Background: Adiponectin is involved in regulating both glucose and fatty acid. Associations of the known adiponectin receptors 1 (ADIPOR1) single nucleotide polymorphism (SNP) with diabetes have been demonstrated whil...Background: Adiponectin is involved in regulating both glucose and fatty acid. Associations of the known adiponectin receptors 1 (ADIPOR1) single nucleotide polymorphism (SNP) with diabetes have been demonstrated while hypertriglyceridemia is frequently associated with cerebrovascular disease (CVD) among diabetes. Triglyceride metabolism was also reported to be different between genders and estrogen was observed to interfere with adiponectin effects via ADIPOR1. It seems important to investigate whether the ADIPOR1 SNP variants may be significant determinants in triglyceride metabolism and hence be a risk of CVD in specific gender. Methods: A survey was performed on random self-reported healthy subjects aged 35 and above with their biochemical data collected. Genotyping for ADIPOR1 SNP (rs1342387) was carried out using?TaqMan Genotyping Assays. Interviews were also conducted regarding stress, adverse diet behavior and exercise. Multivariable logistic regression analyses were performed to identify the strongest contributing variables. Findings: The ADIPOR1 minor allele carrier (T/T and T/C) had significantly (p?= 0.02) higher TG mean compared to homozygous (C/C) major alleles. TG difference was significantly higher in male (p?= 0.02) with a larger difference in mean, whereas the difference disappeared among female (p?= 0.32). Multivariate logistic regression analyses were performed by defining abnormal TG based on NCEP criteria of metabolic syndrome, and when all life style variables were entered in the model with ADIPOR1, only the ADIPOR1 inmale showed significant (p?= 0.03) and very high association with abnormal TG (Exp(β) 16.31). Discussion: The findings provide sample evidence of a relation between ADIPOR1 SNP minor allele carrier and high TG concentrations in male. The association of abnormal TG and ADIPOR1 is much stronger than that compared to life style. The implications of this survey may be further extend to identifying the genetic risk of abnormal TG at young age and reduce the CVD incidence by early intervention.展开更多
Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Ac...Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Accumulating evidence suggests that the generation of elastin-derived peptides(EDPs)and the inhibition of adiponectin receptors(Adipo R)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis.We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix(ECM)and ameliorated liver fibrosis.However,the degradation of the ECM lead to the generation of EDPs,which could further alter liver homeostasis negatively.Thus,in this study,we successfully combined AdipoR1/2 agonist JT003 with V14,which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation.We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other.These effects are induced by the enhancement of the mitochondrial antioxidant capacity,mitophagy,and mitochondrial biogenesis via AMPK pathway.Furthermore,specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress,increased mitophagy and mitochondrial biogenesis.These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.展开更多
文摘Background: Adiponectin is involved in regulating both glucose and fatty acid. Associations of the known adiponectin receptors 1 (ADIPOR1) single nucleotide polymorphism (SNP) with diabetes have been demonstrated while hypertriglyceridemia is frequently associated with cerebrovascular disease (CVD) among diabetes. Triglyceride metabolism was also reported to be different between genders and estrogen was observed to interfere with adiponectin effects via ADIPOR1. It seems important to investigate whether the ADIPOR1 SNP variants may be significant determinants in triglyceride metabolism and hence be a risk of CVD in specific gender. Methods: A survey was performed on random self-reported healthy subjects aged 35 and above with their biochemical data collected. Genotyping for ADIPOR1 SNP (rs1342387) was carried out using?TaqMan Genotyping Assays. Interviews were also conducted regarding stress, adverse diet behavior and exercise. Multivariable logistic regression analyses were performed to identify the strongest contributing variables. Findings: The ADIPOR1 minor allele carrier (T/T and T/C) had significantly (p?= 0.02) higher TG mean compared to homozygous (C/C) major alleles. TG difference was significantly higher in male (p?= 0.02) with a larger difference in mean, whereas the difference disappeared among female (p?= 0.32). Multivariate logistic regression analyses were performed by defining abnormal TG based on NCEP criteria of metabolic syndrome, and when all life style variables were entered in the model with ADIPOR1, only the ADIPOR1 inmale showed significant (p?= 0.03) and very high association with abnormal TG (Exp(β) 16.31). Discussion: The findings provide sample evidence of a relation between ADIPOR1 SNP minor allele carrier and high TG concentrations in male. The association of abnormal TG and ADIPOR1 is much stronger than that compared to life style. The implications of this survey may be further extend to identifying the genetic risk of abnormal TG at young age and reduce the CVD incidence by early intervention.
基金the financial support from the National Natural Science Foundation of China(Nos.91853106,81870420 and 82070590)the Program for Guangdong Introducing Innovative and Enterpre-neurial Teams(No.2016ZT06Y337,China)+3 种基金The Fundamental Research Funds for the Central Universities(No.19ykzd25,China)National Key Research and Development Program(No.2017YFE0109900,China)Special Topics of General Projects of Guangzhou Science and Technology Plan of China(201904010075)CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-074,China)。
文摘Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Accumulating evidence suggests that the generation of elastin-derived peptides(EDPs)and the inhibition of adiponectin receptors(Adipo R)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis.We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix(ECM)and ameliorated liver fibrosis.However,the degradation of the ECM lead to the generation of EDPs,which could further alter liver homeostasis negatively.Thus,in this study,we successfully combined AdipoR1/2 agonist JT003 with V14,which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation.We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other.These effects are induced by the enhancement of the mitochondrial antioxidant capacity,mitophagy,and mitochondrial biogenesis via AMPK pathway.Furthermore,specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress,increased mitophagy and mitochondrial biogenesis.These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.
