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The polarizable and reprogrammable identity of Kupffer cells in nonalcoholic steatohepatitis

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Medical Review 2022年第4期2卷 324-327页

作者： Tarik Zahr Kevin Sun Li Qiang Naomi Berrie Diabetes Center Columbia University1150 St.Nicholas AveNew YorkNY 10032USA Department of Molecular Pharmacology and Therapeutics Columbia UniversityNew YorkNYUSA Department of Pathology and Cell Biology Columbia UniversityNew YorkNY 10032USA

Kupffer cells(KCs)are the resident macrophages of the liver with similar origins to myeloid-derived macrophages.Once differentiated,KCs exhibit distinct cellular machinery capable of longevity and self-renewal,making them a crucial player in promoting effective intrahepatic communication.However,this gets compromised in disease states like nonalcoholic steatohepatitis(NASH),where the loss of embryo-derived KCs(EmKCs)is observed.Despite this,other KC-like and KC-derived populations start to form and contribute to a variety of roles in NASH pathogenesis,often adopting a NASH-associated molecular signature.Here we offer a brief overview of recent reports describing KC polarization and reprogramming in the liver.We describe the complexities of KC cellular identity,their proposed ability to reprogram to fibroblast-like and endothelial-like cells,and the potential implications in NASH.

关键词： Kupffer cells macrophages nonalcoholic steatohepatitis polarization reprogramming

Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3869-3878页

作者： Joseph L.Jilek Kayla L.Frost Kevyn A.Jacobus Wenxi He Erica L.Toth Michael Goedken Nathan J.Cherrington Department of Pharmacology&Toxicology College of PharmacyUniversity of ArizonaTucsonAZ 85724USA Rutgers Translational Sciences Rutgers UniversityPiscatawayNJ 08901USA

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.

关键词： nonalcoholic steatohepatitis NASH Cisplatin Drug transporter Nephrotoxicity

LC-MS-based lipidomic analysis in distinguishing patients with nonalcoholic steatohepatitis from nonalcoholic fatty liver

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Hepatobiliary & Pancreatic Diseases International 2021年第5期20卷 452-459页

作者： Zhong-Hua Wang Kenneth I Zheng Xiao-Dong Wang Jin Qiao Yang-Yang Li Li Zhang Ming-Hua Zheng Jian Wu Department of Medical Microbiology and Parasitology MOE/NHC/CAMS Key Laboratory of Medical Molecular VirologySchool of Basic Medical SciencesFudan University Shanghai Medical CollegeShanghai 200032China NAFLD Research Center Department of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000China Institute of Hepatology Wenzhou Medical UniversityWenzhou 325000China The Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province Wenzhou 325000China Department of General Practice Huaihai Middle Road Community Health Service Center of Huangpu DistrictShanghai 200025China Department of Pathology The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000China Department of Gastroenterology and Hepatology Zhongshan Hospital of Fudan UniversityShanghai 200032China Laboratory of Fatty Liver and Metabolic Diseases Shanghai Institute of Liver DiseasesFudan University Shanghai Medical CollegeShanghai 200032China

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

关键词： Lipidomics nonalcoholic steatohepatitis nonalcoholic fatty liver disease Biomarker nonalcoholic activity score Hepatic fibrosis

Key factors and potential drug combinations of nonalcoholic steatohepatitis:Bioinformatic analysis and experimental validation-based study

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Hepatobiliary & Pancreatic Diseases International 2021年第5期20卷 433-451页

作者： Guang-Han Fan Rong-Li Wei Xu-Yong Wei Chen-Zhi Zhang Zhe-Tuo Qi Hai-Yang Xie Shu-Sen Zheng Xiao Xu Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou 310006China Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China NHC Key Laboratory of Combined Multi-organ Transplantation Hangzhou 310003China Department of Hepatobiliary and Pancreatic Surgery Shulan(Hangzhou)HospitalHangzhou 310000China

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.

关键词： nonalcoholic steatohepatitis Hepatocellular carcinoma microRNA Bioinformatic analysis Drug combination

Metabolic and hepatic effects of liraglutide,obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis

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World Journal of Gastroenterology 2018年第2期24卷 179-194页

作者： Kirstine S Tolbol Maria NB Kristiansen Henrik H Hansen Sanne S Veidal Kristoffer TG Rigbolt Matthew P Gillum Jacob Jelsing Niels Vrang Michael Feigh Gubra Aps Horsholm DK-2970Denmark Department of Biomedical Sciences Faculty of Health SciencesUniversity of CopenhagenCopenhagen DK-2200Denmark Section for Metabolic Imaging and Liver Metabolism The Novo Nordisk Foundation Center for Basic Metabolic ResearchFaculty of Health SciencesUniversity of CopenhagenCopenhagen DK-2200Denmark Department of Chemistry Faculty of ScienceUniversity of CopenhagenCopenhagen DK-2200Denmark

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.

关键词： nonalcoholic steatohepatitis Disease models Pathology Fibrosis Liver biopsy Transcriptomics Pharmacodynamics Glucagon-like peptide-1 receptor Peroxisome proliferator-activated receptor Farnesoid X receptor

Effect of Total Flavone of Haw Leaves on Nuclear Factor Erythroid-2 Related Factor and Other Related Factors in nonalcoholic steatohepatitis Rats

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Chinese Journal of Integrative Medicine 2018年第4期24卷 265-271页

作者： WANG De-jun CAI Yue-qin PAN Shui-zhen ZHANG Li-zong CHEN Yun-xiang CHEN Fang-ming JIN Ming YAN Mao-xiang LI Xiao-dong CHEN Zhi-yun Laboratory Animal Research Center Zhejiang Chinese Medical University Hangzhou 310053 China Drug Safety Evaluation Center Zhejing Academy of Medical Sciences Hangzhou 310053 China The First Affiliated Hospital of Zhejiang Chinese Medical University Hangzhou 310053 China

Objective： To investigate the effect of total flavone of haw leaves（TFHL） on the expression of nuclear factor erythroid-2 related factor（Nrf2） and other related factors in nonalcoholic steatohepatitis（NASH） rats induced by high-fat diet and then to further discuss the mechanism of TFHL＇s prevention against NASH. Methods： High-fat diet was fed to 40 rats to establish the NASH model. Then model rats were intragastrically administrated with 40, 80, 160 mg/（kg·day） TFHL, respectively. The pathological changes of liver tissues in NASH rats were detected by oil red O and hematoxylin-eosin（HE） stainings. The expression of Nrf2 in rat liver was examined through immunohistochemistry. The level of 8-iso-prostaglandin F2α in serum was detected through enzyme linked immunosorbent assay（ELISA）. The mR NA and protein levels of Nrf2 and other related factors in liver tissue were measured by real-time reverse transcriptionpolymerase chain reaction and western blot. Results： Lipid deposition, hepatic steatosis, focal necrosis in lobular inflammation and ballooning degeneration were emerged in livers of NASH rats. The 8-iso-prostaglandin F2α in the serum of NASH rats increased significantly compared with the control group（P〈0.05）. The mR NA of Nrf2, hemeoxyenase1（HO-1） and the mR NA and protein levels of quinine oxidoreductase（NQO1） in NASH rats liver tissue showed a striking increase, while the mR NA levels of Keap1, r-glutamylcysteine synthethase（rG CS） and glutathione S-transferase（GST） were significantly decreased compared with the control group（P〈0.05）. After TFHL treatment, 8-iso-prostaglandin F2α level in serum significantly decreased, and Nrf2 mR NA and protein levels in hepatocytes nucleus enhanced compared with the model group（P〈0.05 or 0.01）. Meanwhile the Keap1 mR NA, the mR NA and protein levels of HO-1, NQO1 antibody, rG CS antibody, GST increased after TFHL treatment（P〈0.05 or 0.01）. Conclusions： Nrf2 and other related factors were involved in development of NASH, and they also served as an important part in its occ

关键词： nonalcoholic steatohepatitis total flavone of Haw leaves nuclear factor erythroid-2 related factor

Promotion of nonalcoholic steatohepatitis by RNA N^(6)-methyladenosine reader IGF2BP2 in mice

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Life Metabolism 2022年第2期1卷 161-174页

作者： Bing Zhou Yunchen Luo Nana Ji Fei Mao Liping Xiang Hua Bian Ming-Hua Zheng Cheng Hu Yao Li Yan Lu Shanghai Diabetes Institute Shanghai Key Laboratory of Diabetes MellitusShanghai Clinical Centre for DiabetesShanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghaiChina Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education Department of Endocrinology and Metabolism of Zhongshan HospitalFudan UniversityShanghaiChina Department of Endocrinology and Metabolism Shanghai General HospitalShanghai Jiao Tong UniversityShanghaiChina Department of Endocrinology and Metabolism Qingpu Branch of Zhongshan HospitalFudan UniversityWenzhouChina NAFLD Research Center Department of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province WenzhouChina Department of Endocrinology and Metabolism Fengxian Central Hospital Affiliated to the Southern Medical UniversityShanghaiChina Department of Laboratory Animal Science Shanghai Jiao Tong University School of MedicineShanghaiChina Institute of Metabolism and Regenerative Medicine Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghaiChina

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.

关键词： nonalcoholic steatohepatitis m6A reader hepatic inflammation IGF2BP2 TAB2

Chronic hepatitis B, nonalcoholic steatohepatitis and physical fitness of military males: CHIEF study

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World Journal of Gastroenterology 2017年第25期23卷 4587-4594页

作者： Yu-Jung Chen Kai-Wen Chen Yu-Leung Shih Fang-Ying Su Yen-Po Lin Fan-Chun Meng Felicia Lin Yun-Shun Yu Chih-Lu Han Chih-Hung Wang Jia-Wei Lin Tsai-Yuan Hsieh Yi-Hwei Li Gen-Min Lin Department of Medicine Hualien-Armed Forces General Hospital Institute of Medical Sciences and Department of Public Health Tzu-Chi University Departments of Medicine Tri-Service General HospitalNational Defense Medical Center Department of Critical Care Medicine Yonghe Cardinal Tien Hospital Department of Medicine Taipei Veterans General Hospital Department of Dentistry National Yang-Ming University Department of Electrical Engineering National Dong Hwa University

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.

关键词： Chronic hepatitis B Military cohort Physical fitness nonalcoholic steatohepatitis

Screening and interventions to prevent nonalcoholic fatty liver disease/nonalcoholic steatohepatitis-associated hepatocellular carcinoma

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World Journal of Gastroenterology 2023年第2期29卷 286-309页

作者： Simona Cernea Danusia Onișor Department M3/Internal Medicine I George Emil Palade University of MedicinePharmacyScience and Technology of Târgu MureșTârgu Mureş540139Romania Diabetes Nutrition and Metabolic Diseases Outpatient UnitEmergency County Clinical HospitalTârgu Mureş540136Romania Department ME2/Internal Medicine VII George Emil Palade University of MedicinePharmacyScienceand Technology of Târgu MureşTârgu Mureş540139Romania Gastroenterology Department MureșCounty Clinical HospitalTârgu Mureș540072Romania

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.***.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.***.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.

关键词： nonalcoholic fatty liver disease nonalcoholic steatohepatitis Hepatocellular carcinoma Risk stratification Lifestyle interventions Prevention