scholarly journals Local Regeneration of Cortisol by 11β-HSD1 Contributes to Insulin Resistance of the Granulosa Cells in PCOS

2016 ◽  
Vol 101 (5) ◽  
pp. 2168-2177 ◽  
Author(s):  
Qinling Zhu ◽  
Rujuan Zuo ◽  
Yaqiong He ◽  
Yuan Wang ◽  
Zi-jiang Chen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Reductase Activity ◽  
Underlying Mechanism ◽  
Cortisol Concentration ◽  
Chromosome 10 ◽  
Phosphatase And Tensin Homolog ◽  
Akt Phosphorylation ◽  
Tensin Homolog

Abstract Context: Insulin resistance (IR) of the granulosa cells may account for the ovarian dysfunctions observed in polycystic ovarian syndrome (PCOS). The underlying mechanism remains largely unresolved. Objective: The objective of the study was to investigate the relationship of IR of the granulosa cells with cortisol in the follicular fluid and 11β-hydroxysteroid dehydrogenase 1 and 2 (11β-HSD1 and -2) in the granulosa cells in PCOS. Design: Follicular fluid and granulosa cells were collected from non-PCOS and PCOS patients with and without IR to measure cortisol concentration and the amounts of 11β-HSD1 and -2, which were then correlated with IR status. The effects of cortisol on the expression of genes pertinent to IR were studied in cultured human granulosa cells. Results: Cortisol concentration in the follicular fluid, 11β-HSD1 but not 11β-HSD2 mRNA in the granulosa cells were significantly elevated in PCOS with IR. Increased reductase and decreased oxidase activities of 11β-HSD were observed in granulosa cells in PCOS with IR. In cultured granulosa cells, insulin-induced Akt phosphorylation was significantly attenuated by cortisol. Cortisol not only increased phosphatase and tensin homolog deleted on chromosome 10, an inhibitor of Akt phosphorylation, but also 11β-HSD1 in the cells. Conclusions: Increased 11β-HSD1 expression and its reductase activity in granulosa cells are the major causes of increased cortisol concentration in the follicular fluid of PCOS with IR. The consequent excessive cortisol might contribute to IR of the granulosa cells in PCOS patients by attenuating Akt phosphorylation via induction of phosphatase and tensin homolog deleted on chromosome 10 expression, which might be further exacerbated by the induction of 11β-HSD1.

scholarly journals Elevated SAA1 promotes the development of insulin resistance in ovarian granulosa cells in polycystic ovary syndrome

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Qinling Zhu ◽  
Yue Yao ◽  
Lizhen Xu ◽  
Hasiximuke Wu ◽  
Wangsheng Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Glucose Transporter ◽  
Polycystic Ovary ◽  
Venous Blood ◽  
Peripheral Tissues ◽  
Akt Phosphorylation ◽  
Ovarian Granulosa Cells ◽  
Tensin Homolog

Abstract Background Insulin resistance (IR) contributes to ovarian dysfunctions in polycystic ovarian syndrome (PCOS) patients. Serum amyloid A1 (SAA1) is an acute phase protein produced primarily by the liver in response to inflammation. In addition to its role in inflammation, SAA1 may participate in IR development in peripheral tissues. Yet, expressional regulation of SAA1 in the ovary and its role in the pathogenesis of ovarian IR in PCOS remain elusive. Methods Follicular fluid, granulosa cells and peripheral venous blood were collected from PCOS and non-PCOS patients with and without IR to measure SAA1 abundance for analysis of its correlation with IR status. The effects of SAA1 on its own expression and insulin signaling pathway were investigated in cultured primary granulosa cells. Results Ovarian granulosa cells were capable of producing SAA1, which could be induced by SAA1 per se. Moreover, the abundance of SAA1 significantly increased in granulosa cells and follicular fluid in PCOS patients with IR. SAA1 treatment significantly attenuated insulin-stimulated membrane translocation of glucose transporter 4 and glucose uptake in granulosa cells through induction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression with subsequent inhibition of Akt phosphorylation. These effects of SAA1 could be blocked by inhibitors for toll-like receptors 2/4 (TLR 2/4) and nuclear factor kappa light chain enhancer of activated B (NF-κB). Conclusions Human granulosa cells are capable of feedforward production of SAA1, which significantly increased in PCOS patients with IR. Excessive SAA1 reduces insulin sensitivity in granulosa cells via induction of PTEN and subsequent inhibition of Akt phosphorylation upon activation of TLR2/4 and NF-κB pathway. These findings highlight that elevation of SAA1 in the ovary promotes the development of IR in granulosa cells of PCOS patients.

scholarly journals Galangin Inhibits Cholangiocarcinoma Cell Growth and Metastasis through Downregulation of MicroRNA-21 Expression

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yang Zou ◽  
Rong Li ◽  
Dabin Kuang ◽  
Meiling Zuo ◽  
Wenqun Li ◽  
...  
Keyword(s):  
Critical Role ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Phosphatase And Tensin Homolog ◽  
Akt Phosphorylation ◽  
Tensin Homolog ◽  
Cholangiocarcinoma Cell ◽  
Proliferation And Metastasis

Galangin, a natural flavonoid product derived from the root of galangal, is emerging as a promising anticancer agent against multiple cancers. Yet, whether it also has antitumor effects on cholangiocarcinoma (CCA) and the underlying mechanism is still unknown. Herein, we demonstrate that galangin exhibits multiple antitumor effects on CCA cells including decreases cell viability; inhibits proliferation, migration, and invasion; and induces apoptosis. Moreover, those phenotypic changes are associated with downregulated microRNA-21 (miR-21) expression. To support, overexpression of miR-21 blocks galangin-mediated antisurvival and metastasis effects on CCA cells. Mechanically, galangin increases the expression of phosphatase and tensin homolog (PTEN), a direct target of miR-21, resulting in decreased phosphorylation of AKT, a protein kinase which plays a critical role in controlling survival and apoptosis. In contrast, overexpression of miR-21 abrogates galangin-regulated PTEN expression and AKT phosphorylation. Taken together, these findings indicate that galangin inhibits CCA cell proliferation and metastasis and induces cell apoptosis through a miR-21-dependent manner, and galangin may provide a novel potential therapeutic adjuvant to treat CCA.

Regulation of Phosphoinositide Metabolism, Akt Phosphorylation, and Glucose Transport by PTEN (Phosphatase and Tensin Homolog Deleted on Chromosome 10) in 3T3-L1 Adipocytes

2001 ◽  
Vol 15 (8) ◽  
pp. 1411-1422 ◽  
Author(s):  
Hiraku Ono ◽  
Hideki Katagiri ◽  
Makoto Funaki ◽  
Motonobu Anai ◽  
Kouichi Inukai ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Dominant Negative ◽  
Phosphoinositide Metabolism ◽  
Transport Activity ◽  
Wild Type ◽  
Chromosome 10 ◽  
Phosphatase And Tensin Homolog ◽  
Akt Phosphorylation ◽  
Tensin Homolog ◽  
Phosphorylation Level

Abstract To investigate the roles of PTEN (phosphatase and tensin homolog deleted on chromosome 10) in the regulation of 3-position phosphorylated phosphoinositide metabolism as well as insulin-induced Akt phosphorylation and glucose metabolism, wild-type PTEN and its phosphatase-dead mutant (C124S) with or without an N-terminal myristoylation tag were overexpressed in Sf-9 cells and 3T3-L1 adipocytes using baculovirus and adenovirus systems, respectively. When expressed in Sf-9 cells together with the p110α catalytic subunit of phosphoinositide 3-kinase, myristoylated PTEN markedly reduced the accumulations of both phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate induced by p110α. In contrast, overexpression of the C124S mutants apparently increased these accumulations. In 3T3-L1 adipocytes, insulin-induced accumulations of phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate were markedly suppressed by overexpression of wild-type PTEN with the N-terminal myristoylation tag, but not by that without the tag. On the contrary, the C124S mutants of PTEN enhanced insulin-induced accumulations of phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. Interestingly, the phosphorylation level of Akt at Thr308 (Akt2 at Thr309), but not at Ser473 (Akt2 at Ser474), was revealed to correlate well with the accumulation of phosphatidylinositol 3,4,5-trisphosphate modified by overexpression of these PTEN proteins. Finally, insulin-induced increases in glucose transport activity were significantly inhibited by the overexpression of myristoylated wild-type PTEN, but were not enhanced by expression of the C124S mutant of PTEN. Therefore, in conclusion, 1) PTEN dephosphorylates both phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate in vivo, and the C124S mutants interrupt endogenous PTEN activity in a dominant-negative manner. 2) The membrane targeting process of PTEN may be important for exerting its function. 3) Phosphorylations of Thr309 and Ser474 of Akt2 are regulated differently, and the former is regulated very sensitively by the function of PTEN. 4) The phosphorylation level of Ser474, but not that of Thr309, in Akt2 correlates well with insulin-stimulated glucose transport activity in 3T3-L1 adipocytes. 5) The activity of endogenous PTEN may not play a major role in the regulation of glucose transport activity in 3T3-L1 adipocytes.

scholarly journals Involvement of Serum Amyloid A1 in the Pathogenesis of Insulin Resistance in Ovarian Granulosa Cells in Polycystic Ovary Syndrome

2021 ◽  
Author(s):  
Qinling Zhu ◽  
Yue Yao ◽  
Lizhen Xu ◽  
Hasiximuke Wu ◽  
Wangsheng Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Glucose Transporter ◽  
Polycystic Ovary ◽  
Serum Amyloid ◽  
Peripheral Tissues ◽  
Akt Phosphorylation ◽  
Ovarian Granulosa Cells ◽  
Serum Amyloid A1

Abstract Background: Insulin resistance (IR) contributes to ovarian dysfunctions in PCOS patients. Serum amyloid A1 (SAA1) is an acute phase protein produced primarily by the liver in response to inflammation. In addition to its role in inflammation, SAA1 may participate in IR development in peripheral tissues. Yet, expressional regulation of SAA1 in the ovary and its role in the pathogenesis of ovarian IR in PCOS remain elusive. Methods: Follicular fluid and granulosa cells were collected from PCOS and non-PCOS patients with and without IR to measure SAA1 abundance for analysis of its correlation with IR status. The effects of SAA1 on its own expression and insulin signaling pathway were investigated in cultured primary granulosa cells. Results: Ovarian granulosa cells were capable of producing SAA1, which could be induced by SAA1 per se. Moreover, the abundance of SAA1 significantly increased in granulosa cells and follicular fluid in PCOS patients with IR. SAA1 treatment significantly attenuated insulin-stimulated membrane translocation of glucose transporter 4 and glucose uptake in granulosa cells through induction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression with subsequent inhibition of Akt phosphorylation. These effects of SAA1 could be blocked by inhibitors for toll-like receptors 2/4 (TLR 2/4) and nuclear factor kappa light chain enhancer of activated B (NF-κB). Conclusions: Human granulosa cells are capable of feedforward production of SAA1, which significantly increased in PCOS patients with IR. Excessive SAA1 reduces insulin sensitivity in granulosa cells via induction of PTEN and subsequent inhibition of Akt phosphorylation upon activation of TLR2/4 and NF-κB pathway. These findings highlight that local excessive synthesis of SAA1 is associated with IR development in granulosa cells of PCOS patients.

scholarly journals Cellular homeostasis, implantation window and unexplained infertility: role of phosphatase and tensin homolog deleted on chromosome 10

2019 ◽  
Vol 8 (7) ◽  
pp. 2754
Author(s):  
Annu Makker ◽  
Madhu Mati Goel ◽  
Kumari Manu ◽  
Renu Makker
Keyword(s):  
Cell Proliferation ◽  
Unexplained Infertility ◽  
Endometrial Cell ◽  
Chromosome 10 ◽  
Cellular Homeostasis ◽  
Phosphatase And Tensin Homolog ◽  
Implantation Window ◽  
Tensin Homolog ◽  
Proliferation And Apoptosis

Background: Balance between endometrial cell proliferation and apoptosis is crucial for successful embryo implantation. PTEN (phosphatase and tensin homolog deleted on chromosome 10), a pro-apoptotic factor, is proposed to be one of the signaling proteins through which estrogen and progesterone act to affect cellular homeostasis. Although reports in literature have suggested role of PTEN in regulating endometrial cell proliferation and apoptosis during window of implantation, its involvement in women with unexplained infertility is not clear. In the present study, we examined expression, cellular distribution and activation status of PTEN, cell proliferation, and apoptosis in midsecretory endometrium from women with unexplained infertility as compared to fertile controls.Methods: Endometrial biopsies from infertile (n=11) and fertile women (n=22) were used for immunohistochemical evaluation of PTEN, phospho-PTEN and Ki67. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay was performed for detection of apoptotic cells.Results: Biopsies from infertile women as compared to fertile controls demonstrated statistically significant: i) decrease in nuclear PTEN (P < 0.001), increase in nuclear phospho-PTEN (P < 0.05), increase in nuclear and cytoplasmic phospho-PTEN/PTEN ratio (P < 0.001 and P < 0.05 respectively) in endometrial stroma, ii) increase in cytoplasmic phospho-PTEN (P < 0.001) and phospho-PTEN/PTEN ratio (P < 0.05) in glandular epithelium (GE), iii) increase in Ki67 labeling in GE (P < 0.01) and stroma (P < 0.05) and, iv) decrease in (P < 0.001) apoptosis.Conclusions: Altered PTEN expression and associated modulation in cellular homeostasis during the implantation window might contribute to mechanism underlying unexplained infertility.

Oncophenotypic Review and Clinical Correlates of Phosphatase and Tensin Homolog on Chromosome 10 Hamartoma Tumor Syndrome

2010 ◽  
Vol 28 (36) ◽  
pp. e767-e768 ◽  
Author(s):  
Mrinal M. Patnaik ◽  
Sania S. Raza ◽  
Sherezade Khambatta ◽  
Peter P. Stanich ◽  
Matthew P. Goetz
Keyword(s):  
Chromosome 10 ◽  
Phosphatase And Tensin Homolog ◽  
Clinical Correlates ◽  
Tensin Homolog

Statins activate the NLRP3 inflammasome and impair insulin signaling via p38 and mTOR

2020 ◽  
Vol 319 (1) ◽  
pp. E110-E116 ◽  
Author(s):  
Brandyn D. Henriksbo ◽  
Akhilesh K. Tamrakar ◽  
Jobanjit S. Phulka ◽  
Nicole G. Barra ◽  
Jonathan D. Schertzer
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
Nlrp3 Inflammasome ◽  
Protein Prenylation ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pyrin Domain ◽  
Opposing Effects ◽  
20 Nm

Statins lower cholesterol and risk of cardiovascular disease. Statins can increase blood glucose and risk of new-onset diabetes. It is unclear why statins can have opposing effects on lipids versus glucose. Statins have cholesterol-independent pleiotropic effects that influence both insulin and glucose control. Statin lowering of isoprenoids required for protein prenylation promotes pancreatic β-cell dysfunction and adipose tissue insulin resistance. Protein prenylation influences immune function and statin-mediated adipose tissue insulin resistance involves the NLR family pyrin domain-containing 3 (NLRP3) inflammasome and IL-1β. However, the intracellular cues that statins engage to activate the NLRP3 inflammasome and those responsible for IL-1β-mediated insulin resistance in adipose tissue have not been identified. We hypothesized that stress kinases or components of the insulin signaling pathway mediated statin-induced insulin resistance. We tested the associations of p38, ERK, JNK, phosphatase, and tensin homolog (PTEN), and mTOR in statin-exposed adipose tissue from WT and IL-1β−/− mice. We found that statins increased phosphorylation of p38 in WT and IL-1β−/− mice. Statin activation of p38 upstream of IL-1β led to priming of this NLRP3 inflammasome effector in macrophages. We found that mTORC1 inhibition with low doses of rapamycin (2 or 20 nM) lowered macrophage priming of IL-1β mRNA and secretion of IL-1β caused by multiple statins. Rapamycin (20 nM) or the rapalog everolimus (20 nM) prevented atorvastatin-induced lowering of insulin-mediated phosphorylation of Akt in mouse adipose tissue. These results position p38 and mTOR as mediators of statin-induced insulin resistance in adipose tissue and highlight rapalogs as candidates to mitigate the insulin resistance and glycemic side effects of statins.

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