Trivalent chromium has long been recognized to benefit carbohydrate and lipid metabolism. Given emerging evidence that suggests chromium improves insulin sensitivity through the maintenance of an optimal level of plas...Trivalent chromium has long been recognized to benefit carbohydrate and lipid metabolism. Given emerging evidence that suggests chromium improves insulin sensitivity through the maintenance of an optimal level of plasma membrane (PM) cholesterol, we delineated the role of this micronutrient in attenuating hyperinsulinemia-induced cholesterol biosynthesis and insulin resistance. Exposing 3T3-L1 adipocytes to physiological hyperinsulinemia (500 pM 12 h), resulted in a marked impairment in insulin-stimulated glucose transport. Concurrent treatment with chromium in the picolinate form (CrPic, 10 nM 16 h) prevented against glucose transport dysfunction. Insulin signaling was neither impaired by hyperinsulinemia nor amplified by chromium to promote this protective action. Instead, it was found that hyperinsulinemia promoted an increase in PM cholesterol content that was observed to impair the acute ability of insulin to stimulate GLUT4 redistribution to the PM. Chromium prevented against the accumulation of PM cholesterol. Mechanistically, hyperinsulinemia promoted increases in O-GlcNAc modification of specificity protein 1 (Sp1), known to engage a cholesterolgenic response. Subsequent chromatin immunoprecipitation and luciferase assays revealed that hyperinsulinemia increased the binding affinity of Sp1 to the promoter region of Hmgcr, encoding 3-hydroxy 3-methyl-glutaryl-CoA reductase (HMGR), as well as HMGR promoter activity. This resulted in gains in mRNA and protein content of HMGR, with resulting elevations in PM cholesterol content. Moreover, treatment with chromium prevented this transcriptional response. Together, these data suggest a mechanism whereby CrPic affords glycemic health through inhibition of a transcriptional cholesterolgenic program detrimental to insulin action.展开更多
E2A is involved in promoting forkhead box P3（FOXP3） and retinoid-related orphan receptor gamma t（RORγt） gene transcription, which are pivotal transcription factors of T regulatory cells and Th17 cells, respective...E2A is involved in promoting forkhead box P3（FOXP3） and retinoid-related orphan receptor gamma t（RORγt） gene transcription, which are pivotal transcription factors of T regulatory cells and Th17 cells, respectively. Little is known about the involvement of E2 A in pregnancy process. This study aimed to investigate the expression of E2 A, cytotoxic T-lymphocyte-associated protein 4（CTLA-4）, and Foxp3 in luteal phase endometrium of women suffering recurrent miscarriage（RM）（n=21） and control group（n=11） by immunohistochemistry, with the Vectra？ automated quantitative pathology imaging system for analysis. The percentage of E2 A＋ cells and CTLA-4＋ cells was significantly higher in the endometrium of women with RM than in the controls. There was positive correlation between E2 A and CTLA-4（r=0.523, P=0.002）, E2 A and FOXP3（r=0.380, P=0.032）, and FOXP3 and CTLA-4（r=0.625, P=0.000） in the mid-secretory phase of endometrium for all subjects. It was concluded that the abnormal expression of endometrial E2 A existed in mid-secretory endometrium of women with RM, and there was a positive correlation between E2 A and FOXP3, and E2 A and CTLA-4, suggesting the possible regulation role of E2 A involved in regulating endometrium receptivity.展开更多
文摘Trivalent chromium has long been recognized to benefit carbohydrate and lipid metabolism. Given emerging evidence that suggests chromium improves insulin sensitivity through the maintenance of an optimal level of plasma membrane (PM) cholesterol, we delineated the role of this micronutrient in attenuating hyperinsulinemia-induced cholesterol biosynthesis and insulin resistance. Exposing 3T3-L1 adipocytes to physiological hyperinsulinemia (500 pM 12 h), resulted in a marked impairment in insulin-stimulated glucose transport. Concurrent treatment with chromium in the picolinate form (CrPic, 10 nM 16 h) prevented against glucose transport dysfunction. Insulin signaling was neither impaired by hyperinsulinemia nor amplified by chromium to promote this protective action. Instead, it was found that hyperinsulinemia promoted an increase in PM cholesterol content that was observed to impair the acute ability of insulin to stimulate GLUT4 redistribution to the PM. Chromium prevented against the accumulation of PM cholesterol. Mechanistically, hyperinsulinemia promoted increases in O-GlcNAc modification of specificity protein 1 (Sp1), known to engage a cholesterolgenic response. Subsequent chromatin immunoprecipitation and luciferase assays revealed that hyperinsulinemia increased the binding affinity of Sp1 to the promoter region of Hmgcr, encoding 3-hydroxy 3-methyl-glutaryl-CoA reductase (HMGR), as well as HMGR promoter activity. This resulted in gains in mRNA and protein content of HMGR, with resulting elevations in PM cholesterol content. Moreover, treatment with chromium prevented this transcriptional response. Together, these data suggest a mechanism whereby CrPic affords glycemic health through inhibition of a transcriptional cholesterolgenic program detrimental to insulin action.
基金supported by the grants from National Natural Science Foundation of China(No.81401276,No.81771618 and No.81771662)the Fund Project of Health and Family Planning Commission of Hubei Province(No.WJ2015MA006 and No.WJ2015Q017)
文摘E2A is involved in promoting forkhead box P3（FOXP3） and retinoid-related orphan receptor gamma t（RORγt） gene transcription, which are pivotal transcription factors of T regulatory cells and Th17 cells, respectively. Little is known about the involvement of E2 A in pregnancy process. This study aimed to investigate the expression of E2 A, cytotoxic T-lymphocyte-associated protein 4（CTLA-4）, and Foxp3 in luteal phase endometrium of women suffering recurrent miscarriage（RM）（n=21） and control group（n=11） by immunohistochemistry, with the Vectra？ automated quantitative pathology imaging system for analysis. The percentage of E2 A＋ cells and CTLA-4＋ cells was significantly higher in the endometrium of women with RM than in the controls. There was positive correlation between E2 A and CTLA-4（r=0.523, P=0.002）, E2 A and FOXP3（r=0.380, P=0.032）, and FOXP3 and CTLA-4（r=0.625, P=0.000） in the mid-secretory phase of endometrium for all subjects. It was concluded that the abnormal expression of endometrial E2 A existed in mid-secretory endometrium of women with RM, and there was a positive correlation between E2 A and FOXP3, and E2 A and CTLA-4, suggesting the possible regulation role of E2 A involved in regulating endometrium receptivity.
