Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism

Matsumoto, Michihiro; Han, Seongah; Kitamura, Tadahiro; Accili, Domenico

doi:10.1172/jci27047

Cited by 283 publications

(359 citation statements)

References 52 publications

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“…Previous studies indicate that FOXO1 overexpression in the liver increased hepatic triacylglycerol content, owing to increased triacylglycerol synthesis [40,41], while recent studies suggest that FOXO proteins suppress hepatic lipogenesis and triacylglycerol levels [42,43]. In this study we show that overexpression of FOXQ1 decreases hepatic and serum triacylglycerol contents in db/db and DIO mice.…”

Section: Discussionsupporting

confidence: 50%

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

et al. 2016

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Aim/hypothesis Hepatic forkhead box q1 (FOXQ1) expression levels are regulated by nutritional and pathophysiological status. In this study we investigated the role of FOXQ1 in the regulation of hepatic gluconeogenesis. Methods We used multiple mouse and cell models to study the role of FOXQ1 in regulating expression of gluconeogenic genes, and cellular and hepatic glucose production. Results Expression of hepatic FOXQ1 was regulated by fasting in normal mice and was dysregulated in diabetic mice. Overexpression of FOXQ1 in primary hepatocytes inhibited expression of gluconeogenic genes and decreased cellular glucose output. Hepatic FOXQ1 rescue in db/db and high-fat diet-induced obese mice markedly decreased blood glucose level and improved glucose intolerance. In contrast, wildtype C57 mice with hepatic FOXQ1 deficiency displayed increased blood glucose levels and impaired glucose tolerance. Interestingly, studies into molecular mechanisms indicated that FOXQ1 interacts with FOXO1, thereby blocking FOXO1 activity on hepatic gluconeogenesis, preventing it from directly binding to insulin response elements mapped in the promoter region of gluconeogenic genes. Conclusions/interpretation FOXQ1 is a novel factor involved in regulating hepatic gluconeogenesis, and the decreased FOXQ1 expression in liver may contribute to the development of type 2 diabetes.

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Section: Discussionsupporting

confidence: 50%

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

et al. 2016

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“…Although FOXO1 is a well-known downstream substrate of Akt, FOXO1 was shown to enhance Akt phosphorylation in hepatocytes [17]. directly increased and decreased the expressions of p110a, the class I PI3K catalytic subunit, and pAkt, the active form of Akt, respectively (Fig.…”

Section: Foxo1 Activation Enhances Pi3k/akt Activitymentioning

confidence: 95%

The forkhead transcription factor FOXO1 mediates cisplatin resistance in gastric cancer cells by activating phosphoinositide 3-kinase/Akt pathway

Park

Yoon

et al. 2013

Gastric Cancer

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Background Cisplatin (CDDP) is one of the most important chemotherapeutic agents in the treatment of advanced gastric cancer, but its efficacy is limited by CDDP resistance. Because the transcription factor FOXO1 is related to chemoresistance in various cancer cells, we investigated the function of FOXO1 in CDDP resistance in human gastric cancer cells. Methods Human gastric cancer cell lines MKN45 and SNU-601 were used. FOXO1 activation was modulated by transfection of FOXO1 AAA mutant gene or FOXO1 shRNA. The effects of FOXO1 on cell growth and CDDP cytotoxicity were assessed by crystal violet assay. Protein expressions of FOXO1, p110a, pAkt, and Akt were analyzed by Western blotting, and FOXO1 mRNA expression was evaluated by semiquantitative reverse transcription-polymerase chain reaction. FOXO1 activity was determined by luciferase reporter assay, and cell apoptosis was assessed by DAPI staining and Western blotting for PARP cleavage. Results Cisplatin treatment induced FOXO1 expression and activation in both gastric cancer cell lines. FOXO1 overexpression increased the CDDP resistance without changes in cell growth, whereas FOXO1 silencing enhanced CDDP cytotoxicity along with apoptotic characteristics. Both constitutive and CDDP-induced FOXO1 activations were accompanied by an increase in p110a and pAkt expression. Furthermore, Akt inhibition by LY294002 treatment restored the CDDP cytotoxicity that was suppressed by FOXO1 overexpression. Conclusion FOXO1 inhibits CDDP-induced apoptosis in gastric cancer cells via activating PI3K/Akt pathway. Thus, FOXO1 may be an useful pharmacological indicator to predict CDDP efficacy in gastric cancer treatment.

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“…In the cytoplasm, Tribs direct the proteosomal degradation of key signaling proteins, including ACC1 (Qi et al, 2006), SMURF1, FoxO (Matsumoto et al, 2006) and C/ EBP Naiki et al, 2007;Selim et al, 2007;Dedhia et al, 2010;Keeshan et al, 2010;Grandinetti et al, 2011). Also in the cytoplasm, Tribs bind to inactivate LAP (Naiki et al, 2007), MKKs (Kiss-Toth et al, 2004;Wang et al, 2011), and Akt (Du et al, 2003).…”

Section: Subcellular Localization Of Tribsmentioning

confidence: 99%

Developmental roles of tribbles protein family members

Dobens

Bouyain

2012

Developmental Dynamics

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The gene tribbles (trbl), identified 12 years ago in genetic screens for mutations that control both cell division and cell migration during embryonic Drosophila development, is the founding member of the Tribbles (Trib) family of kinase-like proteins that have diverse roles in cell signaling, tissue homeostasis, and cancer. Trib proteins share three motifs: (1) a divergent kinase region (Trib domain) with undetermined catalytic activity, (2) a COP1 site used to direct key target proteins to the proteosome for degradation, and (3) a MEK1 site that binds and modulates MAPKK kinase activity. The notion that Tribs act as scaffolding proteins to balance signaling levels in multiple pathways retains an attractive simplicity, but given recent data showing that divergent kinases act by means of novel catalytic mechanisms, the enzymatic activity of Tribs remains untested. Here, we focus on the role of Tribs during development. Developmental analysis of Drosophila trbl phenotypes reveals tissue-specific, sometimes contradictory roles. In mammals, multiple Trib isoforms exhibit overlapping and tissue-specific functions. Recent data indicate the mechanism of Trib activity is conserved and requires the Trib domain. Finally, we discuss the connections between Tribs in disease and cancer that have implications for their normal roles during organogenesis.

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Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism

Cited by 283 publications

References 52 publications

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

The forkhead transcription factor FOXO1 mediates cisplatin resistance in gastric cancer cells by activating phosphoinositide 3-kinase/Akt pathway

Developmental roles of tribbles protein family members

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