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
Recovery of functional beta cell mass offers a biological cure for type 1 diabetes. However, beta cell mass is difficult to regain once lost since the proliferation rate of beta cells after youth is very low. Angiopoi...Recovery of functional beta cell mass offers a biological cure for type 1 diabetes. However, beta cell mass is difficult to regain once lost since the proliferation rate of beta cells after youth is very low. Angiopoietin like-protein 8 (ANGPTL8), a peptide that has a role in the regulation of lipoprotein lipase activity, was reported to increase beta cell proliferation in mice in 2013. Subsequent studies of human ANGPTL8 for short term (3 to 8 days) in non-diabetic mice showed little or no increase in beta cell proliferation. Here, we examined the effect of ANGPTL8 on glucose homeostasis in models that have not been examined previously. We expressed mouse ANGPTL8 using adenovirus in 2 mouse models of diabetes (streptozotocin and Non-Obese Diabetic (NOD) mice) over 2 weeks. Also, we tested ANGPTL8 in NOD mice deficient in leukocyte 12-lipoxygenase (12LO), an enzyme that contributes to insulitis and loss of beta cell function in NOD, in an effort to determine whether 12LO deficiency alters the response to ANGPTL8. Adenovirus-mediated expression of ANGPTL8 lowered blood glucose levels in streptozotocin treated mice without an increase in beta cell proliferation or serum insulin concentration. While ANGPTL8 did not reverse hyperglycemia in overtly hyperglycemic NOD mice or alter glucose homeostasis of non-diabetic NOD mice, ANGPTL8 reduced blood glucose levels in 12LOKO NOD mice. However, the lower glucose levels in 12LOKO NOD were not associated with higher serum insulin levels or beta cell proliferation. In summary, while mouse ANGPTL8 does not increase beta cell proliferation in NOD mice or streptozotocin treated mice in agreement with studies in non-diabetic mice, it lowers blood glucose levels in multiple low-dose streptozotocin induced diabetes and 12LO deficiency indicating that host factors influence the impact of ANGPTL8 on glucose homeostasis.展开更多
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.
文摘Recovery of functional beta cell mass offers a biological cure for type 1 diabetes. However, beta cell mass is difficult to regain once lost since the proliferation rate of beta cells after youth is very low. Angiopoietin like-protein 8 (ANGPTL8), a peptide that has a role in the regulation of lipoprotein lipase activity, was reported to increase beta cell proliferation in mice in 2013. Subsequent studies of human ANGPTL8 for short term (3 to 8 days) in non-diabetic mice showed little or no increase in beta cell proliferation. Here, we examined the effect of ANGPTL8 on glucose homeostasis in models that have not been examined previously. We expressed mouse ANGPTL8 using adenovirus in 2 mouse models of diabetes (streptozotocin and Non-Obese Diabetic (NOD) mice) over 2 weeks. Also, we tested ANGPTL8 in NOD mice deficient in leukocyte 12-lipoxygenase (12LO), an enzyme that contributes to insulitis and loss of beta cell function in NOD, in an effort to determine whether 12LO deficiency alters the response to ANGPTL8. Adenovirus-mediated expression of ANGPTL8 lowered blood glucose levels in streptozotocin treated mice without an increase in beta cell proliferation or serum insulin concentration. While ANGPTL8 did not reverse hyperglycemia in overtly hyperglycemic NOD mice or alter glucose homeostasis of non-diabetic NOD mice, ANGPTL8 reduced blood glucose levels in 12LOKO NOD mice. However, the lower glucose levels in 12LOKO NOD were not associated with higher serum insulin levels or beta cell proliferation. In summary, while mouse ANGPTL8 does not increase beta cell proliferation in NOD mice or streptozotocin treated mice in agreement with studies in non-diabetic mice, it lowers blood glucose levels in multiple low-dose streptozotocin induced diabetes and 12LO deficiency indicating that host factors influence the impact of ANGPTL8 on glucose homeostasis.
