Quantitative In Vivo Proteomics of Metformin Response in Liver Reveals AMPK-Dependent and -Independent Signaling Networks

Stein, Benjamin D.; Calzolari, Diego; Hellberg, Kristina; Hu, Ying; He, Lin; Hung, Chien-Min; Toyama, Erin Quan; Ross, Debbie S.; Lillemeier, Björn F.; Cantley, Lewis C.; Yates, John R.; Shaw, Reuben J.

doi:10.1016/j.celrep.2019.10.117

Cited by 37 publications

(33 citation statements)

References 108 publications

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“…We can exclude a role for AMPK activation in the G6P-lowering mechanism because metformin was equally effective in AMPK-KO hepatocytes. However, we cannot exclude involvement of other stress kinases like PKD and MK2 that may be activated through LKB1-independent mechanisms at high metformin (67). In this study, high substrate challenge showed trends of lower AMPK phosphorylation basally and with low metformin (0.2 mM) but enhanced AMPK phosphorylation with high metformin (0.5 mM), indicating that raised hexose phosphates do not antagonize AMPK activation by the canonical pathway.…”

Section: Metformin Lowers Glucose 6-phosphate In Hepatocytescontrasting

confidence: 57%

Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation

Moonira

Chachra

Ford

et al. 2020

Journal of Biological Chemistry

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The chronic effects of metformin on liver gluconeogenesis involve repression of the G6pc gene, which is regulated by the carbohydrate-response element–binding protein through raised cellular intermediates of glucose metabolism. In this study we determined the candidate mechanisms by which metformin lowers glucose 6-phosphate (G6P) in mouse and rat hepatocytes challenged with high glucose or gluconeogenic precursors. Cell metformin loads in the therapeutic range lowered cell G6P but not ATP and decreased G6pc mRNA at high glucose. The G6P lowering by metformin was mimicked by a complex 1 inhibitor (rotenone) and an uncoupler (dinitrophenol) and by overexpression of mGPDH, which lowers glycerol 3-phosphate and G6P and also mimics the G6pc repression by metformin. In contrast, direct allosteric activators of AMPK (A-769662, 991, and C-13) had opposite effects from metformin on glycolysis, gluconeogenesis, and cell G6P. The G6P lowering by metformin, which also occurs in hepatocytes from AMPK knockout mice, is best explained by allosteric regulation of phosphofructokinase-1 and/or fructose bisphosphatase-1, as supported by increased metabolism of [3-3H]glucose relative to [2-3H]glucose; by an increase in the lactate m2/m1 isotopolog ratio from [1,2-13C2]glucose; by lowering of glycerol 3-phosphate an allosteric inhibitor of phosphofructokinase-1; and by marked G6P elevation by selective inhibition of phosphofructokinase-1; but not by a more reduced cytoplasmic NADH/NAD redox state. We conclude that therapeutically relevant doses of metformin lower G6P in hepatocytes challenged with high glucose by stimulation of glycolysis by an AMP-activated protein kinase–independent mechanism through changes in allosteric effectors of phosphofructokinase-1 and fructose bisphosphatase-1, including AMP, Pi, and glycerol 3-phosphate.

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Section: Metformin Lowers Glucose 6-phosphate In Hepatocytescontrasting

confidence: 57%

Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation

Moonira

Chachra

Ford

et al. 2020

Journal of Biological Chemistry

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“…This indicates the ER as a potential base for alternative activation of AMPK by CAMKK2 through effects on calcium levels. In line with this, multiple studies have now demonstrated a relationship between AMPK and the ER-localized protein stromal interaction molecule 2 (STIM2) (Chauhan et al, 2019;Nelson et al, 2019;Stein et al, 2019). From these studies STIM2 appears to complex with AMPK and CAMKK2 at the ER.…”

Section: Linking Diverse Activating Inputs Of Ampk At the Ermentioning

confidence: 74%

AMPK: restoring metabolic homeostasis over space and time

2021

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The evolution of AMPK and its homologs enabled exquisite responsivity and control of cellular energetic homeostasis. Recent work has been critical in establishing the mechanisms that determine AMPK activity, novel targets of AMPK action, and the distribution of AMPK-mediated control networks across the cellular landscape. The role of AMPK as a hub of metabolic control has led to intense interest in pharmacologic activation as a therapeutic avenue for a number of disease states, including obesity, diabetes, and cancer. As such, critical work on the compartmentalization of AMPK, its downstream targets, and the systems it influences has progressed in recent years. The variegated distribution of AMPK-mediated control of metabolic homeostasis has revealed key insights into AMPK in normal biology and future directions for AMPK-based therapeutic strategies. ll

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“…In the rest part of this study, we further investigated the potential molecular mechanism of C-176 in mediating anti-inflammatory effects under SAH condition. AMP-activated protein kinase (AMPK) is a heterotrimeric protein that functions as a key energy sensor and plays an important role in maintaining metabolism homeostasis by upregulating lipid oxidation and mitochondrial biogenesis [57]. In addition, AMPK has also been identified to be an important regulator of autophagy through upregulating the activity of Unc-51-like autophagy-activating kinase 1 (ULK1) [58].…”

Section: Discussionmentioning

confidence: 99%

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

Peng

Zhuang

Ying

et al. 2020

J Neuroinflammation

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Background: Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. Methods: A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro. Results: STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1β, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust antiinflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro.

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Quantitative In Vivo Proteomics of Metformin Response in Liver Reveals AMPK-Dependent and -Independent Signaling Networks

Cited by 37 publications

References 108 publications

Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation

Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation

AMPK: restoring metabolic homeostasis over space and time

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

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