5-Aminoimidazole-4-Carboxamide-1-β-<scp>d</scp>-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase–Independent Effect on Glucokinase Translocation

Guigas, Bruno; Bertrand, Luc; Taleux, Nellie; Foretz, Marc; Wiernsperger, Nicolas; Vertommen, Didier; Andréelli, Fabrizio; Viollet, Benoı̂t; Hue, Louis

doi:10.2337/diabetes.55.04.06.db05-1178

Cited by 168 publications

(170 citation statements)

References 55 publications

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“…Our results cast doubt on this assertion, since, in our hands, ATP levels decreased dose-dependently above 50 M AICAr. This is consistent with previous reports that concentrations of AICAr above 0.5 mM deplete ATP levels in both hepatocytes and liver (27,37,40). Although the exact mechanism is unknown, it has been suggested that AICAr inhibits hepatic oxidative phosphorylation and glycolysis by an AMPK-independent mechanism (37,41).…”

Section: Discussionsupporting

confidence: 81%

Inhibition of Hepatic Phosphatidylcholine Synthesis by 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside Is Independent of AMP-activated Protein Kinase Activation

Jacobs

Lingrell

Dyck

et al. 2007

Journal of Biological Chemistry

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5-Aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAr), a commonly used indirect activator of AMP-activated protein kinase (AMPK), inhibits phosphatidylcholine (PC) biosynthesis in freshly isolated hepatocytes. In all nucleated mammalian cells, PC is synthesized from choline via the Kennedy (CDP-choline) pathway. The purpose of our study was to provide direct evidence that AMPK regulates phospholipid biosynthesis and to elucidate the mechanism(s) by which AMPK inhibits hepatic PC synthesis. Incubations of hepatocytes with AICAr resulted in a dose-dependent activation of AMPK and inhibition of PC biosynthesis. Surprisingly, adenoviral delivery of constitutively active AMPK did not alter PC biosynthesis. In addition, expression of dominant negative mutants of AMPK was unable to block the AICAr-dependent inhibition of PC biosynthesis, indicating that AICAr was acting independently of AMPK activation. Determination of aqueous intermediates of the CDPcholine pathway indicated that choline kinase, the first enzyme in the pathway, was inhibited by AICAr administration. Flux through the CDP-choline pathway was directly correlated to the level of intracellular ATP concentrations. Therefore, it is possible that inhibition of PC biosynthesis is another process by which the cell can reduce ATP consumption in times of energetic stress. However, unlike cholesterol and triacylglycerol biosynthesis, PC production is not regulated by AMPK. Phosphatidylcholine (PC)4 is quantitatively the most important phospholipid in mammalian membranes, is the primary phospholipid in bile and in plasma lipoproteins, and is a precursor for the synthesis of sphingomyelin and phosphatidylserine. In nucleated cells, PC biosynthesis occurs via the Kennedy (CDP-choline) pathway. Choline kinase (CK), the enzyme catalyzing the first committed step in this pathway, phosphorylates choline to form phosphocholine. Choline kinase is not considered an important site in regulating PC biosynthesis (1-3); however, deletion of the CK␤ isoform results in muscular dystrophy in mice due to lack of PC in muscle (4). CTP:phosphocholine cytidylyltransferase (CT), which catalyzes the rate-limiting conversion of phosphocholine to CDPcholine (1-3), is the most extensively studied enzyme in the Kennedy pathway. CT is found in soluble cell and tissue extracts and bound to membranes. The active form of CT in cells is considered to be membrane-associated, whereas the soluble form is thought to be an inactive reservoir (5, 6). Movement of CT to and from the membrane is linked to cell requirements for PC and is tightly regulated (7-14). The lipid binding domain and the highly phosphorylated C terminus of CT are typically involved in regulating its activity. The last enzyme in the pathway, CDP-choline:1,2-diacylglycerol cholinephosphotransferase, is in excess in cells and thus does not determine the rate of PC biosynthesis. This reaction requires the availability of diacylglycerol, which is synthesized from fatty acids and glycerol.Hepatocytes are unique in that they can a...

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Section: Discussionsupporting

confidence: 81%

Inhibition of Hepatic Phosphatidylcholine Synthesis by 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside Is Independent of AMP-activated Protein Kinase Activation

Jacobs

Lingrell

Dyck

et al. 2007

Journal of Biological Chemistry

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“…Other groups have evidenced that metformin mediates its effects independently of AMPK. For example, Hue's group has recently shown that effects of metformin and AICAR on the function of glucokinase in hepatocytes are still observed in mice lacking a1 and a2 catalytic units (Guigas et al, 2006). These considerations highlight the increasing importance of confirming that the effects of metformin are mediated or not by AMPK using appropriate molecular tools targeting both catalytic units.…”

Section: Discussionmentioning

confidence: 99%

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

et al. 2008

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Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G 0 /G 1 . This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27 kip protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.

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“…44 Indeed, the AMPK-independent effects of AICAR have been observed in other cases. 48,49 Furthermore, this suppressive effect may be cell-type specific because in both murine embryonic fibroblasts and HCT116 colon cancer cells, AICAR and metformin are able to induce autophagy in a p53-dependent manner. 50 Glycogen Autophagy and Neonatal Survival.…”

Section: Effect Of Energy Level and Ampk In Autophagy Induction In Hementioning

confidence: 99%

Autophagy in the liver

2008

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A great part of our current understanding of mammalian macroautophagy is derived from studies of the liver. The term "autophagy" was introduced by Christian de Duve in part based on ultrastructural changes in rat liver following glucagon injection. Subsequent morphological, biochemical, and kinetics studies of autophagy in the liver defined the basic process of autophagosome formation, maturation, and degradation and the regulation of autophagy by hormones, phosphoinositide 3-kinases, and mammalian target of rapamycin. It is now clear that macroautophagy in the liver is important for the balance of energy and nutrients for basic cell functions, the removal of misfolded proteins resulting from genetic mutations or pathophysiological stimulations, and the turnover of major subcellular organelles such as mitochondria, endoplasmic reticulum, and peroxisomes under both normal and pathophysiological conditions. Disturbance of autophagy function in the liver could thus have a major impact on liver physiology and liver disease. (HEPATOLOGY 2008;47: 1773-1785.)

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5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase–Independent Effect on Glucokinase Translocation

Cited by 168 publications

References 55 publications

Inhibition of Hepatic Phosphatidylcholine Synthesis by 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside Is Independent of AMP-activated Protein Kinase Activation

Inhibition of Hepatic Phosphatidylcholine Synthesis by 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside Is Independent of AMP-activated Protein Kinase Activation

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

Autophagy in the liver

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