH mice(0 vs 1.2±0.2,P<0.05 compared to lean chow)and ob/ob NASH(0.1±0.1 vs 3.0±0.2,P<0.001compared to ob/ob chow).Notably,fibrosis stage was significantly(P<0.001)increased in ob/ob-NASH mice,when compared to DIO-NASH mice.CONCLUSION:These data introduce the obese dietinduced DIO-NASH and ob/ob-NASH mouse models with biopsy-confirmed individual disease staging as a preclinical platform for evaluation of novel NASH therapeutics.展开更多
Background:Nonalcoholic fatty liver disease and its advanced stage,nonalcoholic steatohepatitis(NASH),are the major cause of hepatocellular carcinoma(HCC)and other end-stage liver disease.However,the potential mechani...Background:Nonalcoholic fatty liver disease and its advanced stage,nonalcoholic steatohepatitis(NASH),are the major cause of hepatocellular carcinoma(HCC)and other end-stage liver disease.However,the potential mechanism and therapeutic strategies have not been clarified.This study aimed to identify potential roles of mi RNA/m RNA axis in the pathogenesis and drug combinations in the treatment of NASH.Methods:Microarray GSE59045 and GSE48452 were downloaded from the Gene Expression Omnibus and analyzed using R.Then we obtained differentially expressed genes(DE-genes).DAVID database was used for Gene Ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment pathway analysis.Protein-protein interaction(PPI)networks were used for the identification of hub genes.We found upstream regulators of hub genes using mi RTar Base.The expression and correlation of key mi RNA and its targets were detected by q PCR.Drug Pair Seeker was employed to predict drug combinations against NASH.The expression of mi RNA and hub genes in HCC was identified in the Cancer Genome Atlas database and Human Protein Atlas database.Results:Ninety-four DE-genes were accessed.GO and KEGG analysis showed that these predicted genes were linked to lipid metabolism.Eleven genes were identified as hub genes in PPI networks,and they were highly expressed in cells with vigorous lipid metabolism.hsa-mi R-335-5 p was the upstream regulator of 9 genes in the 11 hub genes,and it was identified as a key mi RNA.The hub genes were highly expressed in NASH models,while hsa-mi R-335-5 p was lowly expressed.The correlation of mi RNA-m RNA was established by q PCR.Functional verification indicated that hsa-mi R-335-5 p had inhibitory effect on the development of NASH.Finally,drug combinations were predicted and the expression of mi RNA and hub genes in HCC was identified.Conclusions:In the study,potential mi RNA-m RNA pathways related to NASH were identified.Targeting these pathways may be novel strategies against NASH.展开更多
OBJECTIVE The pathological characteristics of nonalcoholic steatohepatitis(NASH)include liver steatosis,inflammation,and fibrosis.Fibrosis is the most severe and significant pathological feature in NASH.Effective drug...OBJECTIVE The pathological characteristics of nonalcoholic steatohepatitis(NASH)include liver steatosis,inflammation,and fibrosis.Fibrosis is the most severe and significant pathological feature in NASH.Effective drug treatment could reverse early liver fibrosis and is of significance to prevent NASH from progressing into cirrhosis and liver cancer.Identification of drug targets for NASH treatment has been an active research area and is essential for the development of anti-NASH medications.Naringenin(NGN)is a flavonoid compound rich in citrus fruits.Our preliminary data demonstrated that NGN reduced diet-induced lipid accumulation and inflammation in the mouse liver,but whether NGN can attenuate liver fibrosis of NASH is not known.METHODS To study the effect of NGN on NASH fibrosis.WT mice were fed with high fat diet(HFD)and injected intraperitoneally 20%carbon tetrachloride at the same time for 8 weeks to induce NASH,and NGN was administrated by gavage in the meantime.In vitro,LO2 cells and LX2 cells were stimulated by oleic acid(OA)combined with lipopolysaccharide(LPS),respectively.RESULTS Treating the WT mice with NGN 100 mg·kg^(-1)·d-1 significantly attenuated hepatic lipid accumulation,hepatic fibrosis,plasma ALT and AST levels,inhibited protein expression of p-ERK,p-FoxO3a in the mouse livers.In vitro,on OA and LPS stimulated LO2 or LX2 cells,NGN significantly promoted apoptosis of activated hepatic stellate cells while inhibited apoptosis of hepatocytes.Mechanism study indicated that NGN inhibited MAPK pathway and promoted activation of FoxO3a,consequently promoted apoptosis of the activated LX2 cells and inhibited liver fibrosis.CONCLUSION NGN preventes NASH fibrosis via regulating MAPK/FoxO3a pathway,thus promoting apoptosis of the activated hepatic stellate cells.展开更多
Background: Nonalcoholic fatty liver disease(NAFLD) is increasingly occurring in sedentary people, and may progress to NASH and hepatocellular carcinoma. It is essential to design affordable animal models for the stud...Background: Nonalcoholic fatty liver disease(NAFLD) is increasingly occurring in sedentary people, and may progress to NASH and hepatocellular carcinoma. It is essential to design affordable animal models for the study of various diseases, including fatty liver, which was the aim of the study. In this study, a high-fat diet was devised that triggers NASH’s animal model quickly and easily. High-fat diet(HFD) was used both with intra-mouth oral gavage and in combination with animal pellets.Methods: Twenty-four male C57 BL/6 J mice were divided into HFD and ND groups, which received a high-fat diet and a normal diet, respectively. At the end of the experiment(fourth week of treatment), body and liver weights, biochemical parameters, PPAR-α gene expression and histopathologic characteristics of the liver were evaluated.Results: During 4 weeks, body weight of mice did not show a significant increase in the HFD group compared to the ND group, while weight gain of the liver was significant. Histological assessment of the HFD group’s liver confirmed NASH symptoms. In the HFD group, HDL-c, SOD, catalase, FRAP, adiponectin, and PPAR-α decreased significantly, and lipid profiles, hepatic enzymes, MDA, leptin, and TNF-α showed a significant increase compared to the ND group.Conclusion: Our high-fat diet has successfully induced all aspects of NASH with fibrosis in 4 weeks, and with low cost.展开更多
Fatty liver has been present in the lives of patients and physicians for almost two centuries.Vast knowledge has been generated regarding its etiology and consequences,although a long path seeking novel and innovative...Fatty liver has been present in the lives of patients and physicians for almost two centuries.Vast knowledge has been generated regarding its etiology and consequences,although a long path seeking novel and innovative diagnostic biomarkers for nonalcoholic fatty liver disease(NAFLD)and nonalcoholic steatohepatitis(NASH)is still envisioned.On the one hand,proteomics and lipidomics have emerged as potential noninvasive resources for NAFLD diagnosis.In contrast,metabolomics has been able to distinguish between NAFLD and NASH,even detecting degrees of fibrosis.On the other hand,genetic and epigenetic markers have been useful in monitoring disease progression,eventually functioning as target therapies.Other markers involved in immune dysregulation,oxidative stress,and inflammation are involved in the instauration and evolution of the disease.Finally,the fascinating gut microbiome is significantly involved in NAFLD and NASH.This review presents state-of-the-art biomarkers related to NAFLD and NASH and new promises that could eventually be positioned as diagnostic resources for this disease.As is evident,despite great advances in studying these biomarkers,there is still a long path before they translate into clinical benefits.展开更多
Nonalcoholic steatohepatitis is a subtype of metabolic dysfunction-associated liver disease which has emerged as one of the most common causes of cirrhosis and liver transplantation in the United States and many weste...Nonalcoholic steatohepatitis is a subtype of metabolic dysfunction-associated liver disease which has emerged as one of the most common causes of cirrhosis and liver transplantation in the United States and many western countries.The two leading risk factors associated with nonalcoholic steatohepatitis are obesity and insulin resistance with patients often demonstrating features of the metabolic syndrome.Histological improvement including arrest or improvement in fibrosis can occur in patients who are able to modify these risk factors when diagnosed early in the course of their disease.In addition to the development of cirrhosis and its life-threatening complications including hepatocellular carcinoma,variceal bleeding,ascites and hepatic encephalopathy,nonalcoholic steatohepatitis is also associated with coronary artery,carotid artery and peripheral vascular disease with coronary artery disease identified as the most common cause of death.Although multiple clinical trials evaluating a variety of medications targeted at different aspects in the pathogenesis and progression of nonalcoholic steatohepatitis have been completed and are still in progress,there is currently no approved treatment for this disease except for risk factor modification.This article will review the most recent and salient medical advances in the treatment of nonalcoholic steatohepatitis.展开更多
AIM To assess lactase gene(LCT)-13910C>T polymorphisms in Brazilian non-alcoholic fatty liver disease(NAFLD) and nonalcoholic steatohepatitis(NASH) patients in comparison with healthy controls.METHODS This was a tr...AIM To assess lactase gene(LCT)-13910C>T polymorphisms in Brazilian non-alcoholic fatty liver disease(NAFLD) and nonalcoholic steatohepatitis(NASH) patients in comparison with healthy controls.METHODS This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, S?o Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence(LCT-13910C>T) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients(steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher's exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed.RESULTS No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients(66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls(59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism(LCT-13910C>T) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase nonpersistence(low lactase activity or hypolactasia) phenotype was associated with higher insulin levels(23.47 ± 15.94 μU/m L vs 15.8 ± 8.33 μU/m L, P = 0.027) and a higher frequency of insulin resistance(91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes(P = 0.651), dyslipidaemia(P = 0.328), hypertension(P = 0.507) or liver histology in these patients. Moreover, in the NASH patients, hypolactasia was an independent risk factor for insulin resistance even after adjusting for gender and age [OR = 5.0(95%CI: 1.35-20; P = 0.017)].CONCLUSION The LCT-13910 genotype distribution in Brazilian NAFLD patients was the same as that of the general population, but hypolactasia increased the risk of insulin resistance in the NASH patients.展开更多
Thirty-seven males with non-alcoholic staatohepatitis (NASH) (aged 39 - 62) were included in the study. Clinical, biochemical and instrumental studies were used to verify the diagnosis. The control group was comprised...Thirty-seven males with non-alcoholic staatohepatitis (NASH) (aged 39 - 62) were included in the study. Clinical, biochemical and instrumental studies were used to verify the diagnosis. The control group was comprised of thirty-three males of comparable age and without confirmed signs of liver diseases and other pathology of inner organs. Dielectrophoresis was applied to evaluate the structural-and-functional erythrocytic parameters. The patients with NASH erythrocytes tended to differ in their much lower amplitude deformation, polarizability, capacity of erythrocytic membranes, pace of translational motion of cells towards electrodes and much higher levels of overall indices of rigidity, viscosity, electroconductivity, destruction and aggregation as compared to the control group (p < 0.001 - 0.05). We discovered cases of correlation of erythrocytic parameters with biochemical findings reflecting inflammatory and cytolytic syndrome, cholestasis, protein-synthesizing liver function as well as markers of metabolic syndrome (BMI, changes in arterial blood pressure, the degree of disturbances in carbohydrate metabolism, atherogenic dyslipidemia) and microalbuminuria. Aggravation of microcirculatory disturbances leading to an increase of fibrogenes is induced by changes in the properties of erythrocytes under NASH suggests the administration of a number of therapeutic techniques which could improve the status of the parameters of red blood cells. This study aims to evaluate the peculiarities of electric and viscoelastic behavior of erythrocytes in patients with primary NASH in order to determine additional methods of treatment for this disease.展开更多
Nonalcoholic steatohepatitis(NASH)is a spectrum of chronic liver disease characterized by hepatic lipid metabolism disorder.Recent reports emphasized the contribution of triglyceride and diglyceride accumulation to NA...Nonalcoholic steatohepatitis(NASH)is a spectrum of chronic liver disease characterized by hepatic lipid metabolism disorder.Recent reports emphasized the contribution of triglyceride and diglyceride accumulation to NASH,while the other lipids associated with the NASH pathogenesis remained unexplored.The specific purpose of our study was to explore a novel pathogenesis and treatment strategy of NASH via profiling the metabolic characteristics of lipids.Herein,multi-omics techniques based on LC—Q-TOF/MS,LC—MS/MS and MS imaging were developed and used to screen the action targets related to NASH progress and treatment.A methionine and choline deficient(MCD)diet-induced mouse model of NASH was then constructed,and Schisandra lignans extract(SLE)was applied to alleviate hepatic damage by regulating the lipid metabolism-related enzymes CES2A and CYP4A14.Hepatic lipidomics indicated that MCD-diet led to aberrant accumulation of phosphatidylethanolamines(PEs),and SLE could significantly reduce the accumulation of intrahepatic PEs.Notably,exogenous PE(18:0/18:1)was proved to significantly aggravate the mitochondrial damage and hepatocyte apoptosis.Supplementing PE(18:0/18:1)also deteriorated the NASH progress by up regulating intrahepatic proinflammatory and fibrotic factors,while PE synthase inhibitor exerted a prominent hepatoprotective role.The current work provides new insights into the relationship between PE metabolism and the pathogenesis of NASH.展开更多
Background:Lipid dysregulation plays a fundamental role in nonalcoholic steatohepatitis(NASH),which is an emerging critical risk factor that aggravates hepatic ischemia/reperfusion(I/R)injury.However,the specific lipi...Background:Lipid dysregulation plays a fundamental role in nonalcoholic steatohepatitis(NASH),which is an emerging critical risk factor that aggravates hepatic ischemia/reperfusion(I/R)injury.However,the specific lipids that mediate the aggressive I/R injury in NASH livers have not yet been identified.Methods:The mouse model of hepatic I/R injury on NASH was established on C56B/6J mice by first feeding the mice with a Western-style diet to induce NASH,then the NASH mice were subjected to surgical procedures to induce hepatic I/R injury.Untargeted lipidomics were performed to determine hepatic lipids in NASH livers with I/R injury through ultra-high performance liquid chromatography coupled with mass spectrometry.The pathology associated with the dysregulated lipids was examined.Results:Lipidomics analyses identified cardiolipins(CL)and sphingolipids(SL),including ceramides(CER),glycosphingolipids,sphingosines,and sphingomyelins,as the most relevant lipid classes that characterized the lipid dysregulation in NASH livers with I/R injury.CER were increased in normal livers with I/R injury,and the I/R-induced increase of CER was further augmented in NASH livers.Metabolic pathway analysis revealed that the enzymes involved in the synthesis and degradation of CER were highly upregulated in NASH livers with I/R injury,including serine palmitoyltransferase 3(Sptlc3),ceramide synthase 2(Cers2),neutral sphingomyelinase 2(Smpd3),and glucosylceramidase beta 2(Gba2)that produced CER,and alkaline ceramidase 2(Acer2),alkaline ceramidase 3(Acer3),sphingosine kinase 1(Sphk1),sphingosine-1-phosphate lyase(Sgpl1),and sphingosine-1-phosphate phosphatase 1(Sgpp1)that catalyzed the degradation of CER.CL were not affected by I/R challenge in normal livers,but CL was dramatically reduced in NASH livers with I/R injury.Consistently,metabolic pathway analyses revealed that the enzymes catalyzing the generation of CL were downregulated in NASH-I/R injury,including cardiolipin synthase(Crls1)and tafazzin(Taz).Notably,the I/R-induced oxidative stress and cell death were found to be aggravated in NASH livers,which were possibly mediated by the reduction of CL and accumulation of CER.Conclusions:The I/R-induced dysregulation of CL and SL were critically rewired by NASH,which might potentially mediate the aggressive I/R injury in NASH livers.展开更多
Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions.Cisplatin(CDDP)elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion.Alterati...Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions.Cisplatin(CDDP)elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion.Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis(NASH),however,associated changes to substrate toxicity is unknown.To test this,a methionine-and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics,transporter expression,and toxicity.NASH rats administered CDDP(6 mg/kg,i.p.)displayed 20%less nephrotoxicity than healthy rats.Likewise,CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min,renal secretion decreased from 6.23 to 2.80 mL/min,and renal CDDP accumulation decreased by 15%,relative to healthy rats.Renal copper transporter-1 expression decreased,and organic cation transporter-2 and ATPase copper transporting protein-7 b increased slightly,reducing CDDP secretion.Hepatic CDDP accumulation increased 250%in NASH rats relative to healthy rats.Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats,although no drug-related toxicity was observed.These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance,which may alter nephrotoxicity.展开更多
Nonalcoholic steatohepatitis(NASH)has emerged as the major cause of end-stage liver diseases.However,an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies.In the...Nonalcoholic steatohepatitis(NASH)has emerged as the major cause of end-stage liver diseases.However,an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies.In the present study,through systematic screening of genome-wide mRNA expression from three mouse models of hepatic inflammation and fibrosis,we identified IGF2BP2,an N6-methyladenosine modification reader,as a key regulator that promotes NASH progression in mice.Adenovirus or adeno-associated virus-mediated overexpression of IGF2BP2 could induce liver steatosis,inflammation,and fibrosis in mice,at least in part,by increasing Tab2 mRNA stability.Besides,hepatic overexpression of IGF2BP2 mimicked gene expression profiles and molecular pathways of human NASH livers.Of potential clinical significance,IGF2BP2 expression is significantly upregulated in the livers of NASH patients.Moreover,knockdown of IGF2BP2 substantially alleviated liver injury,inflammation,and fibrosis in diet-induced NASH mice.Taken together,our findings reveal an important role of IGF2BP2 in NASH,which may provide a new therapeutic target for the treatment of NASH.展开更多
文摘Liver cancer is the sixth most commonly diagnosed cancer worldwide,with hepatocellular carcinoma(HCC)comprising most cases.Besides hepatitis B and C viral infections,heavy alcohol use,and nonalcoholic steatohepatitis(NASH)-associated advanced fibrosis/cirrhosis,several other risk factors for HCC have been identified(i.e.old age,obesity,insulin resistance,type 2 diabetes).These might in fact partially explain the occurrence of HCC in non-cirrhotic patients without viral infection.HCC surveillance through effective screening programs is still an unmet need for many nonalcoholic fatty liver disease(NAFLD)patients,and identification of pre-cirrhotic individuals who progress to HCC represents a substantial challenge in clinical practice at the moment.Patients with NASHcirrhosis should undergo systematic HCC surveillance,while this might be considered in patients with advanced fibrosis based on individual risk assessment.In this context,interventions that potentially prevent NAFLD/NASH-associated HCC are needed.This paper provided an overview of evidence related to lifestyle changes(i.e.weight loss,physical exercise,adherence to healthy dietary patterns,intake of certain dietary components,etc.)and pharmacological interventions that might play a protective role by targeting the underlying causative factors and pathogenetic mechanisms.However,well-designed prospective studies specifically dedicated to NAFLD/NASH patients are still needed to clarify the relationship with HCC risk.
基金Supported by Traditional Chinese Medicine Development Program of Shandong Province (2021Q097)。
文摘Distinguishing between nonalcoholic steatohepatitis(NASH) and advanced liver fibrosis is the key for clinical diagnosis of non-alcoholic fatty liver disease(NAFLD). Liver biopsy, which is widely used for diagnosis of liver diseases at present, has many drawbacks, such as being invasive, expensive and unstable. This article compares and summarizes the commonly used non-invasive diagnostic methods, including their diagnostic parameters, advantages and disadvantages, in order to provide a useful reference for the diagnosis of NASH.
文摘AIM:To investigate whether a noninvasive measurement of tissue strain has a potential usefulness for management of nonalcoholic steatohepatitis(NASH).METHODS:In total 26 patients,23 NASHs and 3 normal controls were enrolled in this study.NASH was staged based on Brunt criterion.At a region of interest(ROI),a shear wave was evoked by implementing an acoustic radiation force impulse(ARFI),and the propagation velocity was quantif ied.RESULTS:Shear wave velocity(SWV) could be reproducibly quantified at all ROIs in all subjects except for 4 NASH cases,in which a reliable SWV value was not calculated at several ROIs.An average SWV of 1.34 ± 0.26 m/s in fibrous stage 0-1 was significantly slower than 2.20 ± 0.74 m/s and 2.90 ± 1.01 m/s in stages 3 and 4,respectively,but was not significantly different from 1.79 ± 0.78 m/s in stage 2.When a cutoff value was set at 1.47 m/s,receiver operating characteristic analysis showed significance to dissociate stages 3 and 4 from stage 0-1(P=0.0092) with sensitivity,specificity and area under curve of 100%,75% and 94.2%,respectively.In addition,the correlation between SWV and hyaluronic acid was significant(P<0.0001),while a tendency toward negative correlation was observed with serum albumin(P=0.053).CONCLUSION:The clinical implementation of ARFI provides noninvasive repeated evaluations of liver stiffness at an arbitrary position,which has the potential to shed new light on NASH management.
文摘Recently,nonalcoholic steatohepatitis(NASH) has been considered to be another cause of liver cirrhosis and hepatocellular carcinoma(HCC).The natural history and prognosis of NASH are controversial.Accordingly,we assessed the clinicopathological features of NASH-associated HCC in our experience and reviewed the literature of NASH-associated HCC.We experienced 11 patients with NASH-associated HCC(6 male,5 female;mean age 73.8 ± 4.9 years) who received curative treatments.Most(91%) patients had been diagnosed with obesity,diabetes,hypertension,or dyslipidemia.Seven patients(64%) also had a non-cirrhotic liver.The recurrence-free survival rates at 1,3 and 5 years were 72%,60%,and 60%.We also summarized and reviewed 94 cases of NASH-associated HCC which were reported in the literature(64 male;mean age 66 years).The majority of patients(68%) were obese,66% of patients had diabetes,and 24% had dyslipidemia.Furthermore,26% of the HCCs arose from the non-cirrhotic liver.In conclusion,patients with non-cirrhotic NASH may be a high-risk group for HCC,and regular surveillance for HCC is necessary in non-cirrhotic NASH patients as well as cirrhotic patients.
基金Supported by Innovtin Fund Denmark,KSTNo.5016-00168BMNBK,No.5189-00040B
文摘AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis(NASH) in obese mouse models of biopsy-confirmedNASH.METHODS Male wild-type C57 BL/6 J mice(DIO-NASH) and Lep^(ob/ob)(ob/ob-NASH) mice were fed a diet high in trans-fat(40%), fructose(20%) and cholesterol(2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score(NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide(0.2 mg/kg, SC, BID), obeticholic acid(OCA, 30 mg/kg PO, QD), or elafibranor(30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1 a1.RESULTS Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1 a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression(RNA sequencing) and liver lipid biochemistry.CONCLUSION DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH.
基金supported by grants from the Ministry of Science&Technology of China(2016YFE0107400)the National Natural Science Foundation of China(81272436,81572356,81871997,81500665 and 82070588)+1 种基金High Level Creative Talents from Department of Public Health in Zhejiang Province(S2032102600032)Project of New Century 551 Talent Nurturing in Wenzhou。
文摘Background: Nonalcoholic fatty liver disease(NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver(NAFL) and nonalcoholic steatohepatitis(NASH). However, there is no reliable non-invasive parameter in distinguishing NASH from NAFL in clinical practice. The present study was to find a non-invasive way to differentiate these two categories of NAFLD via lipidomic analysis. Methods: Lipidomic analysis was used to determine the changes of lipid moieties in blood from 20 NAFL and 10 NASH patients with liver biopsy. Liver histology was evaluated after hematoxylin and eosin staining and Masson’s trichrome staining. The profile of lipid metabolites in correlation with steatosis, inflammation, hepatocellular necroptosis, fibrosis, and NAFLD activity score(NAS) was analyzed. Results: Compared with NAFL patients, NASH patients had higher degree of steatosis, ballooning degeneration, lobular inflammation. A total of 434 different lipid molecules were identified, which were mainly composed of various phospholipids and triacylglycerols. Many lipids, such as phosphatidylcholine(PC)(P-22:0/18:1), sphingomyelin(SM)(d14:0/18:0), SM(d14:0/24:0), SM(d14:0/22:0), phosphatidylethanolamine(PE)(18:0/22:5), PC(O-22:2/12:0), and PC(26:1/11:0) were elevated in the NASH group compared to those in the NAFL group. Specific analysis revealed an overall lipidomic profile shift from NAFL to NASH, and identified valuable lipid moieties, such as PCs [PC(14:0/18:2), PE(18:0/22:5) and PC(26:1/11:0)] or plasmalogens [PC(O-22:0/0:0), PC(O-18:0/0:0), PC(O-16:0/0:0)], which were significantly altered in NASH patients. In addition, PC(14:0/18:2), phosphatidic acid(18:2/24:4) were positively correlated with NAS;whereas PC(18:0/0:0) was correlated positively with fibrosis score. Conclusions: The present study revealed overall lipidomic profile shift from NAFL to NASH, identified valuable lipid moieties which may be non-invasive biomarkers in the categorization of NAFLD. The correlations between lipid moieties and NAS and fibrosis scores indicate that these lipid biomarkers may be used to predict the severity of the disease.
基金Supported by National Key R&D Program of China,No.2017YFC0908903National Natural Science Foundation of China,No.81700503,No.81873565,and No.81470840+1 种基金WBE Liver Fibrosis Foundation,No.CFHPC2020061Hospital Funded Clinical Research,Clinical Research Unit,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,No.17CSK04.
文摘BACKGROUND The association between PPARGC1A rs8192678 and nonalcoholic fatty liver disease(NAFLD)requires further confirmation.In addition,it is still unknown whether PPARGC1A rs8192678 is associated with hepatic histological features in NAFLD in the Chinese population.AIM To investigate the interaction between PPARGC1A rs8192678 and nonalcoholic steatohepatitis(NASH),and whether this polymorphism is associated with hepatic histological features.METHODS Fifty-nine patients with liver biopsy-proven NAFLD and 93 healthy controls were recruited to a cohort representing the Chinese Han population.The SAF(steatosis,activity,and fibrosis)scoring system was used for hepatic histopathological evaluation.The polymorphisms of PPARGC1A rs8192678 and patatin-like phospholipase domain-containing protein 3(PNPLA3)rs738409 were genotyped.The intrahepatic mRNA expression of PPARGC1A was evaluated by real-time polymerase chain reaction.RESULTS Thirty-seven patients with NAFLD had NASH,of which 12 were nonobese.The PPARGC1A rs8192678 risk A allele(carrying GA and AA genotypes)had the lowest P value in the dominant model;the odds ratio(OR)for NAFLD was 2.321[95%confidence interval(CI):1.121-4.806].After adjusting for age,sex,and the PNPLA3 rs738409 risk G allele,the PPARGC1A rs8192678 A allele was a risk factor for NAFLD(OR 2.202,95%CI:1.030-4.705,P=0.042).The genetic analysis showed that patients with NAFLD,moderate-to-severe steatosis(S2-3),and Activity 2-4(A≥2)were more likely to carry A in PPARGC1A rs8192678(OR 5.000,95%CI:1.343-18.620,P=0.012;and OR 4.071,95%CI:1.076-15.402,P=0.031).The multivariate logistic regression analysis showed that PPARGC1A rs8192678 risk A allele was also independently associated with S2-3,A≥2,and NASH(OR 6.190,95%CI:1.508-25.410,P=0.011;OR 4.506,95%CI 1.070-18.978,P=0.040;and OR 6.337,95%CI:1.135-35.392,P=0.035,respectively)after adjusting for age,sex,body mass index,and PNPLA3 rs738409 risk G allele.The results also showed that this polymorphism was associated with nonobese NASH(OR 22.000,95%CI:1.540-314.292,P=0.021).The intrahepatic expression of PPARGC1A mRNA was significantly lower in the group of patients who carried the risk A allele(P=0.014).CONCLUSION The PPARGC1A rs8192678 risk A allele is associated with NAFLD,and with S2-3,A≥2 and NASH in NAFLD patients,independent of PNPLA3 rs738409,and may be associated with nonobese NASH.
基金Supported by research grants from the Hualien-Armed Forces General Hospital,No.805-C105-10the Ministry of National Defense-Medical Affairs Bureau,No.MAB-106-124
文摘AIM To investigate the association of chronic hepatitis B and nonalcoholic steatohepatitis with physical fitness in a Taiwan Residents military male cohort.METHODS We made a cross-sectional examination of this association using 3669 young adult military males according to cardiorespiratory fitness and hospitalization events recorded in the Taiwan Armed Forces study. Cases of chronic hepatitis B(n = 121) were defined by personal history and positive detection of hepatitis B surface antigen. Cases of nonalcoholic steatohepatitis(n = 129) were defined by alanine transaminase level > 60 U/L, liver ultrasound finding of steatosis, and absence of viral hepatitis A, B or C infection. All other study participants were defined as unaffected(n = 3419). Physical fitness was evaluated by performance in 3000-m run, 2-min sit-ups, and 2-min push-ups exercises, with all the procedures standardized by a computerized scoring system. Multiple linear regression analysis was used to determine the relationship.RESULTS Chronic hepatitis B negatively correlated with 2-min push-up numbers(β =-2.49, P = 0.019) after adjusting for age, service specialty, body mass index, systolic and diastolic blood pressures, current cigarette smoking, alcohol intake status, serum hemoglobin, and average weekly exercise times. Nonalcoholic steatohepatitis was borderline positively correlated with 3000-m running time(β = 11.96, P = 0.084) and negatively correlated with 2-min sit-up numbers(β =-1.47, P = 0.040). CONCLUSION Chronic hepatitis B viral infection and nonalcoholic steatohepatitis affects different physical performances in young adult military males, and future study should determine the underlying mechanism.
文摘AIM:To characterize development of diet-induced nonalcoholic steatohepatitis(NASH)by performing live biopsy in wild-type and genetically obese mice.METHODS:Male wild-type C57BL/6J(C57)mice(DIO NASH)and male Lep ob/Lep ob(ob/ob)mice(ob/ob-NASH were maintained on a diet high in trans-fat(40%)fructose(22%)and cholesterol(2%)for 26 and 12 wk respectively.A normal chow diet served as control in C57 mice(lean chow)and ob/ob mice(ob/ob chow)After the diet-induction period,mice were liver biopsied and a blinded histological assessment of steatosis and fibrosis was conducted.Mice were then stratified into groups counterbalanced for steatosis score and fibrosi stage and continued on diet and to receive daily PO dosing of vehicle for 8 wk.Global gene expression in liver tissue was assessed by RNA sequencing and bioin formatics.Metabolic parameters,plasma liver enzyme and lipids(total cholesterol,triglycerides)as well a hepatic lipids and collagen content were measured b biochemical analysis.Non-alcoholic fatty liver disease activity score(NAS)(steatosis/inflammation/ballooningdegeneration)and fibrosis were scored.Steatosis and fibrosis were also quantified using percent fractional area.RESULTS:Diet-induction for 26 and 12 wk in DIONASH and ob/ob-NASH mice,respectively,elicited progressive metabolic perturbations characterized by increased adiposity,total cholesterol and elevated plasma liver enzymes.The diet also induced clear histological features of NASH including hepatosteatosis and fibrosis.Overall,the metabolic NASH phenotype was more pronounced in ob/ob-NASH vs DIO-NASH mice.During the eight week repeated vehicle dosing period,the metabolic phenotype was sustained in DIO-NASH and ob/ob-NASH mice in conjunction with hepatomegaly and increased hepatic lipids and collagen accumulation.Histopathological scoring demonstrated significantly increased NAS of DIO-NASH mice(0 vs4.7±0.4,P<0.001 compared to lean chow)and ob/ob-NASH mice(2.4±0.3 vs 6.3±0.2,P<0.001compared to ob/ob chow),respectively.Furthermore,fibrosis stage was significantly elevated for DIO-NASH mice(0 vs 1.2±0.2,P<0.05 compared to lean chow)and ob/ob NASH(0.1±0.1 vs 3.0±0.2,P<0.001compared to ob/ob chow).Notably,fibrosis stage was significantly(P<0.001)increased in ob/ob-NASH mice,when compared to DIO-NASH mice.CONCLUSION:These data introduce the obese dietinduced DIO-NASH and ob/ob-NASH mouse models with biopsy-confirmed individual disease staging as a preclinical platform for evaluation of novel NASH therapeutics.
基金supported by grants from Key ProgramNational Natural Science Foundation of China(81930016)+3 种基金National Natural Science Foundation of China(81702858)Key Research&Development Plan of Zhejiang Province(2019C03050)National S&T Major Project(2017ZX10203205)National Natural Science Funds for Distinguished Young Scholar of China(81625003)。
文摘Background:Nonalcoholic fatty liver disease and its advanced stage,nonalcoholic steatohepatitis(NASH),are the major cause of hepatocellular carcinoma(HCC)and other end-stage liver disease.However,the potential mechanism and therapeutic strategies have not been clarified.This study aimed to identify potential roles of mi RNA/m RNA axis in the pathogenesis and drug combinations in the treatment of NASH.Methods:Microarray GSE59045 and GSE48452 were downloaded from the Gene Expression Omnibus and analyzed using R.Then we obtained differentially expressed genes(DE-genes).DAVID database was used for Gene Ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment pathway analysis.Protein-protein interaction(PPI)networks were used for the identification of hub genes.We found upstream regulators of hub genes using mi RTar Base.The expression and correlation of key mi RNA and its targets were detected by q PCR.Drug Pair Seeker was employed to predict drug combinations against NASH.The expression of mi RNA and hub genes in HCC was identified in the Cancer Genome Atlas database and Human Protein Atlas database.Results:Ninety-four DE-genes were accessed.GO and KEGG analysis showed that these predicted genes were linked to lipid metabolism.Eleven genes were identified as hub genes in PPI networks,and they were highly expressed in cells with vigorous lipid metabolism.hsa-mi R-335-5 p was the upstream regulator of 9 genes in the 11 hub genes,and it was identified as a key mi RNA.The hub genes were highly expressed in NASH models,while hsa-mi R-335-5 p was lowly expressed.The correlation of mi RNA-m RNA was established by q PCR.Functional verification indicated that hsa-mi R-335-5 p had inhibitory effect on the development of NASH.Finally,drug combinations were predicted and the expression of mi RNA and hub genes in HCC was identified.Conclusions:In the study,potential mi RNA-m RNA pathways related to NASH were identified.Targeting these pathways may be novel strategies against NASH.
文摘OBJECTIVE The pathological characteristics of nonalcoholic steatohepatitis(NASH)include liver steatosis,inflammation,and fibrosis.Fibrosis is the most severe and significant pathological feature in NASH.Effective drug treatment could reverse early liver fibrosis and is of significance to prevent NASH from progressing into cirrhosis and liver cancer.Identification of drug targets for NASH treatment has been an active research area and is essential for the development of anti-NASH medications.Naringenin(NGN)is a flavonoid compound rich in citrus fruits.Our preliminary data demonstrated that NGN reduced diet-induced lipid accumulation and inflammation in the mouse liver,but whether NGN can attenuate liver fibrosis of NASH is not known.METHODS To study the effect of NGN on NASH fibrosis.WT mice were fed with high fat diet(HFD)and injected intraperitoneally 20%carbon tetrachloride at the same time for 8 weeks to induce NASH,and NGN was administrated by gavage in the meantime.In vitro,LO2 cells and LX2 cells were stimulated by oleic acid(OA)combined with lipopolysaccharide(LPS),respectively.RESULTS Treating the WT mice with NGN 100 mg·kg^(-1)·d-1 significantly attenuated hepatic lipid accumulation,hepatic fibrosis,plasma ALT and AST levels,inhibited protein expression of p-ERK,p-FoxO3a in the mouse livers.In vitro,on OA and LPS stimulated LO2 or LX2 cells,NGN significantly promoted apoptosis of activated hepatic stellate cells while inhibited apoptosis of hepatocytes.Mechanism study indicated that NGN inhibited MAPK pathway and promoted activation of FoxO3a,consequently promoted apoptosis of the activated LX2 cells and inhibited liver fibrosis.CONCLUSION NGN preventes NASH fibrosis via regulating MAPK/FoxO3a pathway,thus promoting apoptosis of the activated hepatic stellate cells.
文摘Background: Nonalcoholic fatty liver disease(NAFLD) is increasingly occurring in sedentary people, and may progress to NASH and hepatocellular carcinoma. It is essential to design affordable animal models for the study of various diseases, including fatty liver, which was the aim of the study. In this study, a high-fat diet was devised that triggers NASH’s animal model quickly and easily. High-fat diet(HFD) was used both with intra-mouth oral gavage and in combination with animal pellets.Methods: Twenty-four male C57 BL/6 J mice were divided into HFD and ND groups, which received a high-fat diet and a normal diet, respectively. At the end of the experiment(fourth week of treatment), body and liver weights, biochemical parameters, PPAR-α gene expression and histopathologic characteristics of the liver were evaluated.Results: During 4 weeks, body weight of mice did not show a significant increase in the HFD group compared to the ND group, while weight gain of the liver was significant. Histological assessment of the HFD group’s liver confirmed NASH symptoms. In the HFD group, HDL-c, SOD, catalase, FRAP, adiponectin, and PPAR-α decreased significantly, and lipid profiles, hepatic enzymes, MDA, leptin, and TNF-α showed a significant increase compared to the ND group.Conclusion: Our high-fat diet has successfully induced all aspects of NASH with fibrosis in 4 weeks, and with low cost.
文摘Fatty liver has been present in the lives of patients and physicians for almost two centuries.Vast knowledge has been generated regarding its etiology and consequences,although a long path seeking novel and innovative diagnostic biomarkers for nonalcoholic fatty liver disease(NAFLD)and nonalcoholic steatohepatitis(NASH)is still envisioned.On the one hand,proteomics and lipidomics have emerged as potential noninvasive resources for NAFLD diagnosis.In contrast,metabolomics has been able to distinguish between NAFLD and NASH,even detecting degrees of fibrosis.On the other hand,genetic and epigenetic markers have been useful in monitoring disease progression,eventually functioning as target therapies.Other markers involved in immune dysregulation,oxidative stress,and inflammation are involved in the instauration and evolution of the disease.Finally,the fascinating gut microbiome is significantly involved in NAFLD and NASH.This review presents state-of-the-art biomarkers related to NAFLD and NASH and new promises that could eventually be positioned as diagnostic resources for this disease.As is evident,despite great advances in studying these biomarkers,there is still a long path before they translate into clinical benefits.
文摘Nonalcoholic steatohepatitis is a subtype of metabolic dysfunction-associated liver disease which has emerged as one of the most common causes of cirrhosis and liver transplantation in the United States and many western countries.The two leading risk factors associated with nonalcoholic steatohepatitis are obesity and insulin resistance with patients often demonstrating features of the metabolic syndrome.Histological improvement including arrest or improvement in fibrosis can occur in patients who are able to modify these risk factors when diagnosed early in the course of their disease.In addition to the development of cirrhosis and its life-threatening complications including hepatocellular carcinoma,variceal bleeding,ascites and hepatic encephalopathy,nonalcoholic steatohepatitis is also associated with coronary artery,carotid artery and peripheral vascular disease with coronary artery disease identified as the most common cause of death.Although multiple clinical trials evaluating a variety of medications targeted at different aspects in the pathogenesis and progression of nonalcoholic steatohepatitis have been completed and are still in progress,there is currently no approved treatment for this disease except for risk factor modification.This article will review the most recent and salient medical advances in the treatment of nonalcoholic steatohepatitis.
文摘AIM To assess lactase gene(LCT)-13910C>T polymorphisms in Brazilian non-alcoholic fatty liver disease(NAFLD) and nonalcoholic steatohepatitis(NASH) patients in comparison with healthy controls.METHODS This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, S?o Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence(LCT-13910C>T) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients(steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher's exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed.RESULTS No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients(66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls(59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism(LCT-13910C>T) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase nonpersistence(low lactase activity or hypolactasia) phenotype was associated with higher insulin levels(23.47 ± 15.94 μU/m L vs 15.8 ± 8.33 μU/m L, P = 0.027) and a higher frequency of insulin resistance(91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes(P = 0.651), dyslipidaemia(P = 0.328), hypertension(P = 0.507) or liver histology in these patients. Moreover, in the NASH patients, hypolactasia was an independent risk factor for insulin resistance even after adjusting for gender and age [OR = 5.0(95%CI: 1.35-20; P = 0.017)].CONCLUSION The LCT-13910 genotype distribution in Brazilian NAFLD patients was the same as that of the general population, but hypolactasia increased the risk of insulin resistance in the NASH patients.
文摘Thirty-seven males with non-alcoholic staatohepatitis (NASH) (aged 39 - 62) were included in the study. Clinical, biochemical and instrumental studies were used to verify the diagnosis. The control group was comprised of thirty-three males of comparable age and without confirmed signs of liver diseases and other pathology of inner organs. Dielectrophoresis was applied to evaluate the structural-and-functional erythrocytic parameters. The patients with NASH erythrocytes tended to differ in their much lower amplitude deformation, polarizability, capacity of erythrocytic membranes, pace of translational motion of cells towards electrodes and much higher levels of overall indices of rigidity, viscosity, electroconductivity, destruction and aggregation as compared to the control group (p < 0.001 - 0.05). We discovered cases of correlation of erythrocytic parameters with biochemical findings reflecting inflammatory and cytolytic syndrome, cholestasis, protein-synthesizing liver function as well as markers of metabolic syndrome (BMI, changes in arterial blood pressure, the degree of disturbances in carbohydrate metabolism, atherogenic dyslipidemia) and microalbuminuria. Aggravation of microcirculatory disturbances leading to an increase of fibrogenes is induced by changes in the properties of erythrocytes under NASH suggests the administration of a number of therapeutic techniques which could improve the status of the parameters of red blood cells. This study aims to evaluate the peculiarities of electric and viscoelastic behavior of erythrocytes in patients with primary NASH in order to determine additional methods of treatment for this disease.
基金supported by the National Natural Science Foundation of China(Grant Number:82274194)Jiangsu Natural Science Funds(Grant Number:BK20211224,China)the Project of State Key Laboratory of Natural Medicines(Grant Number:SKLNMZZ202001,China)。
文摘Nonalcoholic steatohepatitis(NASH)is a spectrum of chronic liver disease characterized by hepatic lipid metabolism disorder.Recent reports emphasized the contribution of triglyceride and diglyceride accumulation to NASH,while the other lipids associated with the NASH pathogenesis remained unexplored.The specific purpose of our study was to explore a novel pathogenesis and treatment strategy of NASH via profiling the metabolic characteristics of lipids.Herein,multi-omics techniques based on LC—Q-TOF/MS,LC—MS/MS and MS imaging were developed and used to screen the action targets related to NASH progress and treatment.A methionine and choline deficient(MCD)diet-induced mouse model of NASH was then constructed,and Schisandra lignans extract(SLE)was applied to alleviate hepatic damage by regulating the lipid metabolism-related enzymes CES2A and CYP4A14.Hepatic lipidomics indicated that MCD-diet led to aberrant accumulation of phosphatidylethanolamines(PEs),and SLE could significantly reduce the accumulation of intrahepatic PEs.Notably,exogenous PE(18:0/18:1)was proved to significantly aggravate the mitochondrial damage and hepatocyte apoptosis.Supplementing PE(18:0/18:1)also deteriorated the NASH progress by up regulating intrahepatic proinflammatory and fibrotic factors,while PE synthase inhibitor exerted a prominent hepatoprotective role.The current work provides new insights into the relationship between PE metabolism and the pathogenesis of NASH.
基金This work was supported by the National Natural Science Foundation of China(No.82070642)to JZthe Guangdong Province Science and Technology Program(No.2020A1515011205)to KW+1 种基金the Guangdong Province Science and Technology Program(No.2021A1515012146)to CJLthe President Foundation of Nanfang Hospital,Southern Medical University(No.2018C029)to JPQ.
文摘Background:Lipid dysregulation plays a fundamental role in nonalcoholic steatohepatitis(NASH),which is an emerging critical risk factor that aggravates hepatic ischemia/reperfusion(I/R)injury.However,the specific lipids that mediate the aggressive I/R injury in NASH livers have not yet been identified.Methods:The mouse model of hepatic I/R injury on NASH was established on C56B/6J mice by first feeding the mice with a Western-style diet to induce NASH,then the NASH mice were subjected to surgical procedures to induce hepatic I/R injury.Untargeted lipidomics were performed to determine hepatic lipids in NASH livers with I/R injury through ultra-high performance liquid chromatography coupled with mass spectrometry.The pathology associated with the dysregulated lipids was examined.Results:Lipidomics analyses identified cardiolipins(CL)and sphingolipids(SL),including ceramides(CER),glycosphingolipids,sphingosines,and sphingomyelins,as the most relevant lipid classes that characterized the lipid dysregulation in NASH livers with I/R injury.CER were increased in normal livers with I/R injury,and the I/R-induced increase of CER was further augmented in NASH livers.Metabolic pathway analysis revealed that the enzymes involved in the synthesis and degradation of CER were highly upregulated in NASH livers with I/R injury,including serine palmitoyltransferase 3(Sptlc3),ceramide synthase 2(Cers2),neutral sphingomyelinase 2(Smpd3),and glucosylceramidase beta 2(Gba2)that produced CER,and alkaline ceramidase 2(Acer2),alkaline ceramidase 3(Acer3),sphingosine kinase 1(Sphk1),sphingosine-1-phosphate lyase(Sgpl1),and sphingosine-1-phosphate phosphatase 1(Sgpp1)that catalyzed the degradation of CER.CL were not affected by I/R challenge in normal livers,but CL was dramatically reduced in NASH livers with I/R injury.Consistently,metabolic pathway analyses revealed that the enzymes catalyzing the generation of CL were downregulated in NASH-I/R injury,including cardiolipin synthase(Crls1)and tafazzin(Taz).Notably,the I/R-induced oxidative stress and cell death were found to be aggravated in NASH livers,which were possibly mediated by the reduction of CL and accumulation of CER.Conclusions:The I/R-induced dysregulation of CL and SL were critically rewired by NASH,which might potentially mediate the aggressive I/R injury in NASH livers.
基金supported by the National Institutes of Health(R01ES028668,P30ES006694,and T32ES007091,USA)。
文摘Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions.Cisplatin(CDDP)elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion.Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis(NASH),however,associated changes to substrate toxicity is unknown.To test this,a methionine-and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics,transporter expression,and toxicity.NASH rats administered CDDP(6 mg/kg,i.p.)displayed 20%less nephrotoxicity than healthy rats.Likewise,CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min,renal secretion decreased from 6.23 to 2.80 mL/min,and renal CDDP accumulation decreased by 15%,relative to healthy rats.Renal copper transporter-1 expression decreased,and organic cation transporter-2 and ATPase copper transporting protein-7 b increased slightly,reducing CDDP secretion.Hepatic CDDP accumulation increased 250%in NASH rats relative to healthy rats.Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats,although no drug-related toxicity was observed.These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance,which may alter nephrotoxicity.
基金This study was supported by the National Key Research and Development Program of China(2018YFA0800402)the Shanghai Outstanding Academic Leaders Projects(21XD1423400)+3 种基金the Basic Research of Science,and Technology Innovation Action Plan(21JC1401300)Shanghai Sailing Program by Shanghai Municipal Science and Technology Committee(22YF1432800)China Postdoctoral Science Foundation Funded Project(2021M702183)the Youth Cultivation Project of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital(ynqn202107).
文摘Nonalcoholic steatohepatitis(NASH)has emerged as the major cause of end-stage liver diseases.However,an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies.In the present study,through systematic screening of genome-wide mRNA expression from three mouse models of hepatic inflammation and fibrosis,we identified IGF2BP2,an N6-methyladenosine modification reader,as a key regulator that promotes NASH progression in mice.Adenovirus or adeno-associated virus-mediated overexpression of IGF2BP2 could induce liver steatosis,inflammation,and fibrosis in mice,at least in part,by increasing Tab2 mRNA stability.Besides,hepatic overexpression of IGF2BP2 mimicked gene expression profiles and molecular pathways of human NASH livers.Of potential clinical significance,IGF2BP2 expression is significantly upregulated in the livers of NASH patients.Moreover,knockdown of IGF2BP2 substantially alleviated liver injury,inflammation,and fibrosis in diet-induced NASH mice.Taken together,our findings reveal an important role of IGF2BP2 in NASH,which may provide a new therapeutic target for the treatment of NASH.
