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
Non-alcoholic fatty liver disease(NAFLD) is increasingly recognized as a significant liver disease,and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis(N...Non-alcoholic fatty liver disease(NAFLD) is increasingly recognized as a significant liver disease,and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis(NASH) to fibrosis,subsequent cirrhosis,end-stage liver failure,and liver cancer with a potential need for liver transplantation.NAFLD and NASH are closely related to obesity,metabolic syndrome,and type 2 diabetes(T2 D).The role of gut hormones,especially glucagon-like peptide 1(GLP-1),is important in NAFLD.Bariatric surgery has the potential for inducing great weight loss and may improve the symptoms of metabolic syndrome and T2 D.Recent data demonstrated significant effects of bariatric surgery on GLP-1 and other gut hormones and important lipid metabolic and inflammatory abnormalities in the pathophysiology of NAFLD.Therefore,bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients.In the present review,we describe NAFLD and NASH pathophysiology and the primary effects of bariatric surgery on metabolic pathways.We performed a systematic review of the beneficial and harmful effects and focused on changes in liver disease severity in NAFLD and NASH patients.The specific focus was liver histopathology as assessed by the invasive liver biopsy.Additionally,we reviewed several non-invasive methods used for the assessment of liver disease severity following bariatric surgery.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
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.
文摘Non-alcoholic fatty liver disease(NAFLD) is increasingly recognized as a significant liver disease,and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis(NASH) to fibrosis,subsequent cirrhosis,end-stage liver failure,and liver cancer with a potential need for liver transplantation.NAFLD and NASH are closely related to obesity,metabolic syndrome,and type 2 diabetes(T2 D).The role of gut hormones,especially glucagon-like peptide 1(GLP-1),is important in NAFLD.Bariatric surgery has the potential for inducing great weight loss and may improve the symptoms of metabolic syndrome and T2 D.Recent data demonstrated significant effects of bariatric surgery on GLP-1 and other gut hormones and important lipid metabolic and inflammatory abnormalities in the pathophysiology of NAFLD.Therefore,bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients.In the present review,we describe NAFLD and NASH pathophysiology and the primary effects of bariatric surgery on metabolic pathways.We performed a systematic review of the beneficial and harmful effects and focused on changes in liver disease severity in NAFLD and NASH patients.The specific focus was liver histopathology as assessed by the invasive liver biopsy.Additionally,we reviewed several non-invasive methods used for the assessment of liver disease severity following bariatric surgery.
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.
