Role of AMP-activated protein kinase in mechanism of metformin action
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5,314 citations
Cites methods from "Role of AMP-activated protein kinas..."
...and was suppressed by inhibition of AMPK with compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine; ref...
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Cites background from "Role of AMP-activated protein kinas..."
...Metformin stimulates AMP-activated protein kinase (AMPK), an enzyme that inhibits lipid synthesis through phosphorylation and inactivation of key lipogenic enzymes (41)....
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...In rat hepatocytes, metformin-induced activation of AMPK also leads to decreased mRNA expression of SREBP-1c and its lipogenic target genes (41), but the basis of this effect is not understood....
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4,316 citations
Cites background from "Role of AMP-activated protein kinas..."
...Emerling BM, Viollet B, Tormos KV, Chandel NS. Compound C inhibits hypoxic activation of HIF-1 independent of AMPK....
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...Shang L, Chen S, Du F, Li S, Zhao L, Wang X. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK....
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...Compound C is an effective and widely used inhibitor of activated (phosphorylated) AMPK.(357) However, being a nonspecific inhibitor of oxidative phosphorylation,(358,359) this drug has been observed to inhibit autophagy under conditions where AMPK is already inactive or knocked out,(360) and has even been shown to stimulate autophagy by an AMP-independent mechanism....
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...In liver cells, AMPK suppresses autophagy at the level of cargo sequestration as indicated by the rapid sequestration-inhibitory effects of a variety of AMPK activators, whereas it appears to stimulate autophagy in many other cell types, including fibroblasts, colon carcinoma cells and skeletal muscle.342-351 Autophagy-promoting effects of AMPK are most evident in cells cultured in a complete medium with serum and amino acids, where cargo sequestration is otherwise largely suppressed.348 Presumably, AMPK antagonizes the autophagy-inhibitory effect of amino acids (at the level of phagophore assembly) by phosphorylating proteins involved in TORC1 signaling, such as TSC2352 and RPTOR/RAPTOR353 as well the TORC1 target ULK1 (see below).354-356 Compound C is an effective and widely used inhibitor of activated (phosphorylated) AMPK.357 However, being a nonspecific inhibitor of oxidative phosphorylation,358,359 this drug has been observed to inhibit autophagy under conditions where AMPK is already inactive or knocked out,360 and has even been shown to stimulate autophagy by an AMP-independent mechanism.359,361 Compound C thus cannot be used as a stand-alone indicator of AMPK involvement....
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...Amino acid starvation, on the other hand, can strongly induce autophagy even in cells completely lacking AMPK catalytic activity.362 AMPK and TORC1 regulate autophagy through coordinated phosphorylation of ULK1; under glucose starvation, AMPK promotes autophagy by directly activating ULK1 through phosphorylation, although the exact AMPK-mediated ULK1 phosphorylation site(s) remains unclear.351,354-356 Under conditions of nutrient sufficiency, high TORC1 activity prevents ULK1 activation by phosphorylating alternate ULK1 residues and disrupting the interaction between ULK1 and AMPK....
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4,298 citations
References
1,918 citations
"Role of AMP-activated protein kinas..." refers background in this paper
...(32) pointed out that more subtle changes in the free ATP/ADP ratio might occur with concentrations of metformin that do not suppress total ATP, but do inhibit gluconeogenesis....
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...Recent observations suggest that metformin can impair oxidative phosphorylation by inhibiting mitochondrial phosphorylation complex 1 (32, 33)....
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...In addition to the fact that high concentrations may be achieved in target tissues, membrane permeability of metformin is a time-dependent and slow process (32)....
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1,560 citations
"Role of AMP-activated protein kinas..." refers background in this paper
...Malonyl-CoA is an initial substrate for de novo fatty acid biosynthesis, and it serves as a potent inhibitor of carnitine palmitoyl transferase I (CPT-I), a rate-limiting step for fatty acid oxidation (34)....
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1,288 citations
"Role of AMP-activated protein kinas..." refers background in this paper
...Although some have reported that very high metformin concentrations (10 mM) can suppress total cellular ATP levels (25, 33), Owen et al....
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...Recent observations suggest that metformin can impair oxidative phosphorylation by inhibiting mitochondrial phosphorylation complex 1 (32, 33)....
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1,059 citations