The global incidence of nonalcoholic fatty liver disease(NAFLD)is escalating considerably.NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis,wh...The global incidence of nonalcoholic fatty liver disease(NAFLD)is escalating considerably.NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis,which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix,leading to fibrosis.Hepatocyte ballooning is a key catalyst for fibrosis progression,potentially advancing to cirrhosis and its decompensated state.Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD;therefore,those with substantial fibrosis require timely intervention.Although liver biopsy is the most reliable method for fibrosis detection,it is associated with certain risks and limitations,particularly in routine screening.Consequently,various noninvasive diagnostic techniques have been introduced.This review examines the increasing prevalence of NAFLD,evaluates the noninvasive diagnostic techniques for fibrosis,and assesses their efficacy in staging the disease.In addition,it critically appraises current and emerging antifibrotic therapies,focusing on their mechanisms,efficacy,and potential in reversing fibrosis.This review underscores the urgent need for effective therapeutic strategies,given the dire consequences of advanced fibrosis.展开更多
BACKGROUND The global prevalence of non-alcoholic steatohepatitis(NASH)and its associated risk of adverse outcomes,particularly in patients with advanced liver fibrosis,underscores the importance of early and accurate...BACKGROUND The global prevalence of non-alcoholic steatohepatitis(NASH)and its associated risk of adverse outcomes,particularly in patients with advanced liver fibrosis,underscores the importance of early and accurate diagnosis.AIM To develop a machine learning-based diagnostic model for advanced liver fibrosis in NASH patients.METHODS A total of 749 patients who underwent liver biopsy at Beijing Ditan Hospital,Capital Medical University,between January 2010 and January 2020 were included.Patients were randomly divided into training(n=522)and validation(n=224)cohorts.Five machine learning models were applied to predict advanced liver fibrosis,with feature selection based on Shapley Additive Explanations(SHAP).The diagnostic performance of these models was compared to traditional scores such as the aspartate aminotransferase to platelet ratio index(APRI)and fibrosis index based on the 4 factors(FIB-4),using metrics including the area under the receiver operating characteristic curve(AUROC),decision curve analysis(DCA),and calibration curves.RESULTS The Extreme Gradient Boosting(XGBoost)model outperformed all other machine learning models,achieving an AUROC of 0.934(95%CI:0.914-0.955)in the training cohort and 0.917(95%CI:0.880-0.953)in the validation cohort(P<0.001).Incorporating liver stiffness measurement into the model further improved its performance,with an AUROC of 0.977(95%CI:0.966-0.980)in the training cohort and 0.970(95%CI:0.950-0.990)in the validation cohort,significantly surpassing APRI and FIB-4 scores(P<0.001).The XGBoost model also demonstrated superior clinical utility,as evidenced by DCA and calibration curve analysis in both cohorts.CONCLUSION The XGBoost model provides a highly accurate,non-invasive diagnosis of advanced liver fibrosis in NASH patients,outperforming traditional methods.An online tool based on this model has been developed to assist clinicians in evaluating the risk of advanced liver fibrosis.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:Nonalcoholic steatohepatitis(NASH)is characterized by liver steatosis,inflammation,and even fibrosis.NASH is likely to develop into cirrhosis and liver cancer,the major causes of liver related deaths.We aim...Background:Nonalcoholic steatohepatitis(NASH)is characterized by liver steatosis,inflammation,and even fibrosis.NASH is likely to develop into cirrhosis and liver cancer,the major causes of liver related deaths.We aimed to study the effect of probiotics on NASH via the gut-l iver axis.Methods:Thirty male Sprague-Dawley rats were divided into three groups.A control group of 10 rats was fed on a standard chow for 16 weeks.Twenty rats fed on a high-fat diet for 8 weeks were separated to two groups:a model group(10 rats)fed on vehicle for 8 weeks and a treatment group(10 rats)supplemented with binary Bacillus subtilis for 8 weeks.Hepatic expression of IL-6 and TNF-ɑand ileum expression of IL-17 and occludin were measured.Results:The high-fat diet caused inflammation of the liver and ileum in rats.Binary Bacillus subtilis treatment reduces liver inflammation through the intestinal liver axis.Increased levels of IL-6 and TNF-αwere detected in rats fed a high-fat diet,which were reduced to lower levels after treatment with binary Bacillus subtilis.In rats on the high-fat diet,elevated IL-17 levels and decreased occludin levels were observed.Treatment with Bacillus subtilis reduced IL-17 levels and restored the expression of occludin.Conclusion:Binary Bacillus subtilis has a beneficial effect on liver inflammation and intestinal damage.展开更多
It is estimated that 30% of the adult population in Japan is affected by nonalcoholic fatty liver disease (NAFLD). Fatty changes of the liver are generally diagnosed using imaging methods such as abdominal ultrasonogr...It is estimated that 30% of the adult population in Japan is affected by nonalcoholic fatty liver disease (NAFLD). Fatty changes of the liver are generally diagnosed using imaging methods such as abdominal ultrasonography (US) and computed tomography (CT), but the sensitivity of these imaging techniques is low in cases of mild steatosis. Alanine aminotransferase levels may be normal in some of these patients, warranting the necessity to establish a set of parameters useful for detecting NAFLD, and the more severe form of the disease, nonalcoholic steatohepatitis (NASH). Although liver biopsy is currently the gold standard for diagnosing progressive NASH, it has many drawbacks, such as sampling error, cost, and risk of complications. Furthermore, it is not realistic to perform liver biopsies on all NAFLD patients. Diagnosis of NASH using various biomarkers, scoring systems and imaging methods, such as elastography, has recently been attempted. The NAFIC score, calculated from the levels of ferritin, fasting insulin, and type IV collagen 7S, is useful for the diagnosis of NASH, while the NAFLD fibrosis score and the FIB-4 index are useful for excluding NASH in cases of advanced fibrosis. This article reviews the limitations and merits of liver biopsy and noninvasive diagnostic tests in the diagnosis of NAFLD/NASH.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
Nonalcoholic fatty liver disease(NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis(NASH),...Nonalcoholic fatty liver disease(NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis(NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma(HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC(SH-HCC), showsfeatures that resemble non-neoplastic steatohepatitis,and is thought to be strongly associated with underlying NASH.In this report,we review the histopathological features of NAFLD/NASH.展开更多
Nonalcoholic fatty liver disease(NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse.Nonalcoholic steatohepatitis(NASH),a severe form of NAFLD,can progres...Nonalcoholic fatty liver disease(NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse.Nonalcoholic steatohepatitis(NASH),a severe form of NAFLD,can progress to liver cirrhosis and hepatocellular carcinoma.NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity,type 2 diabetes,and hyperlipemia.Animal models of NAFLD/NASH give crucial information,not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents.An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH.Animal models of NAFLD/NASH are divided into genetic,dietary,and combination models.In this paper,we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.展开更多
Nonalcoholic fatty liver disease(NAFLD) is one of themajor causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis(NASH), advanced fibro...Nonalcoholic fatty liver disease(NAFLD) is one of themajor causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis(NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury(e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albuminto-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH.展开更多
AIM To evaluate the immunomodulatory effect of oral administration of PRX-106 in the high-fat diet model.METHODS For 22 wk, C57BL/6 HFD-fed mice received daily oral treatments with BY-2 cells expressing recombinant an...AIM To evaluate the immunomodulatory effect of oral administration of PRX-106 in the high-fat diet model.METHODS For 22 wk, C57BL/6 HFD-fed mice received daily oral treatments with BY-2 cells expressing recombinant antitumor necrosis factor alpha fusion protein(PRX-106). Mice were followed for serum liver enzyme and triglyceride levels, liver histology and intrahepatic and systemic FACS.RESULTS The orally administered non-absorbable PRX-106 w a s b i o l o g i c a l l y a c t i v e. A l t e r e d d i s t r i b u t i o n o f CD4+CD25+Fox P3+ between the liver and spleen and an increase in the intrasplenic-to-intrahepatic CD4+CD25+Fox P3+ ratio and a decrease in the intrasplenic-to-intrahepatic CD8+CD25+Fox P3+ ratio were observed. An increase in intrahepatic NKT cells and a decrease in the intrasplenic-to-intrahepatic NKT ratio were noted. Assessment of the CD4-to-CD8 ratios showed sequestration of CD8+ lymphocytes in the liver. These effects were associated with a decrease in serum triglyceride levels, decrease in the aspartate aminotransferase levels, serum glucose levels, and HOMA-IR score. A decrease in hepatic triglycerides content was observed in the high dose-treated mice.CONCLUSION Orally administered PRX-106 shows biological activity and exerts an immunomodulatory effect, alleviating liver damage. The data suggest that PRX-106 may provide an oral immunotherapy for nonalcoholic steatohepatitis.展开更多
AIM: To identify risk factors for nonalcoholic steatohepatitis following pancreaticoduodenectomy, with a focus on factors related to pancreatic secretions. METHODS: The medical records of 228 patients who had a pancre...AIM: To identify risk factors for nonalcoholic steatohepatitis following pancreaticoduodenectomy, with a focus on factors related to pancreatic secretions. METHODS: The medical records of 228 patients who had a pancreaticoduodenectomy over a 16-mo period were reviewed retrospectively. The 193 patients who did not have fatty liver disease preoperatively were included in the final analysis. Hepatic steatosis was diagnosed using the differences between splenic and hepatic attenuation and liver-to-spleen attenuation as measured by non-enhanced computed tomography. RESULTS: Fifteen patients (7.8%) who showed postoperative hepatic fatty changes were assigned to Group A, and the remaining patients were assigned to Group B. Patient demographics, preoperative laboratory findings (including levels of C-peptide, glucagon, insulin and glucose tolerance test results), operation types, and final pathological findings did not differ significantly between the two groups; however, the frequency of pancreatic fistula (P = 0.020) and the method of pancreatic duct stenting (P = 0.005) showed significant differences between the groups. A multivari- ate analysis identified pancreatic fistula (HR = 3.332, P = 0.037) and external pancreatic duct stenting (HR = 4.530, P = 0.017) as independent risk factors for the development of postoperative steatohepatitis. CONCLUSION: Pancreatic fistula and external pancreatic duct stenting were identified as independent risk factors for the development of steatohepatitis following pancreaticoduodenectomy.展开更多
Nonalcoholic fatty liver disease(NAFLD)remains a leading cause of chronic liver disease.In the context of NAFLD,the presence of nonalcoholic steatohepatitis (NASH)portends an adverse prognosis with greater risk of liv...Nonalcoholic fatty liver disease(NAFLD)remains a leading cause of chronic liver disease.In the context of NAFLD,the presence of nonalcoholic steatohepatitis (NASH)portends an adverse prognosis with greater risk of liver fibrosis and cirrhosis.Although liver biopsy is the keystone of patient management in NAFLD,it is also increasingly clear that such evaluation has its limitations.The availability of biochemical markers of NAFLD and NASH has tremendous potential to radically alter management strategies for these conditions,as well as to monitor disease activity.Our article provides an overview of biomarker discovery and selection in the setting of NAFLD and highlights future directions in the field.展开更多
Nonalcoholic fatty liver disease(NAFLD) is highly associated with insulin resistance(IR), type 2 diabetes mellitus and metabolic syndrome, being characterized as the hepatic component of metabolic syndrome. Despite it...Nonalcoholic fatty liver disease(NAFLD) is highly associated with insulin resistance(IR), type 2 diabetes mellitus and metabolic syndrome, being characterized as the hepatic component of metabolic syndrome. Despite its high prevalence, no pharmacological treatment has been established, as of yet. A growing body of evidence, however, shows that reducing IR can result in improvement of the biochemical and histological features of nonalcoholic steatohepatitis(NASH)-the aggressive form of NAFLD that can lead to cirrhosis and hepatocellular carcinoma. Unfortunately, the several trials that have assessed the effect of various antidiabetic agents to date have failed to establish an effective and safe treatment regimen for patients with NAFLD. Glucagon-like peptide-1(commonly known as GLP-1) agonists are a novel class of antidiabetic drugs that improve insulin sensitivity and promote weight loss. They also appear to have a direct effect on the lipid metabolism of hepatocytes, reducing hepatic steatosis. Several trials have demonstrated that GLP-1 agonists can reduce aminotransferase levels and improve liver histology in patients with NAFLD, suggesting that these agents could serve as an alternative treatment option for these patients. This manuscript discusses the role and potential mechanisms of GLP-1 agonists in the treatment of NASH.展开更多
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
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 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(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
The growing diffusion of nonalcoholic fatty liver disease(NAFLD) is a consequence of the worldwide increase in the prevalence of obesity.Oxidative stress is widely recognized to play a pivotal role in NAFLD evolution ...The growing diffusion of nonalcoholic fatty liver disease(NAFLD) is a consequence of the worldwide increase in the prevalence of obesity.Oxidative stress is widely recognized to play a pivotal role in NAFLD evolution to nonalcoholic steatohepatitis(NASH).Here we review recent evidence suggesting that oxidative stress-derived antigens originating within fatty livers stimulate both humoral and cellular adaptive immune responses and the possible mechanisms involved in sustaining hepatic inflammation in NASH.展开更多
In light of the growing epidemics of nonalcoholic fatty liver disease(NAFLD),identification and validation of the novel biochemical surrogate markers for nonalcoholic steatohepatitis(NASH)are paramount to reduce the n...In light of the growing epidemics of nonalcoholic fatty liver disease(NAFLD),identification and validation of the novel biochemical surrogate markers for nonalcoholic steatohepatitis(NASH)are paramount to reduce the necessity for liver biopsy.The availability of such markers has tremendous potential to radically alter the management strategies of NAFLD patients and to monitor the disease activity.Although current biomarkers do not entirely fulfill the many requirements for the identification of patients with NASH,they should not discourage our quest,but remind us that we need to cognize the challenges ahead.展开更多
文摘The global incidence of nonalcoholic fatty liver disease(NAFLD)is escalating considerably.NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis,which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix,leading to fibrosis.Hepatocyte ballooning is a key catalyst for fibrosis progression,potentially advancing to cirrhosis and its decompensated state.Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD;therefore,those with substantial fibrosis require timely intervention.Although liver biopsy is the most reliable method for fibrosis detection,it is associated with certain risks and limitations,particularly in routine screening.Consequently,various noninvasive diagnostic techniques have been introduced.This review examines the increasing prevalence of NAFLD,evaluates the noninvasive diagnostic techniques for fibrosis,and assesses their efficacy in staging the disease.In addition,it critically appraises current and emerging antifibrotic therapies,focusing on their mechanisms,efficacy,and potential in reversing fibrosis.This review underscores the urgent need for effective therapeutic strategies,given the dire consequences of advanced fibrosis.
基金Supported by the Natural Science Foundation of China,No.81970512the Beijing Hospitals Authority Youth Programme,No.QMl220201802+1 种基金the Beijing Traditional Chinese Medicine Science and Technology Development Fund Project,No.Qn-2020-25High-Level Public Health Technical Personnel Construction Project.
文摘BACKGROUND The global prevalence of non-alcoholic steatohepatitis(NASH)and its associated risk of adverse outcomes,particularly in patients with advanced liver fibrosis,underscores the importance of early and accurate diagnosis.AIM To develop a machine learning-based diagnostic model for advanced liver fibrosis in NASH patients.METHODS A total of 749 patients who underwent liver biopsy at Beijing Ditan Hospital,Capital Medical University,between January 2010 and January 2020 were included.Patients were randomly divided into training(n=522)and validation(n=224)cohorts.Five machine learning models were applied to predict advanced liver fibrosis,with feature selection based on Shapley Additive Explanations(SHAP).The diagnostic performance of these models was compared to traditional scores such as the aspartate aminotransferase to platelet ratio index(APRI)and fibrosis index based on the 4 factors(FIB-4),using metrics including the area under the receiver operating characteristic curve(AUROC),decision curve analysis(DCA),and calibration curves.RESULTS The Extreme Gradient Boosting(XGBoost)model outperformed all other machine learning models,achieving an AUROC of 0.934(95%CI:0.914-0.955)in the training cohort and 0.917(95%CI:0.880-0.953)in the validation cohort(P<0.001).Incorporating liver stiffness measurement into the model further improved its performance,with an AUROC of 0.977(95%CI:0.966-0.980)in the training cohort and 0.970(95%CI:0.950-0.990)in the validation cohort,significantly surpassing APRI and FIB-4 scores(P<0.001).The XGBoost model also demonstrated superior clinical utility,as evidenced by DCA and calibration curve analysis in both cohorts.CONCLUSION The XGBoost model provides a highly accurate,non-invasive diagnosis of advanced liver fibrosis in NASH patients,outperforming traditional methods.An online tool based on this model has been developed to assist clinicians in evaluating the risk of advanced liver fibrosis.
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funding support from the Natural Science Foundation of Jiangxi Province(20171BAB205011,20202BABL206014)。
文摘Background:Nonalcoholic steatohepatitis(NASH)is characterized by liver steatosis,inflammation,and even fibrosis.NASH is likely to develop into cirrhosis and liver cancer,the major causes of liver related deaths.We aimed to study the effect of probiotics on NASH via the gut-l iver axis.Methods:Thirty male Sprague-Dawley rats were divided into three groups.A control group of 10 rats was fed on a standard chow for 16 weeks.Twenty rats fed on a high-fat diet for 8 weeks were separated to two groups:a model group(10 rats)fed on vehicle for 8 weeks and a treatment group(10 rats)supplemented with binary Bacillus subtilis for 8 weeks.Hepatic expression of IL-6 and TNF-ɑand ileum expression of IL-17 and occludin were measured.Results:The high-fat diet caused inflammation of the liver and ileum in rats.Binary Bacillus subtilis treatment reduces liver inflammation through the intestinal liver axis.Increased levels of IL-6 and TNF-αwere detected in rats fed a high-fat diet,which were reduced to lower levels after treatment with binary Bacillus subtilis.In rats on the high-fat diet,elevated IL-17 levels and decreased occludin levels were observed.Treatment with Bacillus subtilis reduced IL-17 levels and restored the expression of occludin.Conclusion:Binary Bacillus subtilis has a beneficial effect on liver inflammation and intestinal damage.
基金Supported by Scholarship Funds from MSD Co.Ltd.(to Sumida Y)+3 种基金Scholarship Funds from MSD Co.Ltd.Dainippon Sumitomo Pharma Co.Ltd.(to Ioh Y)
文摘It is estimated that 30% of the adult population in Japan is affected by nonalcoholic fatty liver disease (NAFLD). Fatty changes of the liver are generally diagnosed using imaging methods such as abdominal ultrasonography (US) and computed tomography (CT), but the sensitivity of these imaging techniques is low in cases of mild steatosis. Alanine aminotransferase levels may be normal in some of these patients, warranting the necessity to establish a set of parameters useful for detecting NAFLD, and the more severe form of the disease, nonalcoholic steatohepatitis (NASH). Although liver biopsy is currently the gold standard for diagnosing progressive NASH, it has many drawbacks, such as sampling error, cost, and risk of complications. Furthermore, it is not realistic to perform liver biopsies on all NAFLD patients. Diagnosis of NASH using various biomarkers, scoring systems and imaging methods, such as elastography, has recently been attempted. The NAFIC score, calculated from the levels of ferritin, fasting insulin, and type IV collagen 7S, is useful for the diagnosis of NASH, while the NAFLD fibrosis score and the FIB-4 index are useful for excluding NASH in cases of advanced fibrosis. This article reviews the limitations and merits of liver biopsy and noninvasive diagnostic tests in the diagnosis of NAFLD/NASH.
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.
文摘Nonalcoholic fatty liver disease(NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis(NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma(HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC(SH-HCC), showsfeatures that resemble non-neoplastic steatohepatitis,and is thought to be strongly associated with underlying NASH.In this report,we review the histopathological features of NAFLD/NASH.
文摘Nonalcoholic fatty liver disease(NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse.Nonalcoholic steatohepatitis(NASH),a severe form of NAFLD,can progress to liver cirrhosis and hepatocellular carcinoma.NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity,type 2 diabetes,and hyperlipemia.Animal models of NAFLD/NASH give crucial information,not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents.An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH.Animal models of NAFLD/NASH are divided into genetic,dietary,and combination models.In this paper,we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.
文摘Nonalcoholic fatty liver disease(NAFLD) is one of themajor causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis(NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury(e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albuminto-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH.
基金Supported by Protalix Biotherapeutics and The Roman-Epstein Liver Research Foundation(in part)
文摘AIM To evaluate the immunomodulatory effect of oral administration of PRX-106 in the high-fat diet model.METHODS For 22 wk, C57BL/6 HFD-fed mice received daily oral treatments with BY-2 cells expressing recombinant antitumor necrosis factor alpha fusion protein(PRX-106). Mice were followed for serum liver enzyme and triglyceride levels, liver histology and intrahepatic and systemic FACS.RESULTS The orally administered non-absorbable PRX-106 w a s b i o l o g i c a l l y a c t i v e. A l t e r e d d i s t r i b u t i o n o f CD4+CD25+Fox P3+ between the liver and spleen and an increase in the intrasplenic-to-intrahepatic CD4+CD25+Fox P3+ ratio and a decrease in the intrasplenic-to-intrahepatic CD8+CD25+Fox P3+ ratio were observed. An increase in intrahepatic NKT cells and a decrease in the intrasplenic-to-intrahepatic NKT ratio were noted. Assessment of the CD4-to-CD8 ratios showed sequestration of CD8+ lymphocytes in the liver. These effects were associated with a decrease in serum triglyceride levels, decrease in the aspartate aminotransferase levels, serum glucose levels, and HOMA-IR score. A decrease in hepatic triglycerides content was observed in the high dose-treated mice.CONCLUSION Orally administered PRX-106 shows biological activity and exerts an immunomodulatory effect, alleviating liver damage. The data suggest that PRX-106 may provide an oral immunotherapy for nonalcoholic steatohepatitis.
文摘AIM: To identify risk factors for nonalcoholic steatohepatitis following pancreaticoduodenectomy, with a focus on factors related to pancreatic secretions. METHODS: The medical records of 228 patients who had a pancreaticoduodenectomy over a 16-mo period were reviewed retrospectively. The 193 patients who did not have fatty liver disease preoperatively were included in the final analysis. Hepatic steatosis was diagnosed using the differences between splenic and hepatic attenuation and liver-to-spleen attenuation as measured by non-enhanced computed tomography. RESULTS: Fifteen patients (7.8%) who showed postoperative hepatic fatty changes were assigned to Group A, and the remaining patients were assigned to Group B. Patient demographics, preoperative laboratory findings (including levels of C-peptide, glucagon, insulin and glucose tolerance test results), operation types, and final pathological findings did not differ significantly between the two groups; however, the frequency of pancreatic fistula (P = 0.020) and the method of pancreatic duct stenting (P = 0.005) showed significant differences between the groups. A multivari- ate analysis identified pancreatic fistula (HR = 3.332, P = 0.037) and external pancreatic duct stenting (HR = 4.530, P = 0.017) as independent risk factors for the development of postoperative steatohepatitis. CONCLUSION: Pancreatic fistula and external pancreatic duct stenting were identified as independent risk factors for the development of steatohepatitis following pancreaticoduodenectomy.
文摘Nonalcoholic fatty liver disease(NAFLD)remains a leading cause of chronic liver disease.In the context of NAFLD,the presence of nonalcoholic steatohepatitis (NASH)portends an adverse prognosis with greater risk of liver fibrosis and cirrhosis.Although liver biopsy is the keystone of patient management in NAFLD,it is also increasingly clear that such evaluation has its limitations.The availability of biochemical markers of NAFLD and NASH has tremendous potential to radically alter management strategies for these conditions,as well as to monitor disease activity.Our article provides an overview of biomarker discovery and selection in the setting of NAFLD and highlights future directions in the field.
文摘Nonalcoholic fatty liver disease(NAFLD) is highly associated with insulin resistance(IR), type 2 diabetes mellitus and metabolic syndrome, being characterized as the hepatic component of metabolic syndrome. Despite its high prevalence, no pharmacological treatment has been established, as of yet. A growing body of evidence, however, shows that reducing IR can result in improvement of the biochemical and histological features of nonalcoholic steatohepatitis(NASH)-the aggressive form of NAFLD that can lead to cirrhosis and hepatocellular carcinoma. Unfortunately, the several trials that have assessed the effect of various antidiabetic agents to date have failed to establish an effective and safe treatment regimen for patients with NAFLD. Glucagon-like peptide-1(commonly known as GLP-1) agonists are a novel class of antidiabetic drugs that improve insulin sensitivity and promote weight loss. They also appear to have a direct effect on the lipid metabolism of hepatocytes, reducing hepatic steatosis. Several trials have demonstrated that GLP-1 agonists can reduce aminotransferase levels and improve liver histology in patients with NAFLD, suggesting that these agents could serve as an alternative treatment option for these patients. This manuscript discusses the role and potential mechanisms of GLP-1 agonists in the treatment of NASH.
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 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.
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.
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The growing diffusion of nonalcoholic fatty liver disease(NAFLD) is a consequence of the worldwide increase in the prevalence of obesity.Oxidative stress is widely recognized to play a pivotal role in NAFLD evolution to nonalcoholic steatohepatitis(NASH).Here we review recent evidence suggesting that oxidative stress-derived antigens originating within fatty livers stimulate both humoral and cellular adaptive immune responses and the possible mechanisms involved in sustaining hepatic inflammation in NASH.
文摘In light of the growing epidemics of nonalcoholic fatty liver disease(NAFLD),identification and validation of the novel biochemical surrogate markers for nonalcoholic steatohepatitis(NASH)are paramount to reduce the necessity for liver biopsy.The availability of such markers has tremendous potential to radically alter the management strategies of NAFLD patients and to monitor the disease activity.Although current biomarkers do not entirely fulfill the many requirements for the identification of patients with NASH,they should not discourage our quest,but remind us that we need to cognize the challenges ahead.
