Objective To detect the relationship between the polymorphism of the glycogen-targeting regulatory subunit of the skeletal muscle glycogen-associated protein phosphatase 1 (PPP1R3) gene and type 2 diabetes by case-con...Objective To detect the relationship between the polymorphism of the glycogen-targeting regulatory subunit of the skeletal muscle glycogen-associated protein phosphatase 1 (PPP1R3) gene and type 2 diabetes by case-control study. Methods We genotyped the PPP1R3 gene Asp905Tyr polymorphism and a common 3'-untranslated region AT (AU)-rich element (ARE) polymorphism in 101 type 2 diabetic patients and 101controls by oligonucleotide ligation assay (OLA) and polyacrylamide gel elecrophoresis, respectively. Results Subjects with Tyr/Tyr genotypes whose body mass index (BMI)<25 were used as the reference group. Those whose BMI25 with Asp905 had a 3.66-fold increase (95% CI: 1.48-9.06, P=0.005) in type 2 diabetes risk. No association was found between 3'UTR ARE polymorphism and type 2 diabetes mellitus (OR=1.15; 95% CI: 0.62-2.14, P=0.65). Conclusion A joint effect between the Asp905 and BMI increases the risk of type 2 diabetes, and Asp905Tyr and ARE polymorphism of PPP1R3 gene are not the major diabetogenic gene variants in Chinese population.展开更多
Objective To investigate the regulatory relationship of Protein Phosphatase 2 Regulatory Subunit B"Alpha(PPP2R3A)and hexokinase 1(HK1)in glycolysis of hepatocellular carcinoma(HCC).Methods In HepG2 and Huh7 cells...Objective To investigate the regulatory relationship of Protein Phosphatase 2 Regulatory Subunit B"Alpha(PPP2R3A)and hexokinase 1(HK1)in glycolysis of hepatocellular carcinoma(HCC).Methods In HepG2 and Huh7 cells,PPP2R3A expression was silenced by small interfering RNA(siRNA)and overexpression by plasmid transfection.The PPP2R3A-related genes were searched by RNA sequencing.Glycolysis levels were measured by glucose uptake and lactate production.QRT-PCR,ELISA,western blot and immunofluorescence assay were performed to detect the changes of PPP2R3A and HK1.Cell proliferation,migration and invasion assay were used to study the roles of HK1 regulation by PPP2R3A.Results RNA sequencing data revealed that PPP2R3A siRNA significantly downregulated the expression of HK1.PPP2R3A gene overexpression promotes,while gene silencing suppresses,the level of HK1 and glycolysis in HCC cells.In HCC tissue samples,PPP2R3A and HK1 were colocalized in the cytoplasm,and their expression showed a positive correlation.HK1 inhibition abrogated the promotion of glycolysis,proliferation,migration and invasion by PPP2R3A overexpression in liver cancer cells.Conclusion Our findings showed the correlation of PPP2R3A and HK1 in the glycolysis of HCC,which reveals a new mechanism for the oncogenic roles of PPP2R3A in cancer.展开更多
Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease that progresses to fibrosis and cirrhosis, resulting from the gradual destruction of intrahepatic bile ducts. Exploring genetic variants ass...Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease that progresses to fibrosis and cirrhosis, resulting from the gradual destruction of intrahepatic bile ducts. Exploring genetic variants associated with PBC is essential to understand the pathogenesis of PBC. Here we identify a zebrafish balloon dog (blg) mutant with intrahepatic bile duct branching defects, exhibiting several key pathological PBC-like features, including immunodominant autoantigen PDC-E2 production, cholangiocyte apoptosis, immune cell infiltration, inflammatory activation, and liver fibrosis. blg encodes the protein phosphatase 1 regulatory subunit 21 (Ppp1r21), which is enriched in the liver and its peripheral tissues and plays a vital role in the early intrahepatic bile duct formation stage. Further studies show an excessive activation of the PI3K/AKT/mTOR pathway in the hepatic tissues in the mutant, while treatment with the pathway inhibitor LY294002 and rapamycin partially rescues intrahepatic bile duct branching defects and alleviates the PBC-like symptoms. These findings implicate the potential role of the Ppp1r21-mediated PI3K/AKT/mTOR pathway in the pathophysiology of PBC.展开更多
文摘Objective To detect the relationship between the polymorphism of the glycogen-targeting regulatory subunit of the skeletal muscle glycogen-associated protein phosphatase 1 (PPP1R3) gene and type 2 diabetes by case-control study. Methods We genotyped the PPP1R3 gene Asp905Tyr polymorphism and a common 3'-untranslated region AT (AU)-rich element (ARE) polymorphism in 101 type 2 diabetic patients and 101controls by oligonucleotide ligation assay (OLA) and polyacrylamide gel elecrophoresis, respectively. Results Subjects with Tyr/Tyr genotypes whose body mass index (BMI)<25 were used as the reference group. Those whose BMI25 with Asp905 had a 3.66-fold increase (95% CI: 1.48-9.06, P=0.005) in type 2 diabetes risk. No association was found between 3'UTR ARE polymorphism and type 2 diabetes mellitus (OR=1.15; 95% CI: 0.62-2.14, P=0.65). Conclusion A joint effect between the Asp905 and BMI increases the risk of type 2 diabetes, and Asp905Tyr and ARE polymorphism of PPP1R3 gene are not the major diabetogenic gene variants in Chinese population.
基金supported by National Natural Science Foundation of China [81372595]
文摘Objective To investigate the regulatory relationship of Protein Phosphatase 2 Regulatory Subunit B"Alpha(PPP2R3A)and hexokinase 1(HK1)in glycolysis of hepatocellular carcinoma(HCC).Methods In HepG2 and Huh7 cells,PPP2R3A expression was silenced by small interfering RNA(siRNA)and overexpression by plasmid transfection.The PPP2R3A-related genes were searched by RNA sequencing.Glycolysis levels were measured by glucose uptake and lactate production.QRT-PCR,ELISA,western blot and immunofluorescence assay were performed to detect the changes of PPP2R3A and HK1.Cell proliferation,migration and invasion assay were used to study the roles of HK1 regulation by PPP2R3A.Results RNA sequencing data revealed that PPP2R3A siRNA significantly downregulated the expression of HK1.PPP2R3A gene overexpression promotes,while gene silencing suppresses,the level of HK1 and glycolysis in HCC cells.In HCC tissue samples,PPP2R3A and HK1 were colocalized in the cytoplasm,and their expression showed a positive correlation.HK1 inhibition abrogated the promotion of glycolysis,proliferation,migration and invasion by PPP2R3A overexpression in liver cancer cells.Conclusion Our findings showed the correlation of PPP2R3A and HK1 in the glycolysis of HCC,which reveals a new mechanism for the oncogenic roles of PPP2R3A in cancer.
基金This work was supported by the National Natural Science Foundation of China(32270859 and 32192400)the National Key R&D Program of China(2021YFA0805000).
文摘Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease that progresses to fibrosis and cirrhosis, resulting from the gradual destruction of intrahepatic bile ducts. Exploring genetic variants associated with PBC is essential to understand the pathogenesis of PBC. Here we identify a zebrafish balloon dog (blg) mutant with intrahepatic bile duct branching defects, exhibiting several key pathological PBC-like features, including immunodominant autoantigen PDC-E2 production, cholangiocyte apoptosis, immune cell infiltration, inflammatory activation, and liver fibrosis. blg encodes the protein phosphatase 1 regulatory subunit 21 (Ppp1r21), which is enriched in the liver and its peripheral tissues and plays a vital role in the early intrahepatic bile duct formation stage. Further studies show an excessive activation of the PI3K/AKT/mTOR pathway in the hepatic tissues in the mutant, while treatment with the pathway inhibitor LY294002 and rapamycin partially rescues intrahepatic bile duct branching defects and alleviates the PBC-like symptoms. These findings implicate the potential role of the Ppp1r21-mediated PI3K/AKT/mTOR pathway in the pathophysiology of PBC.
