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
[Objectives]To study the protective effects and mechanism of POLYGONI PERFOLIATI HERBA on rats with nonalcoholic steatohepatitis( NASH). [Methods] Sixty rats were randomly divided into normal group,model group,metform...[Objectives]To study the protective effects and mechanism of POLYGONI PERFOLIATI HERBA on rats with nonalcoholic steatohepatitis( NASH). [Methods] Sixty rats were randomly divided into normal group,model group,metformin group( 0. 5 mg/kg),and high dose,medium dose,and low dose groups of total flavonoids of POLYGONI PERFOLIATI HERBA( 600,300,150 mg/kg). The standard feed was given to the normal group,and the model group and the total flavonoids groups were fed with high-fat diet for 13 weeks to establish the NASH rat model. At the 8 th week,the metformin group and the POLYGONI PERFOLIATI HERBA total flavonoids groups were given with the corresponding drug treatment for 6 weeks,blood was taken from the eyeball to collect liver tissue. Biochemical method was used to determine ALT,AST,TC,TG,HDL-c,LDL-c,SOD,MDA,GSH-Px activity or content in serum and HOMA-IR,and ELISA was used to measure the TNF-α,IL-1β and IL-6 content in liver tissue; Western blotting was used to detect the expression levels of AMPK,p-AMPK and ACC in liver tissue. [Results] Total flavonoids of POLYGONI PERFOLIATI HERBA could significantly decrease the activity or content of ALT,AST and MDA in serum of NASH rats( P < 0. 05,P < 0. 01),and enhance the activity of SOD and GSH-Px( P < 0. 05,P < 0. 01),reduce serum TC,TG,LDL-c levels and insulin resistance index,increase HDL-c levels( P < 0. 05,P < 0. 01); down-regulate liver IL-1β,IL-6,TNF-α,ACC levels and up-regulate p-AMPK expression( P < 0. 05,P < 0. 01). [Conclusions]The total flavonoids of POLYGONI PERFOLIATI HERBA have a good protective effect on NASH rats,and its mechanism may be related to the functions of regulating the lipid metabolism,alleviating insulin resistance,inhibiting oxidative stress,inhibiting inflammatory reaction and regulating AMPK and ACC protein expression.展开更多
Nonalcoholic steatohepatitis(NASH),a severe type of nonalcoholic fatty liver disease(NAFLD),progresses toward liver fibrosis/cirrhosis,liver failure,and furthermore,hepatocellular carcinoma(HCC)[1].The pathological ma...Nonalcoholic steatohepatitis(NASH),a severe type of nonalcoholic fatty liver disease(NAFLD),progresses toward liver fibrosis/cirrhosis,liver failure,and furthermore,hepatocellular carcinoma(HCC)[1].The pathological manifestations are hepatocyte steatosis( >5%),lobular inflammation,and ballooning degeneration,with or without fibrogenesis[2].NAFLD/NASH results from sedentary life style,western diet,and obesity.We have witnessed the conversion of spectrum of chronic liver diseases from viral hepatitis as the leading cause to NAFLD/NASH worldwide[3].Diagnosis of NASH is therefore of great importance for the clinical management,evaluation,and follow-up.展开更多
Background:Lipid dysregulation plays a fundamental role in nonalcoholic steatohepatitis(NASH),which is an emerging critical risk factor that aggravates hepatic ischemia/reperfusion(I/R)injury.However,the specific lipi...Background:Lipid dysregulation plays a fundamental role in nonalcoholic steatohepatitis(NASH),which is an emerging critical risk factor that aggravates hepatic ischemia/reperfusion(I/R)injury.However,the specific lipids that mediate the aggressive I/R injury in NASH livers have not yet been identified.Methods:The mouse model of hepatic I/R injury on NASH was established on C56B/6J mice by first feeding the mice with a Western-style diet to induce NASH,then the NASH mice were subjected to surgical procedures to induce hepatic I/R injury.Untargeted lipidomics were performed to determine hepatic lipids in NASH livers with I/R injury through ultra-high performance liquid chromatography coupled with mass spectrometry.The pathology associated with the dysregulated lipids was examined.Results:Lipidomics analyses identified cardiolipins(CL)and sphingolipids(SL),including ceramides(CER),glycosphingolipids,sphingosines,and sphingomyelins,as the most relevant lipid classes that characterized the lipid dysregulation in NASH livers with I/R injury.CER were increased in normal livers with I/R injury,and the I/R-induced increase of CER was further augmented in NASH livers.Metabolic pathway analysis revealed that the enzymes involved in the synthesis and degradation of CER were highly upregulated in NASH livers with I/R injury,including serine palmitoyltransferase 3(Sptlc3),ceramide synthase 2(Cers2),neutral sphingomyelinase 2(Smpd3),and glucosylceramidase beta 2(Gba2)that produced CER,and alkaline ceramidase 2(Acer2),alkaline ceramidase 3(Acer3),sphingosine kinase 1(Sphk1),sphingosine-1-phosphate lyase(Sgpl1),and sphingosine-1-phosphate phosphatase 1(Sgpp1)that catalyzed the degradation of CER.CL were not affected by I/R challenge in normal livers,but CL was dramatically reduced in NASH livers with I/R injury.Consistently,metabolic pathway analyses revealed that the enzymes catalyzing the generation of CL were downregulated in NASH-I/R injury,including cardiolipin synthase(Crls1)and tafazzin(Taz).Notably,the I/R-induced oxidative stress and cell death were found to be aggravated in NASH livers,which were possibly mediated by the reduction of CL and accumulation of CER.Conclusions:The I/R-induced dysregulation of CL and SL were critically rewired by NASH,which might potentially mediate the aggressive I/R injury in NASH livers.展开更多
Background:Animal organ meat(offal)is a food with high nutrient density that is popular in different parts of the world,but its relationship with nonalcoholic steatohepatitis(NASH)is unclear.We aimed to examine whethe...Background:Animal organ meat(offal)is a food with high nutrient density that is popular in different parts of the world,but its relationship with nonalcoholic steatohepatitis(NASH)is unclear.We aimed to examine whether daily animal organ meat consumption is associated with the presence of NASH in individuals with nonalcoholic fatty liver disease(NAFLD).Methods:A total of 136 Chinese adults with biopsy-proven NAFLD were included.Definite NASH was defined as NAFLD activity score≥4 and at least one point for steatosis,ballooning,and lobular inflammation.Daily animal organ meat consumption was estimated using a self-administered validated food frequency questionnaire.Logistic regression analysis was performed to assess the association between animal organ meat intake and liver disease severity.Results:The 136 participants(80.9%men)of the study had a mean±standard deviation(SD)age of 39.0±12.5 years and body mass index of 27.4±3.6 kg/m2.Prevalence of definite NASH was 65.4%.Daily median organ meat consumption was 1.30 g/1,000 kcal.Animal organ meat consumption was inversely associated with the presence of NASH even after adjustment of demographics,lifestyle variables,metabolic and dietary factors,as well as liver fibrosis stage;adjusted-odds ratios(95%confidence intervals)for NASH were 0.15(0.03,0.69)for the highest tertile and 0.18(0.05,0.70)for the medium tertile,compared to the lowest(reference)tertile of animal organ meat intake(P value for trend=0.024).Conclusions:Our results suggest for the first time that higher animal organ meat consumption is associated with a lower prevalence of NASH in Chinese individuals with biopsy-proven NAFLD.展开更多
As obesity continues to escalate worldwide,nonalcoholic fatty liver disease(NAFLD)has emerged as the most prevalent form of liver disease,with a reported global prevalence of 30.1%(1).The prevalence of NAFLD,which was...As obesity continues to escalate worldwide,nonalcoholic fatty liver disease(NAFLD)has emerged as the most prevalent form of liver disease,with a reported global prevalence of 30.1%(1).The prevalence of NAFLD,which was around 25%in the 1990s,has been increasing year by year in recent years and has exceeded 35%in the past few years(1).The spectrum of disease includes nonalcoholic fatty liver(NAFL),characterized by macrovesicular hepatic steatosis that may be accompanied by mild inflammation,and nonalcoholic steatohepatitis(NASH),which is additionally characterized by the presence of inflammation and cellular injury(2).展开更多
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.
基金Supported by Project of National Natural Science Foundation(81460602)Natural Science Foundation Project of Guangxi(2017GXNSFAA198326)
文摘[Objectives]To study the protective effects and mechanism of POLYGONI PERFOLIATI HERBA on rats with nonalcoholic steatohepatitis( NASH). [Methods] Sixty rats were randomly divided into normal group,model group,metformin group( 0. 5 mg/kg),and high dose,medium dose,and low dose groups of total flavonoids of POLYGONI PERFOLIATI HERBA( 600,300,150 mg/kg). The standard feed was given to the normal group,and the model group and the total flavonoids groups were fed with high-fat diet for 13 weeks to establish the NASH rat model. At the 8 th week,the metformin group and the POLYGONI PERFOLIATI HERBA total flavonoids groups were given with the corresponding drug treatment for 6 weeks,blood was taken from the eyeball to collect liver tissue. Biochemical method was used to determine ALT,AST,TC,TG,HDL-c,LDL-c,SOD,MDA,GSH-Px activity or content in serum and HOMA-IR,and ELISA was used to measure the TNF-α,IL-1β and IL-6 content in liver tissue; Western blotting was used to detect the expression levels of AMPK,p-AMPK and ACC in liver tissue. [Results] Total flavonoids of POLYGONI PERFOLIATI HERBA could significantly decrease the activity or content of ALT,AST and MDA in serum of NASH rats( P < 0. 05,P < 0. 01),and enhance the activity of SOD and GSH-Px( P < 0. 05,P < 0. 01),reduce serum TC,TG,LDL-c levels and insulin resistance index,increase HDL-c levels( P < 0. 05,P < 0. 01); down-regulate liver IL-1β,IL-6,TNF-α,ACC levels and up-regulate p-AMPK expression( P < 0. 05,P < 0. 01). [Conclusions]The total flavonoids of POLYGONI PERFOLIATI HERBA have a good protective effect on NASH rats,and its mechanism may be related to the functions of regulating the lipid metabolism,alleviating insulin resistance,inhibiting oxidative stress,inhibiting inflammatory reaction and regulating AMPK and ACC protein expression.
基金supported by grants from the National Key Research and Development Plan "Precision Medicine Research"(2017YFC0908903)National Natural Science Foundation of China(81070346,81270492,81470859,81270491,and 81470840)+1 种基金State Key Development Program for Basic Research of China(2012CB517501)Shanghai Leading Talents(019)
文摘Nonalcoholic steatohepatitis(NASH),a severe type of nonalcoholic fatty liver disease(NAFLD),progresses toward liver fibrosis/cirrhosis,liver failure,and furthermore,hepatocellular carcinoma(HCC)[1].The pathological manifestations are hepatocyte steatosis( >5%),lobular inflammation,and ballooning degeneration,with or without fibrogenesis[2].NAFLD/NASH results from sedentary life style,western diet,and obesity.We have witnessed the conversion of spectrum of chronic liver diseases from viral hepatitis as the leading cause to NAFLD/NASH worldwide[3].Diagnosis of NASH is therefore of great importance for the clinical management,evaluation,and follow-up.
基金This work was supported by the National Natural Science Foundation of China(No.82070642)to JZthe Guangdong Province Science and Technology Program(No.2020A1515011205)to KW+1 种基金the Guangdong Province Science and Technology Program(No.2021A1515012146)to CJLthe President Foundation of Nanfang Hospital,Southern Medical University(No.2018C029)to JPQ.
文摘Background:Lipid dysregulation plays a fundamental role in nonalcoholic steatohepatitis(NASH),which is an emerging critical risk factor that aggravates hepatic ischemia/reperfusion(I/R)injury.However,the specific lipids that mediate the aggressive I/R injury in NASH livers have not yet been identified.Methods:The mouse model of hepatic I/R injury on NASH was established on C56B/6J mice by first feeding the mice with a Western-style diet to induce NASH,then the NASH mice were subjected to surgical procedures to induce hepatic I/R injury.Untargeted lipidomics were performed to determine hepatic lipids in NASH livers with I/R injury through ultra-high performance liquid chromatography coupled with mass spectrometry.The pathology associated with the dysregulated lipids was examined.Results:Lipidomics analyses identified cardiolipins(CL)and sphingolipids(SL),including ceramides(CER),glycosphingolipids,sphingosines,and sphingomyelins,as the most relevant lipid classes that characterized the lipid dysregulation in NASH livers with I/R injury.CER were increased in normal livers with I/R injury,and the I/R-induced increase of CER was further augmented in NASH livers.Metabolic pathway analysis revealed that the enzymes involved in the synthesis and degradation of CER were highly upregulated in NASH livers with I/R injury,including serine palmitoyltransferase 3(Sptlc3),ceramide synthase 2(Cers2),neutral sphingomyelinase 2(Smpd3),and glucosylceramidase beta 2(Gba2)that produced CER,and alkaline ceramidase 2(Acer2),alkaline ceramidase 3(Acer3),sphingosine kinase 1(Sphk1),sphingosine-1-phosphate lyase(Sgpl1),and sphingosine-1-phosphate phosphatase 1(Sgpp1)that catalyzed the degradation of CER.CL were not affected by I/R challenge in normal livers,but CL was dramatically reduced in NASH livers with I/R injury.Consistently,metabolic pathway analyses revealed that the enzymes catalyzing the generation of CL were downregulated in NASH-I/R injury,including cardiolipin synthase(Crls1)and tafazzin(Taz).Notably,the I/R-induced oxidative stress and cell death were found to be aggravated in NASH livers,which were possibly mediated by the reduction of CL and accumulation of CER.Conclusions:The I/R-induced dysregulation of CL and SL were critically rewired by NASH,which might potentially mediate the aggressive I/R injury in NASH livers.
基金supported by grants from the National Natural Science Foundation of China(No.82070588)High Level Creative Talents from Department of Public Health in Zhejiang Province(No.S2032102600032)+1 种基金Project of New Century 551 Talent Nurturing in Wenzhou,Wenzhou Science and Technology Bureau(No.Y20190530)the University School of Medicine of Verona in Italy to GT and in part by the Southampton NIHR Biomedical Research Centre in UK(No.IS-BRC-20004 to CDB).
文摘Background:Animal organ meat(offal)is a food with high nutrient density that is popular in different parts of the world,but its relationship with nonalcoholic steatohepatitis(NASH)is unclear.We aimed to examine whether daily animal organ meat consumption is associated with the presence of NASH in individuals with nonalcoholic fatty liver disease(NAFLD).Methods:A total of 136 Chinese adults with biopsy-proven NAFLD were included.Definite NASH was defined as NAFLD activity score≥4 and at least one point for steatosis,ballooning,and lobular inflammation.Daily animal organ meat consumption was estimated using a self-administered validated food frequency questionnaire.Logistic regression analysis was performed to assess the association between animal organ meat intake and liver disease severity.Results:The 136 participants(80.9%men)of the study had a mean±standard deviation(SD)age of 39.0±12.5 years and body mass index of 27.4±3.6 kg/m2.Prevalence of definite NASH was 65.4%.Daily median organ meat consumption was 1.30 g/1,000 kcal.Animal organ meat consumption was inversely associated with the presence of NASH even after adjustment of demographics,lifestyle variables,metabolic and dietary factors,as well as liver fibrosis stage;adjusted-odds ratios(95%confidence intervals)for NASH were 0.15(0.03,0.69)for the highest tertile and 0.18(0.05,0.70)for the medium tertile,compared to the lowest(reference)tertile of animal organ meat intake(P value for trend=0.024).Conclusions:Our results suggest for the first time that higher animal organ meat consumption is associated with a lower prevalence of NASH in Chinese individuals with biopsy-proven NAFLD.
文摘As obesity continues to escalate worldwide,nonalcoholic fatty liver disease(NAFLD)has emerged as the most prevalent form of liver disease,with a reported global prevalence of 30.1%(1).The prevalence of NAFLD,which was around 25%in the 1990s,has been increasing year by year in recent years and has exceeded 35%in the past few years(1).The spectrum of disease includes nonalcoholic fatty liver(NAFL),characterized by macrovesicular hepatic steatosis that may be accompanied by mild inflammation,and nonalcoholic steatohepatitis(NASH),which is additionally characterized by the presence of inflammation and cellular injury(2).
