Insulin resistance and metabolic syndrome are rapidly expanding public health problems. Acting through the PI3K/Akt pathway, insulin and insulin-like growth factor-1 (IGF-1) inactivate FoxO transcription factors, a class of highly conserved proteins important in numerous physiological functions. However, even as FoxO is a downstream target of insulin, FoxO factors also control upstream signaling elements governing insulin sensitivity and glucose metabolism. Here, we report that sustained activation of either FoxO1 or FoxO3 in cardiac myocytes increases basal levels of Akt phosphorylation and kinase activity. FoxO-activated Akt directly interacts with and phosphorylates FoxO, providing feedback inhibition. We reported previously that FoxO factors attenuate cardiomyocyte calcineurin (PP2B) activity. We now show that calcineurin forms a complex with Akt and inhibition of calcineurin enhances Akt phosphorylation. In addition, FoxO activity suppresses protein phosphatase 2A (PP2A) and disrupts Akt-PP2A and Akt-calcineurin interactions. Repression of Akt-PP2A/B interactions and phosphatase activities contributes, at least in part, to FoxO-dependent increases in Akt phosphorylation and kinase activity. Resveratrol, an activator of Sirt1, increases the transcriptional activity of FoxO1 and triggers Akt phosphorylation in heart. Importantly, FoxO-mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4, and decreased insulintriggered glucose uptake. Also, inactivation of the gene coding for FoxO3 enhances insulin-dependent Akt phosphorylation. Taken together, this study demonstrates that changes in FoxO activity have a dose-responsive repressive effect on insulin signaling in cardiomyocytes through inhibition of protein phosphatases, which leads to altered Akt activation, reduced insulin sensitivity, and impaired glucose metabolism.cardiomyocyte ͉ calcineurin ͉ insulin resistance ͉ cardiomyopathy
An ADC decrease in renal fibrosis is associated with an increased number of cells, including fibroblasts. ADC has the potential to serve as a sensitive noninvasive biomarker of renal fibrosis.
The nuclear receptor pregnane X receptor (PXR) is activated by a range of xenochemicals, including chemotherapeutic drugs, and has been suggested to play a role in the development of tumor cell resistance to anticancer drugs. PXR also has been implicated as a regulator of the growth and apoptosis of colon tumors. Here, we have used a xenograft model of colon cancer to define a molecular mechanism that might underlie PXR-driven colon tumor growth and malignancy. Activation of PXR was found to be sufficient to enhance the neoplastic characteristics, including cell growth, invasion, and metastasis, of both human colon tumor cell lines and primary human colon cancer tissue xenografted into immunodeficient mice. Furthermore, we were able to show that this PXR-mediated phenotype required FGF19 signaling. PXR bound to the FGF19 promoter in both human colon tumor cells and "normal" intestinal crypt cells. However, while both cell types proliferated in response to PXR ligands, the FGF19 promoter was activated by PXR only in cancer cells. Taken together, these data indicate that colon cancer growth in the presence of a specific PXR ligand results from tumor-specific induction of FGF19. These observations may lead to improved therapeutic regimens for colon carcinomas.
R e s e a R c h a R t i c l e 4 5 4 4jci.org Volume 125 Number 12 December 2015 IntroductionVascular calcification is a major complication in patients who are aging, have diabetes, or have chronic kidney disease (CKD) and is an active process that differentiates vascular smooth muscle cells (VSMCs) into osteoblast-like cells (1, 2). This process is highly regulated by transcription factors involved in osteogenic differentiation, such as RUNX2, MSX2, and ATF4 (3-5). Several in vitro and in vivo studies have shown lipids to play a causative role in the pathogenesis of vascular calcification in addition to inorganic phosphate, inflammatory cytokines, and oxidative stress (6-13). Treatment with unsaturated fatty acids (UFAs) inhibits vascular mineralization and osteogenic differentiation (14, 15), whereas oxidized lipids, such as oxysterols and oxidized phospholipids, elicit procalcific effects in vascular cells (9,16,17). In addition to this evidence, we also previously reported that saturated fatty acids (SFAs) and calcium simultaneously accumulate during osteogenic differentiation of vascular cells (18,19). Ectopic accumulation of excess lipids, called lipotoxicity, plays a central role in the pathogenesis of cardio-metabolic diseases, including diabetes, obesity, atherosclerosis, and vascular calcification (20-24). However, evidence from a number of experimental systems is emerging, stating that SFAs and UFAs have distinct contributions to lipotoxicity (25,26). SFAs such as palmitic acid (16:0) and stearic acid (18:0) induce apoptosis, oxidative stress, and ER stress in a variety of mammalian cell lines (including hepatocytes, macrophages, and VSMCs), whereas UFAs such as oleic acid have no or minimal lipotoxic properties (5,(25)(26)(27)(28)(29)(30). In addition, cotreatment with UFAs blocks SFA-mediated lipotoxic effects (25,29). However, the specific metabolite of SFAs that induces lipotoxicity, the mechanism underlying SFA-mediated lipotoxicity, and how UFAs block SFA-mediated lipotoxicity are largely unknown.Proper intracellular SFA and UFA balance is controlled by a lipogenic enzyme called stearoyl-CoA desaturase (SCD) (31,32). SCD catalyzes the conversion of SFAs to monounsaturated FAs, mainly 16:0 into palmitoleate (16:1n-7), and 18:0 into oleate (18:1n-9) (33,34). This introduction of a double bond markedly impacts several chemical properties, including a decrease in melting point and an increase in solubility. The activation of SCD therefore neutralizes SFA-mediated lipotoxicity (5, 25). The expression of SCD is highly regulated by a number of hormonal and dietary factors (33,(35)(36)(37). Recently, we found that the accumulation of SFAs by either supplementation with exogenous SFAs or inhibition of SCD induces mineralization of VSMCs (5,19). In addition, SFA-mediated lipotoxicity and vascular calcification were completely blocked by an acyl-CoA synthetase inhibitor and were attenuated by the shRNA-mediated inhibition of fatty acid elongase-6 (Elovl6) (5), suggesting that stearoyl-CoA (18:0-CoA) or its ...
No abstract
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.