Metformin Suppresses Expression of the Selenoprotein P Gene via an AMP-activated Kinase (AMPK)/FoxO3a Pathway in H4IIEC3 Hepatocytes

Takayama, Hiroaki; Makino, Hírofumi; Iwama, Hisakazu; Chikamoto, Keita; Saito, Yoshiro; Murao, Koji; Teraguchi, Atsushi; Lan, Fei; Kikuchi, Akihiro; Saito, Reina; Tajima, Natsumi; Shirasaki, Takayoshi; Matsugo, Seiichi; Miyamoto, Ken Ichi; Kaneko, Shuichi; Takamura, Toshinari

doi:10.1074/jbc.m113.479386

Cited by 72 publications

(61 citation statements)

References 43 publications

(23 reference statements)

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“…However, reserpine inhibited the FHRE-Luc, and metformin, a well known AMPK activator, also inhibited FHRE-Luc activity. 18 These results suggest that there exist another signaling link between AMPK and FOXO3a dependent transcription.…”

Section: 6mentioning

confidence: 74%

Reserpine treatment activates AMP activated protein kinase (AMPK)

et al. 2017

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− Reserpine is a well-known medicine for the treatment of hypertension, however the role of reserpine in cell signaling is not fully understood. Here, we report that reserpine treatment induces the phosphorylation of AMP activated protein kinase (AMPK) at threonine 172 (T172) in PC12 cells. Phosphorylation of AMPK T172 is regulated by upstream signaling molecules, and the increase of phospho-T172 indicates that AMPK is activated. When we examined the FOXO3a dependent transcription by using the FHRE-Luc reporter assay, reserpine treatment repressed the FHRE-Luc reporter activity in a dose dependent manner. Finally, we showed that reserpine treatment induced the phosphorylation of AMPK as well as cell death in MCF-7 cells. These results suggest that AMPK is a potential cellular target of reserpine.

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Section: 6mentioning

confidence: 74%

Reserpine treatment activates AMP activated protein kinase (AMPK)

et al. 2017

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“…Metformin, a biguanide that is used primarily to treat type 2 diabetes, has been reported to activate FOXO3 or its activator, AMPK, in various cell lines and in hepatocytes. 28,[30][31][32][33][34]67 We first determined the effect of metformin on FOXO3 expression and activity in human erythroid progenitor cells and found that metformin (1) We then treated human HSPCs with metformin to test our hypothesis that HbF could be induced. Our rationale was that, because knockdown of FOXO3 results in a decline in HbF, an increase in FOXO3 via drug induction would result in an increase in HbF (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…[27][28][29] Metformin, a biguanide class agent commonly used as an oral antidiabetic drug, has been shown to activate FOXO3 in nonerythroid cell lines and hepatocytes. 28,[30][31][32][33][34] Here, we investigate the role of FOXO3 in g-globin gene regulation through lentiviral expression, RNA interference, and induction by metformin.…”

Section: Introductionmentioning

confidence: 99%

Metformin induces FOXO3-dependent fetal hemoglobin production in human primary erythroid cells

Zhang

Paikari

Sumazin

et al. 2018

Blood

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Induction of red blood cell (RBC) fetal hemoglobin (HbF; α2γ2) ameliorates the pathophysiology of sickle cell disease (SCD) by reducing the concentration of sickle hemoglobin (HbS; α2β2) to inhibit its polymerization. Hydroxyurea (HU), the only US Food and Drug Administration (FDA)-approved drug for SCD, acts in part by inducing HbF; however, it is not fully effective, reflecting the need for new therapies. Whole-exome sequence analysis of rare genetic variants in SCD patients identified as a candidate regulator of RBC HbF. We validated these genomic findings through loss- and gain-of-function studies in normal human CD34 hematopoietic stem and progenitor cells induced to undergo erythroid differentiation. gene silencing reduced γ-globin RNA levels and HbF levels in erythroblasts, whereas overexpression of FOXO3 produced the opposite effect. Moreover, treatment of primary CD34 cell-derived erythroid cultures with metformin, an FDA-approved drug known to enhance FOXO3 activity in nonerythroid cells, caused dose-related FOXO3-dependent increases in the percentage of HbF protein and the fraction of HbF-immunostaining cells (F cells). Combined HU and metformin treatment induced HbF additively and reversed the arrest in erythroid maturation caused by HU treatment alone. HbF induction by metformin in erythroid precursors was dependent on FOXO3 expression and did not alter expression of BCL11A, MYB, or KLF1. Collectively, our data implicate FOXO3 as a positive regulator of γ-globin expression and identify metformin as a potential therapeutic agent for SCD.

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“…However, the role of SeP in NAFLD remains to be well elucidated, even if they are able to act, as mentioned earlier, by their ability to modulate inflammatory response and insulin resistance. In addition, different evidence suggests that metformin improves systemic insulin sensitivity through the regulation of SeP production, suggesting a novel potential therapeutic approach to treating type 2 diabetes [185]. …”

Section: Liver-released Compoundsmentioning

confidence: 99%

Pathophysiology of Non Alcoholic Fatty Liver Disease

Petta

Gastaldelli

Rebelos

et al. 2016

IJMS

135

103

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The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation.

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Metformin Suppresses Expression of the Selenoprotein P Gene via an AMP-activated Kinase (AMPK)/FoxO3a Pathway in H4IIEC3 Hepatocytes

Cited by 72 publications

References 43 publications

Reserpine treatment activates AMP activated protein kinase (AMPK)

Reserpine treatment activates AMP activated protein kinase (AMPK)

Metformin induces FOXO3-dependent fetal hemoglobin production in human primary erythroid cells

Pathophysiology of Non Alcoholic Fatty Liver Disease

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