Elevated expression of forkhead box protein O1 (FoxO1) in alcohol-induced intestinal barrier dysfunction

Wang, Ying; Tong, Jing; Zou, Dawei; Chang, Bing; Wang, Baifang; Wang, Bingyuan

doi:10.1016/j.acthis.2012.12.005

Cited by 7 publications

(7 citation statements)

References 28 publications

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“…Next, considering that TNFα promotes FoxO1 nuclear accumulation [ 26 ] and ZO-1 reorganization which has been associated with impaired epithelial barrier function [ 27 ], and PTK6 knockout intestinal epithelial cells showed diminished FoxO1 nuclear accumulation [ 21 ], we hypothesized that PTK6 may mediate TNFα/IFNγ induced FoxO1 nuclear translocation and ZO-1 redistribution. Therefore, immunocytochemistry experiments were performed to visually identify nuclear accumulation of FoxO1 in PTK6-/- vs. WT YAMC after treatment with TNFα/IFNγ.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, it has been shown that nuclear accumulation of FoxO1 is necessary for the downregulation of tight junction proteins in response to cytokine stimulation in vitro [ 14 ]. Other studies have shown that FoxO1 knockdown improved ethanol induced intestinal epithelial barrier dysfunction, suggesting a potential for FoxO1 in regulating epithelial junction dynamics [ 15 ]. Taking this information together, we sought to determine whether PTK6 contributes to TNFα and IFNγ mediated epithelial barrier dysfunction in a FoxO1 dependent manner.…”

Section: Introductionmentioning

confidence: 99%

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TNFα/IFNγ Mediated Intestinal Epithelial Barrier Dysfunction Is Attenuated by MicroRNA-93 Downregulation of PTK6 in Mouse Colonic Epithelial Cells

et al. 2016

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Since inflammatory bowel diseases (IBD) represent significant morbidity and mortality in the US, the need for defining novel drug targets and inflammatory mechanisms would be of considerable benefit. Although protein tyrosine kinase 6 (PTK6, also known as breast tumor kinase BRK) has been primarily studied in an oncogenic context, it was noted that PTK6 null mice exhibited significantly enhanced colonic epithelial barrier function. Considering that the inflammatory functions of PTK6 have not yet been explored, we hypothesized that cytokines responsible for mediating IBD, such as TNFα/IFNγ, may solicit the action of PTK6 to alter barrier function. After first assessing critical mediators of TNFα/IFNγ driven epithelial barrier dysfunction, we further explored the possibility of PTK6 in this inflammatory context. In this report, we showed that PTK6 siRNA and PTK6 null young adult mouse colonic epithelial cells (YAMC) exhibited significant attenuation of TNFα/IFNγ induced barrier dysfunction as measured by electric cell-substrate impedance sensing (ECIS) assay and permeability assays. In addition, PTK6 null cells transfected with PTK6 cDNA displayed restored barrier dysfunction in response to TNFα/IFNγ, while the cells transfected with vector alone showed similar attenuation of barrier dysfunction. Furthermore, using subcellular fractionation and immunocytochemistry experiments, we found that PTK6 plays a role in FoxO1 nuclear accumulation leading to down-regulation of claudin-3, a tight junction protein. Moreover, we searched for relevant miRNA candidates putative for targeting PTK6 in order to identify and assess the impact of microRNA that target PTK6 with respect to TNFα/IFNγ induced barrier dysfunction. Subsequently, we assayed likely targets and determined their effectiveness in attenuating PTK6 expression as well as cytokine induced barrier dysfunction. Results showed that miR-93 reduced PTK6 expression and attenuated TNFα/IFNγ imposed decrease in transepithelial electrical resistance (TER), as well as excluded FoxO1 from the nucleus. Our results indicate that PTK6 may act as a novel mediator of intestinal epithelial permeability during inflammatory injury, and miR-93 may protect intestinal epithelial barrier function, at least in part, by targeting PTK6.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TNFα/IFNγ Mediated Intestinal Epithelial Barrier Dysfunction Is Attenuated by MicroRNA-93 Downregulation of PTK6 in Mouse Colonic Epithelial Cells

et al. 2016

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“…The serious consequence is that TG accumulates in the liver. The large amount of fat that accumulated in liver cells further inhibits the sensitivity of hepatocytes to insulin and forms a vicious circle (Wang et al, 2013; Gu et al, 2015). MFA can improve alcohol-induced insulin resistance and abnormal glycolipid metabolism by activating the PI3K/AKT signaling pathway in the liver.…”

Section: Discussionmentioning

confidence: 99%

Ethanol-Induced Hepatic Insulin Resistance is Ameliorated by Methyl Ferulic Acid Through the PI3K/AKT Signaling Pathway

Cheng

Yang

et al. 2019

Front. Pharmacol.

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One of the key events during the development of alcoholic liver disease (ALD) is that alcohol inhibits the insulin signaling pathway in liver and leads to disorders of glucose and lipid metabolism. Methyl ferulic acid (MFA) is a biologically active monomer isolated from the root of Securidaca inappendiculata Hasskarl. It has been reported that MFA has a hepatoprotective effect against alcohol-induced liver injury in vivo and in vitro . However, the effect of MFA on ethanol-induced insulin resistance in ALD remains unclear. In this study, we investigated whether MFA could exert protective effects against hepatic insulin resistance in ethanol-induced L-02 cells and ALD rats. ALD was induced in vivo by feeding Lieber-DeCarli diet containing 5% (w/v) alcohol for 16 weeks to Sprague-Dawley rats. Insulin resistance was induced in vitro in human hepatocyte L-02 cells with 200 mM ethanol for 24 h followed by 10-7 nM insulin for 30 min. MFA exhibited the effects of inhibited insulin resistance, reduced enzymatic capacity for hepatic gluconeogenesis, and increased hepatic glycogen synthesis both in vivo and in vitro . In addition, the results of transcriptome sequencing of liver tissues in the ethanol- and MFA-treated groups indicated that “pyruvate metabolism,” “glycolysis/gluconeogenesis,” and “fatty acid metabolism” were significantly different between ethanol- and MFA-treated groups. Further studies suggested that MFA activated the hepatic phosphatidylinositol 3-kinase (PI3K)/AKT pathway in vivo and in vitro . Taken together, these findings suggested that MFA effectively ameliorated hepatic insulin resistance in ALD at least partially by acting on the PI3K/AKT pathway.

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“…Zfp125 is induced by Foxo1, a transcription factor that mediates the transition between fed and fasting states in the liver (Fernandes et al., ). Notably, feeding an EtOH‐containing diet reportedly increases hepatic Foxo1 mRNA levels and reduces the levels of inactive phospho‐Foxo1 (Lieber et al., ), In addition, chronic EtOH feeding to mice also increases Foxo1 expression in different intestinal segments, particularly in the ileum (Wang et al., ). It is thus conceivable that in the present studies, EtOH feeding induced Zfp125 secondary to Foxo1 activation.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Inactivation of the Type 2 Deiodinase Confers Resistance to Alcoholic Liver Steatosis

Fonseca

Fernandes

Bocco

et al. 2019

Alcoholism Clin & Exp Res

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Background: A mouse with hepatocyte-specific deiodinase type II inactivation (Alb-D2KO) is resistant to diet-induced obesity, hepatic steatosis, and hypertriglyceridemia due to perinatal epigenetic modifications in the liver. This phenotype is linked to low levels of Zfp125, a hepatic transcriptional repressor that promotes liver steatosis by inhibiting genes involved in packaging and secretion of verylow-density lipoprotein.Methods: Here, we used chronic and binge ethanol (EtOH) in mice to cause liver steatosis.Results: The EtOH treatment causes a 2.3-fold increase in hepatic triglyceride content; Zfp125 levels were approximately 50% higher in these animals. In contrast, Alb-D2KO mice did not develop EtOHinduced liver steatosis. They also failed to elevate Zfp125 to the same levels, despite being on the EtOHcontaining diet for the same period of time. Their phenotype was associated with 1.3-to 2.9-fold up-regulation of hepatic genes involved in lipid transport and export that are normally repressed by Zfp125, that is, Mttp, Abca1, Ldlr, Apoc1, Apoc3, Apoe, Apoh, and Azgp1. Furthermore, genes involved in the EtOH metabolic pathway, that is, Aldh2 and Acss2, were also 1.6-to 3.1-fold up-regulated in Alb-D2KO EtOH mice compared with control animals kept on EtOH.Conclusions: EtOH consumption elevates expression of Zfp125. Alb-D2KO animals, which have lower levels of Zfp125, are much less susceptible to EtOH-induced liver steatosis.

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Elevated expression of forkhead box protein O1 (FoxO1) in alcohol-induced intestinal barrier dysfunction

Cited by 7 publications

References 28 publications

TNFα/IFNγ Mediated Intestinal Epithelial Barrier Dysfunction Is Attenuated by MicroRNA-93 Downregulation of PTK6 in Mouse Colonic Epithelial Cells

TNFα/IFNγ Mediated Intestinal Epithelial Barrier Dysfunction Is Attenuated by MicroRNA-93 Downregulation of PTK6 in Mouse Colonic Epithelial Cells

Ethanol-Induced Hepatic Insulin Resistance is Ameliorated by Methyl Ferulic Acid Through the PI3K/AKT Signaling Pathway

Hepatic Inactivation of the Type 2 Deiodinase Confers Resistance to Alcoholic Liver Steatosis

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