BACKGROUND The prevalence of metabolic dysfunction-associated fatty liver disease(MAFLD)is rapidly increasing,currently affecting approximately 25%of the global population.Liver fibrosis represents a crucial stage in ...BACKGROUND The prevalence of metabolic dysfunction-associated fatty liver disease(MAFLD)is rapidly increasing,currently affecting approximately 25%of the global population.Liver fibrosis represents a crucial stage in the development of MAFLD,with advanced liver fibrosis elevating the risks of cirrhosis and hepatocellular carcinoma.Simple serum markers are less effective in diagnosing liver fibrosis compared to more complex markers.However,imaging techniques like transient elastography face limitations in clinical application due to equipment and technical constraints.Consequently,it is imperative to identify a straightforward yet effective method for assessing MAFLD-associated liver fibrosis.AIM To investigate the predictive value of angiopoietin-like protein 8(ANGPTL8)in MAFLD and its progression.METHODS We analyzed 160 patients who underwent abdominal ultrasonography in the Endocrinology Department,Xiaogan Central Hospital affiliated to Wuhan University of Science and Technology,during September 2021-July 2022.Using abdominal ultrasonography and MAFLD diagnostic criteria,among the 160 patients,80 patients(50%)were diagnosed with MAFLD.The MAFLD group was divided into the liver fibrosis group(n=23)and non-liver fibrosis group(n=57)by using a cut-off fibrosis-4 index≥1.45.Logistical regression was used to analyze the risk of MAFLD and the risk factors for its progression.Receiver operating characteristic curves were used to evaluate the predictive value of serum ANGPTL8 in MAFLD and its progression.RESULTS Compared with non-MAFLD patients,MAFLD patients had higher serum ANGPTL8 and triglyceride-glucose(TyG)index(both P<0.05).Serum ANGPTL8(r=0.576,P<0.001)and TyG index(r=0.473,P<0.001)were positively correlated with MAFLD.Serum ANGPTL8 was a risk factor for MAFLD[odds ratio(OR):1.123,95%confidence interval(CI):1.066-1.184,P<0.001).Serum ANGPTL8 and ANGPTL8+TyG index predicted MAFLD[area under the curve(AUC):0.832 and 0.886,respectively;both P<0.05].Compared with MAFLD patients without fibrosis,those with fibrosis had higher serum ANGPTL8 and TyG index(both P<0.05),and both parameters were positively correlated with MAFLD-associated fibrosis.Elevated serum ANGPTL8(OR:1.093,95%CI:1.044-1.144,P<0.001)and TyG index(OR:2.383,95%CI:1.199-4.736,P<0.013)were risk factors for MAFLD-associated fibrosis.Serum ANGPTL8 and ANGPTL8+TyG index predicted MAFLD-associated fibrosis(AUC:0.812 and 0.835,respectively;both P<0.05).CONCLUSION The serum levels of ANGPTL8 are elevated and positively correlated with MAFLD.They can serve as predictors for the risk of MAFLD and liver fibrosis,with the ANGPTL8+TyG index potentially exhibiting even higher predictive value.展开更多
AIM：To confirm the role of angiopoietin-like protein 8（Angptl 8） in proliferative diabetic retinopathy（PDR）.METHODS：The sera and aqueous humor of 10 PDR patients and 10 non-diabetic retinopathy（NDR） patients（...AIM：To confirm the role of angiopoietin-like protein 8（Angptl 8） in proliferative diabetic retinopathy（PDR）.METHODS：The sera and aqueous humor of 10 PDR patients and 10 non-diabetic retinopathy（NDR） patients（idiopathic macular hole patients） were collected and the expression of Angptl 8 was detected by enzyme linked immune-sorbent assay（ELISA）.Experimental diabetes mice model was induced with streptozotocin.The expression of glycosylated hemoglobin and Angptl 8 in sera was detected.Recombinant Angptl 8 was re-infused into wild type（WT） diabetic mice and spatial frequency threshold and contrast sensitivity were measured.In vitro retinal pigment epithelium（RPE） were stimulated by recombinant Angptl 8 for 24 h.MMT assay were used to detect cell proliferation.At the same time,q RT-PCR and Western blot was used to measure the expression of proliferation-related factors in PRE cells.RESULTS：The expression of Angptl 8 was markedly increased in the sera and aqueous humor of PDR patients（F=99.02,P〈0.0001 in sera;t=10.42,P〈0.0001 in aqueous）.After successfully establishing the diabetic mice model,we found that glycosylated hemoglobin and Angptl 8 expression levels were increased.Re-infusion of recombinant Angptl 8 into WT diabetic mice could further decrease spatial frequency threshold and contrast sensitivity（P〈0.01）.In vitro,RPE cells stimulated by recombinant Angptl 8could increase the relative absorbance of MMT assay（1.486±0.042 vs 1.000±0.104,P〈0.05） and proliferating cell nuclear antigen（PCNA） expression（0.55±0.01 vs 0.29±0.03,P〈0.05）.The proliferative effect of Angptl 8 is mainly mediated by increasing the expression of proliferation-activating factors cyclin A1（4.973±0.205 vs 2.720±0.197,P〈0.05）,cyclin F（5.690±0.219 vs 4.297±0.292,P〈0.05） and E2 F2（2.297±0.102 vs 1.750±0.146,P〈0.05）,and reducing the expression of proliferation-inhibiting factors cdkn1（2.370±0.074 vs 3.317±0.135,P〈0.05） and cdkn2（4.793±0.065 vs 5.387±0.149,P〈0.05）.CONCLUSION：The expression of Angptl 8 is increased in PDR,and the increased Angptl 8 can promote proliferation and increase proliferation-related factors.展开更多
Three members of the angiopoietin-like(ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8-are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the int...Three members of the angiopoietin-like(ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8-are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function(LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia(FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides.展开更多
Pregnancy toxemia is a metabolic disorder of lipid and glucose. Recent investigations have found that angiopoietin-like protein 3 （ANGPTL3） can contribute to disorder of carbohydrate and lipid metabolism. The presen...Pregnancy toxemia is a metabolic disorder of lipid and glucose. Recent investigations have found that angiopoietin-like protein 3 （ANGPTL3） can contribute to disorder of carbohydrate and lipid metabolism. The present study was conducted to investigate the change of ANGPTL3 expression during pregnancy toxemia, We firstly cloned the full-length cDNA of ANGPTL3 in Liuyang Black goats, revealing that goat ANGPTL3 had the typical structure of the angiopoietin-like family, and its mRNA was exclusively expressed in liver. Pregnancy toxemia of pregnant goat does with twins during late gestation was induced by being fasted for 72 h, and then they were recovered after 5 d ofrefeeding. Hepatic ANGPTL3 gene expression was significantly down-regulated concomitantly with decreased serum glucose concentration, elevated serum β-hydroxybutyrate and free fatty acid levels in pregnant toxemic goats, and these changes were reversed after refeeding. These results suggest ANGPTL3 may play a certain role in the development of pregnancy toxemia in goats.展开更多
BACKGROUND Intestinal barrier breakdown,a frequent complication of intestinal ischemiareperfusion(I/R)including dysfunction and the structure changes of the intestine,is characterized by a loss of tight junction and e...BACKGROUND Intestinal barrier breakdown,a frequent complication of intestinal ischemiareperfusion(I/R)including dysfunction and the structure changes of the intestine,is characterized by a loss of tight junction and enhanced permeability of the intestinal barrier and increased mortality.To develop effective and novel therapeutics is important for the improvement of outcome of patients with intestinal barrier deterioration.Recombinant human angiopoietin-like protein 4(rhANGPTL4)is reported to protect the blood-brain barrier when administered exogenously,and endogenous ANGPTL4 deficiency deteriorates radiationinduced intestinal injury.AIM To identify whether rhANGPTL4 may protect intestinal barrier breakdown induced by I/R.METHODS Intestinal I/R injury was elicited through clamping the superior mesenteric artery for 60 min followed by 240 min reperfusion.Intestinal epithelial(Caco-2)cells and human umbilical vein endothelial cells were challenged by hypoxia/reoxygenation to mimic I/R in vitro.RESULTS Indicators including fluorescein isothiocyanate-conjugated dextran(4 kilodaltons;FD-4)clearance,ratio of phosphorylated myosin light chain/total myosin light chain,myosin light chain kinase and loss of zonula occludens-1,claudin-2 and VE-cadherin were significantly increased after intestinal I/R or cell hypoxia/reoxygenation.rhANGPTL4 treatment significantly reversed these indicators,which were associated with inhibiting the inflammatory and oxidative cascade,excessive activation of cellular autophagy and apoptosis and improvement of survival rate.Similar results were observed in vitro when cells were challenged by hypoxia/reoxygenation,whereas rhANGPTL4 reversed the indicators close to normal level in Caco-2 cells and human umbilical vein endothelial cells significantly.CONCLUSION rhANGPTL4 can function as a protective agent against intestinal injury induced by intestinal I/R and improve survival via maintenance of intestinal barrier structure and functions.展开更多
Light is an environmental signaling,whereas Aux/IAA proteins and Auxin Response Factors(ARFs)are regulators of auxin signalling.Aux/IAA proteins are unstable,and their degradation dependents on 26S ubiquitin-proteasom...Light is an environmental signaling,whereas Aux/IAA proteins and Auxin Response Factors(ARFs)are regulators of auxin signalling.Aux/IAA proteins are unstable,and their degradation dependents on 26S ubiquitin-proteasome and is promoted by Auxin.Auxin binds directly to a SCF-type ubiquitin-protein ligase,TIR1,facilitates the interaction between Aux/IAA proteins and TIR1,and then the degradation of Aux/IAA proteins.A few studies have reported that some ARFs are also unstable proteins,and their degradation is also mediated by 26S proteasome.In this study,by using of antibodies recognizing endogenous ARF7 proteins,we found that protein stability of ARF7 was affected by light.By expressing MYC tagged ARF activators in protoplasts,we found that degradation of ARF7 was inhibited by 26 proteasome inhibitors.In addition,at least ARF5 and ARF19 were also unstable proteins,and degradation of ARF5 via 26S proteasome was further confirmed by using stable transformed plants overexpressing ARF5 with a GUS tag.展开更多
基金Supported by Youth Talents Project of Joint Fund of Hubei Health Commission,No.WJ2019H170and Xiaogan Natural Science Project,No.XGKJ2020010033。
文摘BACKGROUND The prevalence of metabolic dysfunction-associated fatty liver disease(MAFLD)is rapidly increasing,currently affecting approximately 25%of the global population.Liver fibrosis represents a crucial stage in the development of MAFLD,with advanced liver fibrosis elevating the risks of cirrhosis and hepatocellular carcinoma.Simple serum markers are less effective in diagnosing liver fibrosis compared to more complex markers.However,imaging techniques like transient elastography face limitations in clinical application due to equipment and technical constraints.Consequently,it is imperative to identify a straightforward yet effective method for assessing MAFLD-associated liver fibrosis.AIM To investigate the predictive value of angiopoietin-like protein 8(ANGPTL8)in MAFLD and its progression.METHODS We analyzed 160 patients who underwent abdominal ultrasonography in the Endocrinology Department,Xiaogan Central Hospital affiliated to Wuhan University of Science and Technology,during September 2021-July 2022.Using abdominal ultrasonography and MAFLD diagnostic criteria,among the 160 patients,80 patients(50%)were diagnosed with MAFLD.The MAFLD group was divided into the liver fibrosis group(n=23)and non-liver fibrosis group(n=57)by using a cut-off fibrosis-4 index≥1.45.Logistical regression was used to analyze the risk of MAFLD and the risk factors for its progression.Receiver operating characteristic curves were used to evaluate the predictive value of serum ANGPTL8 in MAFLD and its progression.RESULTS Compared with non-MAFLD patients,MAFLD patients had higher serum ANGPTL8 and triglyceride-glucose(TyG)index(both P<0.05).Serum ANGPTL8(r=0.576,P<0.001)and TyG index(r=0.473,P<0.001)were positively correlated with MAFLD.Serum ANGPTL8 was a risk factor for MAFLD[odds ratio(OR):1.123,95%confidence interval(CI):1.066-1.184,P<0.001).Serum ANGPTL8 and ANGPTL8+TyG index predicted MAFLD[area under the curve(AUC):0.832 and 0.886,respectively;both P<0.05].Compared with MAFLD patients without fibrosis,those with fibrosis had higher serum ANGPTL8 and TyG index(both P<0.05),and both parameters were positively correlated with MAFLD-associated fibrosis.Elevated serum ANGPTL8(OR:1.093,95%CI:1.044-1.144,P<0.001)and TyG index(OR:2.383,95%CI:1.199-4.736,P<0.013)were risk factors for MAFLD-associated fibrosis.Serum ANGPTL8 and ANGPTL8+TyG index predicted MAFLD-associated fibrosis(AUC:0.812 and 0.835,respectively;both P<0.05).CONCLUSION The serum levels of ANGPTL8 are elevated and positively correlated with MAFLD.They can serve as predictors for the risk of MAFLD and liver fibrosis,with the ANGPTL8+TyG index potentially exhibiting even higher predictive value.
文摘AIM：To confirm the role of angiopoietin-like protein 8（Angptl 8） in proliferative diabetic retinopathy（PDR）.METHODS：The sera and aqueous humor of 10 PDR patients and 10 non-diabetic retinopathy（NDR） patients（idiopathic macular hole patients） were collected and the expression of Angptl 8 was detected by enzyme linked immune-sorbent assay（ELISA）.Experimental diabetes mice model was induced with streptozotocin.The expression of glycosylated hemoglobin and Angptl 8 in sera was detected.Recombinant Angptl 8 was re-infused into wild type（WT） diabetic mice and spatial frequency threshold and contrast sensitivity were measured.In vitro retinal pigment epithelium（RPE） were stimulated by recombinant Angptl 8 for 24 h.MMT assay were used to detect cell proliferation.At the same time,q RT-PCR and Western blot was used to measure the expression of proliferation-related factors in PRE cells.RESULTS：The expression of Angptl 8 was markedly increased in the sera and aqueous humor of PDR patients（F=99.02,P〈0.0001 in sera;t=10.42,P〈0.0001 in aqueous）.After successfully establishing the diabetic mice model,we found that glycosylated hemoglobin and Angptl 8 expression levels were increased.Re-infusion of recombinant Angptl 8 into WT diabetic mice could further decrease spatial frequency threshold and contrast sensitivity（P〈0.01）.In vitro,RPE cells stimulated by recombinant Angptl 8could increase the relative absorbance of MMT assay（1.486±0.042 vs 1.000±0.104,P〈0.05） and proliferating cell nuclear antigen（PCNA） expression（0.55±0.01 vs 0.29±0.03,P〈0.05）.The proliferative effect of Angptl 8 is mainly mediated by increasing the expression of proliferation-activating factors cyclin A1（4.973±0.205 vs 2.720±0.197,P〈0.05）,cyclin F（5.690±0.219 vs 4.297±0.292,P〈0.05） and E2 F2（2.297±0.102 vs 1.750±0.146,P〈0.05）,and reducing the expression of proliferation-inhibiting factors cdkn1（2.370±0.074 vs 3.317±0.135,P〈0.05） and cdkn2（4.793±0.065 vs 5.387±0.149,P〈0.05）.CONCLUSION：The expression of Angptl 8 is increased in PDR,and the increased Angptl 8 can promote proliferation and increase proliferation-related factors.
文摘Three members of the angiopoietin-like(ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8-are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function(LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia(FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides.
基金the National Natural Science Foundation of China (31072167)the Key Project of Hunan Provincial Science & Technology Department, China(2009FJ1005)Innovation Project of Hunan Provincial Education Department (CX2009B153), China
文摘Pregnancy toxemia is a metabolic disorder of lipid and glucose. Recent investigations have found that angiopoietin-like protein 3 （ANGPTL3） can contribute to disorder of carbohydrate and lipid metabolism. The present study was conducted to investigate the change of ANGPTL3 expression during pregnancy toxemia, We firstly cloned the full-length cDNA of ANGPTL3 in Liuyang Black goats, revealing that goat ANGPTL3 had the typical structure of the angiopoietin-like family, and its mRNA was exclusively expressed in liver. Pregnancy toxemia of pregnant goat does with twins during late gestation was induced by being fasted for 72 h, and then they were recovered after 5 d ofrefeeding. Hepatic ANGPTL3 gene expression was significantly down-regulated concomitantly with decreased serum glucose concentration, elevated serum β-hydroxybutyrate and free fatty acid levels in pregnant toxemic goats, and these changes were reversed after refeeding. These results suggest ANGPTL3 may play a certain role in the development of pregnancy toxemia in goats.
基金the National Natural Science Foundation of China,No.81600446the Science and Technology of Traditional Chinese Medicine Foundation in Qingdao,No.2021-zyyz03the Science and technology development of Medicine and health Foundation in Shandong Province,China,No.202004010508.
文摘BACKGROUND Intestinal barrier breakdown,a frequent complication of intestinal ischemiareperfusion(I/R)including dysfunction and the structure changes of the intestine,is characterized by a loss of tight junction and enhanced permeability of the intestinal barrier and increased mortality.To develop effective and novel therapeutics is important for the improvement of outcome of patients with intestinal barrier deterioration.Recombinant human angiopoietin-like protein 4(rhANGPTL4)is reported to protect the blood-brain barrier when administered exogenously,and endogenous ANGPTL4 deficiency deteriorates radiationinduced intestinal injury.AIM To identify whether rhANGPTL4 may protect intestinal barrier breakdown induced by I/R.METHODS Intestinal I/R injury was elicited through clamping the superior mesenteric artery for 60 min followed by 240 min reperfusion.Intestinal epithelial(Caco-2)cells and human umbilical vein endothelial cells were challenged by hypoxia/reoxygenation to mimic I/R in vitro.RESULTS Indicators including fluorescein isothiocyanate-conjugated dextran(4 kilodaltons;FD-4)clearance,ratio of phosphorylated myosin light chain/total myosin light chain,myosin light chain kinase and loss of zonula occludens-1,claudin-2 and VE-cadherin were significantly increased after intestinal I/R or cell hypoxia/reoxygenation.rhANGPTL4 treatment significantly reversed these indicators,which were associated with inhibiting the inflammatory and oxidative cascade,excessive activation of cellular autophagy and apoptosis and improvement of survival rate.Similar results were observed in vitro when cells were challenged by hypoxia/reoxygenation,whereas rhANGPTL4 reversed the indicators close to normal level in Caco-2 cells and human umbilical vein endothelial cells significantly.CONCLUSION rhANGPTL4 can function as a protective agent against intestinal injury induced by intestinal I/R and improve survival via maintenance of intestinal barrier structure and functions.
文摘Light is an environmental signaling,whereas Aux/IAA proteins and Auxin Response Factors(ARFs)are regulators of auxin signalling.Aux/IAA proteins are unstable,and their degradation dependents on 26S ubiquitin-proteasome and is promoted by Auxin.Auxin binds directly to a SCF-type ubiquitin-protein ligase,TIR1,facilitates the interaction between Aux/IAA proteins and TIR1,and then the degradation of Aux/IAA proteins.A few studies have reported that some ARFs are also unstable proteins,and their degradation is also mediated by 26S proteasome.In this study,by using of antibodies recognizing endogenous ARF7 proteins,we found that protein stability of ARF7 was affected by light.By expressing MYC tagged ARF activators in protoplasts,we found that degradation of ARF7 was inhibited by 26 proteasome inhibitors.In addition,at least ARF5 and ARF19 were also unstable proteins,and degradation of ARF5 via 26S proteasome was further confirmed by using stable transformed plants overexpressing ARF5 with a GUS tag.
