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Tao Mei, Jianhe Zhang, Liangfeng Wei, Xingfeng Qi, Yiming Ma, Xianhua Liu, Shaohua Chen, Songyuan Li, Jianwu Wu and Shousen Wang

/Akt), AMP-activated protein kinase/mammalian target of rapamycin 1 (AMPK/mTOR1) and tumor suppressor gene p53 signaling pathways. Among these, the HIF-1 pathway plays a major role in ischemia and hypoxia ( 7 ). HIF-1α not only plays an important role in

Open access

Hong-Fa Yan, Zhao-Yu Liu, Zhi-Ang Guan and Chuang Guo

hypoxia-inducible factor-1α (HIF-1α) activity, resulting in an increase in proteins related to lipid metabolism, including peroxisome proliferator-activated receptor-γ (PPARγ), PPARγ co-activator 1 alpha (PGC-1α) and uncoupling protein (UCP) 1 ( 10 ). Of

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Emmely M de Vries, Hermina C van Beeren, Albert C.w.a. van Wijk, Andries Kalsbeek, Johannes A Romijn, Eric Fliers and Anita Boelen

Fasting induces profound changes in the hypothalamus-pituitary-thyroid axis and peripheral thyroid hormone (TH) metabolism, ultimately leading to lower serum thyroid hormone (TH) concentrations. In the present study, we aimed to investigate the regulation of type 3 deiodinase (D3) during fasting in two metabolic tissues: liver and white adipose tissue (WAT). To this end, we studied the effect of modulation of the mammalian target of rapamycin (mTOR) and hypoxia inducible factor 1α (HIF1α) on D3 expression in a primary rat hepatocytes and in 3T3-L1 adipocytes. In addition, we studied the role of the constitutive androstane receptor (CAR) on liver TH metabolism using primary hepatocytes and CAR-/- mice. Twenty-four hour fasting increased liver D3 expression in mice. Inhibition of mTOR using mTOR inhibitors markedly induced D3 mRNA expression in primary hepatocytes; this increase was accompanied by a small increase in D3 activity. Stimulation of these cells with a CAR agonist induced both D3 mRNA expression and activity. Fasting increased hepatic D3 expression in WT but not in CAR-/- mice. In WAT, D3 mRNA expression increased 5-fold after 48h fasting. Treatment of 3T3-L1 adipocytes with mTOR inhibitors induced D3 mRNA expression, whereas stimulation of these cells with cobalt chloride, a compound that mimics hypoxia and stabilizes HIF1α, did not induce D3 mRNA expression. In conclusion, our results indicate an important role of mTOR in the upregulation of D3 in WAT and liver during fasting. Furthermore, CAR plays a role in the fasting induced D3 increase in the liver.

Open access

Hichem Bouguerra, Amal Gorrab, Stephan Clavel, Hammouda Boussen, Jean François Louet and Asma Gati

Large prospective studies established a link between obesity and breast cancer (BC) development. Yet, the mechanisms underlying this association are not fully understood. Among the diverse adipocytokine secreted by hypertrophic adipose tissue, leptin is emerging as a key candidate molecule linking obesity and cancer, since it promotes proliferation and invasiveness of tumors. However, the potential implication of leptin on tumor escape mechanisms remains unknown. This study aims to explore the effect of leptin on tumor resistance to NK lysis and the underlying mechanism. We found that leptin promotes both BC resistance to NK92-mediated lysis and β oxidation on MCF-7, by the up-regulation of a master regulator of mitochondrial biogenesis, peroxisome proliferator activated receptor coactivator-1 α (PGC-1α). Using adenoviral approaches, we show that acute elevation of PGC-1α enhances the fatty acid oxidation pathway and decreases the susceptibility of BC cells to NK92-mediated lysis. Importantly, we identified new regulatory functions of PGC-1α and leptin in regulating the expression of hypoxia-inducible factor-1 alpha (HIF-1α by tumor cells, a transcriptional factor with pleiotropic role in cancer. We further demonstrate that basal BC cells MDA-MB-231 and BT-20 exhibit an increased PGC-1α mRNA level, an enhanced activity of oxidative phosphorylation and are more resistance to NK92 lysis in comparison with luminal BC cells (MCF7 and MDA-361). Altogether, our results demonstrate for the first time how leptin could promote tumor resistance to immune attacks. Reagents blocking leptin or PGC-1α activity might aid in developing new therapeutic strategies to limit tumor development in obese BC patients.

Open access

Xuhua Mao, Hucheng Chen, Junmin Tang, Liangliang Wang and Tingting Shu

pathway may link gluco-toxicity and hepcidin regulation. High glucose concentrations induce high oxygen consumption leading to intracellular hypoxia and activation of hypoxia inducible factor 1α (HIF-1α) ( 24 , 25 ). Activated HIF-1α suppresses the

Open access

Madalena von Hafe, João Sergio Neves, Catarina Vale, Marta Borges-Canha and Adelino Leite-Moreira

factor-1α (HIF-1α) and mediated by activation of integrin αVβ3 ( 19 , 22 ). T3-induced angiogenesis has been observed in several experimental rat models of ischemia, hypertension and diabetic cardiomyopathy ( 23 ). Table 1 T3-regulated genes

Open access

Qiuli Liu, Gang Yuan, Dali Tong, Gaolei Liu, Yuting Yi, Jun Zhang, Yao Zhang, Lin-ang Wang, Luofu Wang, Dianzheng Zhang, Rongrong Chen, Yanfang Guan, Xin Yi, Weihua Lan and Jun Jiang

proteasomal degradation of the hypoxia-inducible factors (HIFs), HIF-1α and HIF-2α. Elevated levels of HIFs subsequently result in overactivation of the downstream pathways involved in vascular endothelial growth factor, platelet-derived growth factor and

Open access

Zhen-yu Song, Qiuming Yao, Zhiyuan Zhuo, Zhe Ma and Gang Chen

oxidative stress in since it increased both the expression and activity of antioxidants, such as glucose-6-phosphate dehydrogenase and glutathione ( 41 ). Ben-Shoshan and colleagues demonstrated that 1,25(OH) 2 D inhibited angiogenesis by reducing HIF-1α

Open access

Darling M Rojas-Canales, Michaela Waibel, Aurelien Forget, Daniella Penko, Jodie Nitschke, Fran J Harding, Bahman Delalat, Anton Blencowe, Thomas Loudovaris, Shane T Grey, Helen E Thomas, Thomas W H Kay, Chris J Drogemuller, Nicolas H Voelcker and Patrick T Coates

WJ O’Connell PJ Stolp J Grey S Loudovaris T Kay TW. Hypoxia-inducible factor-1α (HIF-1α) potentiates β-cell survival after islet transplantation of human and mouse islets . Cell Transplantation 2013

Open access

E T Aristizabal Prada and C J Auernhammer

-1α and c-Met activation and increased tumour invasion and metastasis ( 110 , 111 , 112 ). In contrast, treatment with the dual VEGFR/c-Met inhibitor cabozantinib (XL184) or the c-Met inhibitor PF-04217903 reduces invasion and metastasis ( 110