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
Intestinal dysbiosis and disrupted bile acid(BA)homeostasis are associated with obesity,but the precise mechanisms remain insufficiently explored.Hepatic protein phosphatase 1 regulatory subunit 3G(PPP1R3G)plays a piv...Intestinal dysbiosis and disrupted bile acid(BA)homeostasis are associated with obesity,but the precise mechanisms remain insufficiently explored.Hepatic protein phosphatase 1 regulatory subunit 3G(PPP1R3G)plays a pivotal role in regulating glycolipid metabolism;nevertheless,its obesity-combatting potency remains unclear.In this study,a substantial reduction was observed in serum PPP1R3G levels in high-body mass index(BMI)and high-fat diet(HFD)-exposed mice,establishing a positive correlation between PPP1R3G and non-12a-hydroxylated(non-12-OH)BA content.Additionally,hepatocyte-specific overexpression of Ppp1r3g(PPP1R3G HOE)mitigated HFD-induced obesity as evidenced by reduced weight,fat mass,and an improved serum lipid profile;hepatic steatosis alleviation was confirmed by normalized liver enzymes and histology.PPP1R3G HOE considerably impacted systemic BA homeostasis,which notably increased the non-12-OH BAs ratio,particularly lithocholic acid(LCA).16S ribosomal DNA(16S rDNA)sequencing assay indicated that PPP1R3G HOE reversed HFD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidetes ratio and Lactobacillus population,and elevating the relative abundance of Blautia,which exhibited a positive correlation with serum LCA levels.A fecal microbiome transplantation test confirmed that the anti-obesity effect of hepatic PPP1R3G was gut microbiotadependent.Mechanistically,PPP1R3G HOE markedly suppressed hepatic cholesterol 7a-hydroxylase(CYP7A1)and sterol-12a-hydroxylase(CYP8B1),and concurrently upregulated oxysterol 7-a hydroxylase and Takeda G protein-coupled BA receptor 5(TGR5)expression under HFD conditions.Furthermore,LCA administration significantly mitigated the HFD-induced obesity phenotype and elevated non-12-OH BA levels.These findings emphasize the significance of hepatic PPP1R3G in ameliorating diet-induced adiposity and hepatic steatosis through the gut microbiota-BA axis,which may serve as potential therapeutic targets for obesity-related disorders.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 the Natural Science Foundation for Young Scientists of China(Grant No.:82201545)the Natural Science Foundation of Jiangsu Province,China(Grant No.:BK20221221)+4 种基金the Practice Innovation Program of Jiangsu Province,China(Grant No.:KYCX21_2641)the Medical Science Foundation of Jiangsu Province,China(Grant No.:H2019007)the Key Medical Talents Training Project of Xuzhou,China(Grant No.:XWRCHT20220060)the Xuzhou“Pengcheng Talent”Youth Medical Reserve Talent Project,China(Grant No.:XWRCHT20220014)the Science and Technology Projects of Xuzhou,China(Grant No.:KC21061).
文摘Intestinal dysbiosis and disrupted bile acid(BA)homeostasis are associated with obesity,but the precise mechanisms remain insufficiently explored.Hepatic protein phosphatase 1 regulatory subunit 3G(PPP1R3G)plays a pivotal role in regulating glycolipid metabolism;nevertheless,its obesity-combatting potency remains unclear.In this study,a substantial reduction was observed in serum PPP1R3G levels in high-body mass index(BMI)and high-fat diet(HFD)-exposed mice,establishing a positive correlation between PPP1R3G and non-12a-hydroxylated(non-12-OH)BA content.Additionally,hepatocyte-specific overexpression of Ppp1r3g(PPP1R3G HOE)mitigated HFD-induced obesity as evidenced by reduced weight,fat mass,and an improved serum lipid profile;hepatic steatosis alleviation was confirmed by normalized liver enzymes and histology.PPP1R3G HOE considerably impacted systemic BA homeostasis,which notably increased the non-12-OH BAs ratio,particularly lithocholic acid(LCA).16S ribosomal DNA(16S rDNA)sequencing assay indicated that PPP1R3G HOE reversed HFD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidetes ratio and Lactobacillus population,and elevating the relative abundance of Blautia,which exhibited a positive correlation with serum LCA levels.A fecal microbiome transplantation test confirmed that the anti-obesity effect of hepatic PPP1R3G was gut microbiotadependent.Mechanistically,PPP1R3G HOE markedly suppressed hepatic cholesterol 7a-hydroxylase(CYP7A1)and sterol-12a-hydroxylase(CYP8B1),and concurrently upregulated oxysterol 7-a hydroxylase and Takeda G protein-coupled BA receptor 5(TGR5)expression under HFD conditions.Furthermore,LCA administration significantly mitigated the HFD-induced obesity phenotype and elevated non-12-OH BA levels.These findings emphasize the significance of hepatic PPP1R3G in ameliorating diet-induced adiposity and hepatic steatosis through the gut microbiota-BA axis,which may serve as potential therapeutic targets for obesity-related disorders.
