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Sartoretto, Juliano L.

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Sartoretto

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Juliano L.

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Sartoretto, Juliano L.
Author's Publications: search.filters.isAuthorOfPublication.03e36446-3680-4914-841a-5dc67dbdc6be

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    KLF15 Is a Molecular Link between Endoplasmic Reticulum Stress and Insulin Resistance
    (Public Library of Science, 2013) Jung, Dae Young; Chalasani, UmaDevi; Pan, Ning; Friedline, Randall H.; Prosdocimo, Domenick A.; Nam, Minwoo; Azuma, Yoshihiro; Maganti, Rajanikanth; Yu, Kristine; Velagapudi, Ashish; O’Sullivan-Murphy, Bryan; Sartoretto, Juliano L.; Jain, Mukesh K.; Cooper, Marcus P.; Urano, Fumihiko; Kim, Jason K.; Gray, Susan
    Obesity places major demands on the protein folding capacity of the endoplasmic reticulum (ER), resulting in ER stress, a condition that promotes hepatic insulin resistance and steatosis. Here we identify the transcription factor, Kruppel-like factor 15 (KLF15), as an essential mediator of ER stress-induced insulin resistance in the liver. Mice with a targeted deletion of KLF15 exhibit increased hepatic ER stress, inflammation, and JNK activation compared to WT mice; however, KLF15-/- mice are protected against hepatic insulin resistance and fatty liver under high-fat feeding conditions and in response to pharmacological induction of ER stress. The mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cellular energy homeostasis, has been shown to cooperate with ER stress signaling pathways to promote hepatic insulin resistance and lipid accumulation. We find that the uncoupling of ER stress and insulin resistance in KLF15-/- liver is associated with the maintenance of a low energy state characterized by decreased mTORC1 activity, increased AMPK phosphorylation and PGC-1α expression and activation of autophagy, an intracellular degradation process that enhances hepatic insulin sensitivity. Furthermore, in primary hepatocytes, KLF15 deficiency markedly inhibits activation of mTORC1 by amino acids and insulin, suggesting a mechanism by which KLF15 controls mTORC1-mediated insulin resistance. This study establishes KLF15 as an important molecular link between ER stress and insulin action.
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    Caveolin-1 Is a Critical Determinant of Autophagy, Metabolic Switching, and Oxidative Stress in Vascular Endothelium
    (Public Library of Science, 2014) Shiroto, Takashi; Romero, Natalia; Sugiyama, Toru; Sartoretto, Juliano L.; Kalwa, Hermann; Yan, Zhonghua; Shimokawa, Hiroaki; Michel, Thomas
    Caveolin-1 is a scaffolding/regulatory protein that interacts with diverse signaling molecules. Caveolin-1null mice have marked metabolic abnormalities, yet the underlying molecular mechanisms are incompletely understood. We found the redox stress plasma biomarker plasma 8-isoprostane was elevated in caveolin-1null mice, and discovered that siRNA-mediated caveolin-1 knockdown in endothelial cells promoted significant increases in intracellular H2O2. Mitochondrial ROS production was increased in endothelial cells after caveolin-1 knockdown; 2-deoxy-D-glucose attenuated this increase, implicating caveolin-1 in control of glycolytic pathways. We performed unbiased metabolomic characterizations of endothelial cell lysates following caveolin-1 knockdown, and discovered strikingly increased levels (up to 30-fold) of cellular dipeptides, consistent with autophagy activation. Metabolomic analyses revealed that caveolin-1 knockdown led to a decrease in glycolytic intermediates, accompanied by an increase in fatty acids, suggesting a metabolic switch. Taken together, these results establish that caveolin-1 plays a central role in regulation of oxidative stress, metabolic switching, and autophagy in the endothelium, and may represent a critical target in cardiovascular diseases.
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    Role of Ca\(^{2+}\) in the Control of H\(_2\)O\(_2\)-Modulated Phosphorylation Pathways Leading to eNOS Activation in Cardiac Myocytes
    (Public Library of Science, 2012) Shiroto, Takashi; Sartoretto, Simone M.; Pluth, Michael D.; Lippard, Stephen J.; Sartoretto, Juliano L.; Kalwa, Hermann; Michel, Thomas
    Nitric oxide (NO) and hydrogen peroxide (H\(_2\)O\(_2\)) play key roles in physiological and pathological responses in cardiac myocytes. The mechanisms whereby H\(_2\)O\(_2\)–modulated phosphorylation pathways regulate the endothelial isoform of nitric oxide synthase (eNOS) in these cells are incompletely understood. We show here that H\(_2\)O\(_2\) treatment of adult mouse cardiac myocytes leads to increases in intracellular Ca\(^{2+}\) ([Ca\(^{2+}\)]\(_i\)), and document that activity of the L-type Ca\(^{2+}\) channel is necessary for the H\(_2\)O\(_2\)-promoted increase in sarcomere shortening and of [Ca\(^{2+}\)]\(_i\). Using the chemical NO sensor Cu\(_2\)(FL2E), we discovered that the H\(_2\)O\(_2\)-promoted increase in cardiac myocyte NO synthesis requires activation of the L-type Ca\(^{2+}\) channel, as well as phosphorylation of the AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase kinase 1/2 (MEK1/2). Moreover, H\(_2\)O\(_2\)-stimulated phosphorylations of eNOS, AMPK, MEK1/2, and ERK1/2 all depend on both an increase in [Ca\(^{2+}\)]\(_i\) as well as the activation of protein kinase C (PKC). We also found that H\(_2\)O\(_2\)-promoted cardiac myocyte eNOS translocation from peripheral membranes to internal sites is abrogated by the L-type Ca\(^{2+}\) channel blocker nifedipine. We have previously shown that kinase Akt is also involved in H\(_2\)O\(_2\)-promoted eNOS phosphorylation. Here we present evidence documenting that H\(_2\)O\(_2\)-promoted Akt phosphorylation is dependent on activation of the L-type Ca\(^{2+}\)channel, but is independent of PKC. These studies establish key roles for Ca\(^{2+}\)- and PKC-dependent signaling pathways in the modulation of cardiac myocyte eNOS activation by H\(_2\)O\(_2\).