The Experts below are selected from a list of 2517 Experts worldwide ranked by ideXlab platform
Benoit Viollet - One of the best experts on this subject based on the ideXlab platform.
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metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1 ampk pathway via a decrease in hepatic energy state
Journal of Clinical Investigation, 2010Co-Authors: Marc Foretz, Sophie Hebrard, Jocelyne Leclerc, Elham Zarrinpashneh, Maud Soty, Gilles Mithieux, Kei Sakamoto, Fabrizio Andreelli, Benoit ViolletAbstract:Metformin is widely used to treat hyperglycemia in individuals with type 2 diabetes. Recently the LKB1/AMP-activated Protein Kinase (LKB1/AMPK) pathway was proposed to mediate the action of metformin on hepatic gluconeogenesis. However, the molecular mechanism by which this pathway operates had remained elusive. Surprisingly, here we have found that in mice lacking AMPK in the liver, blood glucose levels were comparable to those in wild-type mice, and the hypoglycemic effect of metformin was maintained. Hepatocytes lacking AMPK displayed normal glucose production and gluconeogenic gene expression compared with wild-type hepatocytes. In contrast, gluconeogenesis was upregulated in LKB1-deficient hepatocytes. Metformin decreased expression of the gene encoding the catalytic subunit of glucose-6-phosphatase (G6Pase), while cytosolic phosphoenolpyruvate carboxyKinase (Pepck) gene expression was unaffected in wild-type, AMPK-deficient, and LKB1-deficient hepatocytes. Surprisingly, metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient compared with wild-type hepatocytes. This inhibition correlated in a dose-dependent manner with a reduction in intracellular ATP content, which is crucial for glucose production. Moreover, metformin-induced inhibition of glucose production was preserved under forced expression of gluconeogenic genes through PPARgamma coactivator 1alpha (PGC-1alpha) overexpression, indicating that metformin suppresses gluconeogenesis via a transcription-independent process. In conclusion, we demonstrate that metformin inhibits hepatic gluconeogenesis in an LKB1- and AMPK-independent manner via a decrease in hepatic energy state.
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hypoxic activation of ampk is dependent on mitochondrial ros but independent of an increase in amp atp ratio
Free Radical Biology and Medicine, 2009Co-Authors: Brooke M Emerling, Frank Weinberg, Colleen Snyder, Zach Burgess, Gokhan M Mutlu, Benoit Viollet, G Scott R Budinger, Navdeep S ChandelAbstract:AMP-activated Protein Kinase (AMPK) is a sensor of cellular energy status found in metazoans that is known to be activated by stimuli that increase the cellular AMP/ATP ratio. Full activation of AMPK requires specific phosphorylation within the activation loop of the catalytic domain of the α-subunit by upstream Kinases such as the serine/threonine Protein Kinase LKB1. Here we show that hypoxia activates AMPK through LKB1 without an increase in the AMP/ATP ratio. Hypoxia increased reactive oxygen species (ROS) levels and the antioxidant EUK-134 abolished the hypoxic activation of AMPK. Cells deficient in mitochondrial DNA (ρ0 cells) failed to activate AMPK during hypoxia but are able to in the presence of exogenous H2O2. Furthermore, we provide genetic evidence that ROS generated within the mitochondrial electron transport chain and not oxidative phosphorylation is required for hypoxic activation of AMPK. Collectively, these data indicate that oxidative stress and not an increase in the AMP/ATP ratio is required for hypoxic activation of AMPK.
Johan Botling - One of the best experts on this subject based on the ideXlab platform.
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The Protein Kinase LKB1 negatively regulates bone morphogenetic Protein receptor signaling.
Oncotarget, 2015Co-Authors: Erna Raja, Kalliopi Tzavlaki, Robin Vuilleumier, Karolina Edlund, Kaoru Kahata, Agata Zieba, Anita Morén, Yukihide Watanabe, Iryna Voytyuk, Johan BotlingAbstract:The Protein Kinase LKB1 regulates cell metabolism and growth and is implicated in intestinal and lung cancer. Bone morphogenetic Protein (BMP) signaling regulates cell differentiation during development and tissue homeostasis. We demonstrate that LKB1 physically interacts with BMP type I receptors and requires Smad7 to promote downregulation of the receptor. Accordingly, LKB1 suppresses BMP-induced osteoblast differentiation and affects BMP signaling in Drosophila wing longitudinal vein morphogenesis. LKB1 Protein expression and Smad1 phosphorylation analysis in a cohort of non-small cell lung cancer patients demonstrated a negative correlation predominantly in a subset enriched in adenocarcinomas. Lung cancer patient data analysis indicated strong correlation between LKB1 loss-of-function mutations and high BMP2 expression, and these two events further correlated with expression of a gene subset functionally linked to apoptosis and migration. This new mechanism of BMP receptor regulation by LKB1 has ramifications in physiological organogenesis and disease.
Per Ottar Seglen - One of the best experts on this subject based on the ideXlab platform.
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Stimulation of hepatocytic AMP-activated Protein Kinase by okadaic acid and other autophagy-suppressive toxins.
The Biochemical journal, 2005Co-Authors: Hamid R. Samari, Michael T. N. Møller, Lise Holden, Tonje Asmyhr, Per Ottar SeglenAbstract:Autophagic activity in isolated rat hepatocytes is strongly suppressed by OA (okadaic acid) and other PP (Protein phosphatase)-inhibitory toxins as well as by AICAR (5-aminoimidazole-4-carboxamide riboside), a direct activator of AMPK (AMP-activated Protein Kinase). To investigate whether AMPK is a mediator of the effects of the toxin, a phosphospecific antibody directed against the activation of phosphorylation of the AMPK alpha (catalytic)-subunit at Thr172 was used to assess the activation status of this enzyme. AICAR as well as all the toxins tested (OA, microcystin-LR, calyculin A, cantharidin and tautomycin) induced strong, dose-dependent AMPKalpha phosphorylation, correlating with AMPK activity in situ (in intact hepatocytes) as measured by the AMPK-dependent phosphorylation of acetyl-CoA carboxylase at Ser79. All treatments induced the appearance of multiple, phosphatase-sensitive, low-mobility forms of the AMPK alpha-subunit, consistent with phosphorylation at several sites other than Thr172. The flavonoid naringin, an effective antagonist of OA-induced autophagy suppression, inhibited the AMPK phosphorylation and mobility shifting induced by AICAR, OA or microcystin, but not the changes induced by calyculin A or cantharidin. AMPK may thus be activated both by a naringin-sensitive and a naringin-resistant mechanism, probably involving the PPs PP2A and PP1 respectively. Neither the Thr172-phosphorylating Protein Kinase LKB1 nor the Thr172-dephosphorylating PP, PP2C, were mobility-shifted after treatment with toxins or AICAR, whereas a slight mobility shifting of the regulatory AMPK beta-subunit was indicated. Immunoblotting with a phosphospecific antibody against pSer108 at the beta-subunit revealed a naringin-sensitive phosphorylation induced by OA, microcystin and AICAR and a naringin-resistant phosphorylation induced by calyculin A and cantharidin, suggesting that beta-subunit phosphorylation could play a role in AMPK activation. Naringin antagonized the autophagy-suppressive effects of AICAR and OA, but not the autophagy suppression caused by cantharidin, consistent with AMPK-mediated inhibition of autophagy by toxins as well as by AICAR.
David Carling - One of the best experts on this subject based on the ideXlab platform.
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LKB1 is the upstream Kinase in the AMP-activated Protein Kinase cascade.
Current Biology - CB, 2003Co-Authors: Angela Woods, Stephen R Johnstone, Kristina Dickerson, Fiona Leiper, Lee Fryer, Dietbert Neumann, Uwe Schlattner, Theo Wallimann, Marian Carlson, David CarlingAbstract:Inactivating mutations in the Protein Kinase LKB1 lead to a dominantly inherited cancer in humans termed Peutz-Jeghers syndrome. The role of LKB1 is unclear, and only one target for LKB1 has been identified in vivo [3]. AMP-activated Protein Kinase (AMPK) is the downstream component of a Protein Kinase cascade that plays a pivotal role in energy homeostasis. AMPK may have a role in protecting the body from metabolic diseases including type 2 diabetes, obesity, and cardiac hypertrophy. We previously reported the identification of three Protein Kinases (Elm1, Pak1, and Tos3 [9]) that lie upstream of Snf1, the yeast homologue of AMPK. LKB1 shares sequence similarity with Elm1, Pak1, and Tos3, and we demonstrated that LKB1 phosphorylates AMPK on the activation loop threonine (Thr172) within the catalytic subunit and activates AMPK in vitro [9]. Here, we have investigated whether LKB1 corresponds to the major AMPKK activity present in cell extracts. AMPKK purified from rat liver corresponds to LKB1, and blocking LKB1 activity in cells abolishes AMPK activation in response to different stimuli. These results identify a link between two Protein Kinases, previously thought to lie in unrelated, distinct pathways, that are associated with human diseases.
Erna Raja - One of the best experts on this subject based on the ideXlab platform.
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The Protein Kinase LKB1 negatively regulates bone morphogenetic Protein receptor signaling.
Oncotarget, 2015Co-Authors: Erna Raja, Kalliopi Tzavlaki, Robin Vuilleumier, Karolina Edlund, Kaoru Kahata, Agata Zieba, Anita Morén, Yukihide Watanabe, Iryna Voytyuk, Johan BotlingAbstract:The Protein Kinase LKB1 regulates cell metabolism and growth and is implicated in intestinal and lung cancer. Bone morphogenetic Protein (BMP) signaling regulates cell differentiation during development and tissue homeostasis. We demonstrate that LKB1 physically interacts with BMP type I receptors and requires Smad7 to promote downregulation of the receptor. Accordingly, LKB1 suppresses BMP-induced osteoblast differentiation and affects BMP signaling in Drosophila wing longitudinal vein morphogenesis. LKB1 Protein expression and Smad1 phosphorylation analysis in a cohort of non-small cell lung cancer patients demonstrated a negative correlation predominantly in a subset enriched in adenocarcinomas. Lung cancer patient data analysis indicated strong correlation between LKB1 loss-of-function mutations and high BMP2 expression, and these two events further correlated with expression of a gene subset functionally linked to apoptosis and migration. This new mechanism of BMP receptor regulation by LKB1 has ramifications in physiological organogenesis and disease.
