BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a major health burden with an increasing global incidence.Unfortunately,the unavailability of knowledge underlying NAFLD pathogenesis inhibits effective preventive...BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a major health burden with an increasing global incidence.Unfortunately,the unavailability of knowledge underlying NAFLD pathogenesis inhibits effective preventive and therapeutic measures.AIM To explore the molecular mechanism of NAFLD.METHODS Whole genome sequencing(WGS)analysis was performed on liver tissues from patients with NAFLD(n=6)and patients with normal metabolic conditions(n=6)to identify the target genes.A NAFLD C57BL6/J mouse model induced by 16 wk of high-fat diet feeding and a hepatocyte-specific F-box only protein 2(FBXO2)overexpression mouse model were used for in vivo studies.Plasmid transfection,co-immunoprecipitation-based mass spectrometry assays,and ubiquitination in HepG2 cells and HEK293T cells were used for in vitro studies.RESULTS A total of 30982 genes were detected in WGS analysis,with 649 up-regulated and 178 down-regulated.Expression of FBXO2,an E3 ligase,was upregulated in the liver tissues of patients with NAFLD.Hepatocyte-specific FBXO2 overexpression facilitated NAFLD-associated phenotypes in mice.Overexpression of FBXO2 aggravated odium oleate(OA)-induced lipid accumulation in HepG2 cells,resulting in an abnormal expression of genes related to lipid metabolism,such as fatty acid synthase,peroxisome proliferator-activated receptor alpha,and so on.In contrast,knocking down FBXO2 in HepG2 cells significantly alleviated the OA-induced lipid accumulation and aberrant expression of lipid metabolism genes.The hydroxyl CoA dehydrogenase alpha subunit(HADHA),a protein involved in oxidative stress,was a target of FBXO2-mediated ubiquitination.FBXO2 directly bound to HADHA and facilitated its proteasomal degradation in HepG2 and HEK293T cells.Supplementation with HADHA alleviated lipid accumulation caused by FBXO2 overexpression in HepG2 cells.CONCLUSION FBXO2 exacerbates lipid accumulation by targeting HADHA and is a potential therapeutic target for NAFLD。展开更多
螺旋霉素链霉菌生物合成螺旋霉素的过程受许多酶的调控作用。酰基激酶和酰基 Co A合成酶是螺旋霉素内酯环合成的重要酶。实验测定了它们的酶活趋势和酶的影响因子。结果表明 ,酰基激酶和酰基 Co A合成酶都有两个活力峰 ,前者活性集中在...螺旋霉素链霉菌生物合成螺旋霉素的过程受许多酶的调控作用。酰基激酶和酰基 Co A合成酶是螺旋霉素内酯环合成的重要酶。实验测定了它们的酶活趋势和酶的影响因子。结果表明 ,酰基激酶和酰基 Co A合成酶都有两个活力峰 ,前者活性集中在发酵中前期 ,后者活性集中在发酵中后期。实验发现 Co2 + 、Mn2 + 对酰基激酶和酰基 Co A合成酶有较强的激活作用 ,Cu2 + 对酰基激酶有抑制作用 ,但对酰基 Co A合成酶有很强的激活作用。在发酵中期向摇瓶中补加二价阳离子比在发酵初期加入有更明显的激活作用 ,平均效价最高提高了 31 %展开更多
HMG-CoA reductase converts HMG-CoA to mevalonate,with this catalysis constituting a committed step in the biosynthesis of cholesterol.So,it’s primary drone in treatment coronary artery disease.At present,several stat...HMG-CoA reductase converts HMG-CoA to mevalonate,with this catalysis constituting a committed step in the biosynthesis of cholesterol.So,it’s primary drone in treatment coronary artery disease.At present,several statins are available in the drug market,however,up to now the quantitative structure-activity relationship of all of known inhibitors hasn’t been reported.In order to provide a theoretical guide for the synthesis of novel inhibitors,the quantitative structure-activity relationship of the inhibitors of HMG-CoA reductase were performed by using 3D-QSAR approach: comparative molecular field analysis(CoMFA).The computed obtained CoMFA model with(q^2=0.4,) r^2=0.955,SE=0.110,F=85.335.It not only can be used to explain the structure-activity relationship of compound but also has powerful predictive ability.展开更多
基金the National Natural Science Foundation of China,No.82070869 and 82270914.
文摘BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a major health burden with an increasing global incidence.Unfortunately,the unavailability of knowledge underlying NAFLD pathogenesis inhibits effective preventive and therapeutic measures.AIM To explore the molecular mechanism of NAFLD.METHODS Whole genome sequencing(WGS)analysis was performed on liver tissues from patients with NAFLD(n=6)and patients with normal metabolic conditions(n=6)to identify the target genes.A NAFLD C57BL6/J mouse model induced by 16 wk of high-fat diet feeding and a hepatocyte-specific F-box only protein 2(FBXO2)overexpression mouse model were used for in vivo studies.Plasmid transfection,co-immunoprecipitation-based mass spectrometry assays,and ubiquitination in HepG2 cells and HEK293T cells were used for in vitro studies.RESULTS A total of 30982 genes were detected in WGS analysis,with 649 up-regulated and 178 down-regulated.Expression of FBXO2,an E3 ligase,was upregulated in the liver tissues of patients with NAFLD.Hepatocyte-specific FBXO2 overexpression facilitated NAFLD-associated phenotypes in mice.Overexpression of FBXO2 aggravated odium oleate(OA)-induced lipid accumulation in HepG2 cells,resulting in an abnormal expression of genes related to lipid metabolism,such as fatty acid synthase,peroxisome proliferator-activated receptor alpha,and so on.In contrast,knocking down FBXO2 in HepG2 cells significantly alleviated the OA-induced lipid accumulation and aberrant expression of lipid metabolism genes.The hydroxyl CoA dehydrogenase alpha subunit(HADHA),a protein involved in oxidative stress,was a target of FBXO2-mediated ubiquitination.FBXO2 directly bound to HADHA and facilitated its proteasomal degradation in HepG2 and HEK293T cells.Supplementation with HADHA alleviated lipid accumulation caused by FBXO2 overexpression in HepG2 cells.CONCLUSION FBXO2 exacerbates lipid accumulation by targeting HADHA and is a potential therapeutic target for NAFLD。
文摘螺旋霉素链霉菌生物合成螺旋霉素的过程受许多酶的调控作用。酰基激酶和酰基 Co A合成酶是螺旋霉素内酯环合成的重要酶。实验测定了它们的酶活趋势和酶的影响因子。结果表明 ,酰基激酶和酰基 Co A合成酶都有两个活力峰 ,前者活性集中在发酵中前期 ,后者活性集中在发酵中后期。实验发现 Co2 + 、Mn2 + 对酰基激酶和酰基 Co A合成酶有较强的激活作用 ,Cu2 + 对酰基激酶有抑制作用 ,但对酰基 Co A合成酶有很强的激活作用。在发酵中期向摇瓶中补加二价阳离子比在发酵初期加入有更明显的激活作用 ,平均效价最高提高了 31 %
文摘HMG-CoA reductase converts HMG-CoA to mevalonate,with this catalysis constituting a committed step in the biosynthesis of cholesterol.So,it’s primary drone in treatment coronary artery disease.At present,several statins are available in the drug market,however,up to now the quantitative structure-activity relationship of all of known inhibitors hasn’t been reported.In order to provide a theoretical guide for the synthesis of novel inhibitors,the quantitative structure-activity relationship of the inhibitors of HMG-CoA reductase were performed by using 3D-QSAR approach: comparative molecular field analysis(CoMFA).The computed obtained CoMFA model with(q^2=0.4,) r^2=0.955,SE=0.110,F=85.335.It not only can be used to explain the structure-activity relationship of compound but also has powerful predictive ability.
