Regulation and Function of Trefoil Factor Family 3 Expression in the Biliary Tree

Nozaki, Isao; Lunz, John G.; Specht, Susan; Park, Jong In; Giraud, Andrew S.; Murase, Noriko; Demetris, Anthony J.

doi:10.1016/s0002-9440(10)63243-9

Cited by 43 publications

(35 citation statements)

References 46 publications

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“…40 In the biliary tract, IL-6 knockout mice were sensitive to biliary cirrhosis after bile duct ligation. 41,42 Consistent with the role of GP130/STAT3 in tissue repair, the present study demonstrated that the activation of STAT3 in airway epithelial cells following naphthalene injury was blocked in Gp130 ⌬/⌬ mice. The observation that abnormalities in bronchiolar repair were similar in Stat3 ⌬/⌬ and Gp130…”

Section: The Role Of Gp130-stat3 Signaling In Wound Repairsupporting

confidence: 84%

GP130-STAT3 Regulates Epithelial Cell Migration and Is Required for Repair of the Bronchiolar Epithelium

Kida

Mucenski

Thitoff

et al. 2008

The American Journal of Pathology

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Following injury, bronchiolar cells undergo rapid squamous metaplasia, followed by proliferation and re-establishment of the complex columnar epithelium that is characteristic of the normal airway. Mechanisms that regulate the repair of bronchiolar epithelium are of considerable relevance for understanding the pathogenesis of both acute and chronic lung diseases associated with airway remodeling. This study was designed to identify the role of the GP130-STAT3 signaling pathway during repair of the bronchiolar epithelium. STAT3 ( The respiratory epithelium is recurrently subject to injury by pathogens, particles, and toxicants. Following extensive bronchiolar injury, remaining cells undergo squamous metaplasia to maintain the epithelial barrier. Thereafter, epithelial cell proliferation and differentiation restore the normal populations of ciliated and nonciliated cells lining the bronchioles. Since acute and chronic airway injuries are associated with many pulmonary diseases, the mechanisms and cellular processes regulating repair of the respiratory epithelium are of considerable interest. Repair of the bronchiolar epithelium has been studied using various agents to cause epithelial cell injury, including naphthalene, respiratory pathogens, and inhaled toxicants (see review 1 ). Naphthalene has been used to selectively kill nonciliated bronchiolar cells in the mouse lung in vivo.2-4 Within 24 hours after naphthalene exposure, Clara cells are sloughed from the bronchiolar surface. Remaining cells, consisting primarily of ciliated cells and nonciliated, naphthalene-resistant cells, undergo squamous metaplasia and spread to maintain the epithelial lining. Dynamic changes in cell shape are accompanied by the expression of a number of transcription factors and cellular markers that are also associated with the differentiation of respiratory epithelial cells during

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Section: The Role Of Gp130-stat3 Signaling In Wound Repairsupporting

confidence: 84%

GP130-STAT3 Regulates Epithelial Cell Migration and Is Required for Repair of the Bronchiolar Epithelium

Kida

Mucenski

Thitoff

et al. 2008

The American Journal of Pathology

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“…25 Screening gene array analysis suggested that noncoordinate upregulation of the BEC SPRR2 genes might be at least partially responsible for the phenotype observed in the IL-6 À/À mice. 26 SPRR expression has not been previously described in the liver. Therefore, this initial study was carried out to investigate the (patho-)physiologic function(-s) of SPRR2 in the biliary tree.…”

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confidence: 86%

Small proline-rich proteins 2 are noncoordinately upregulated by IL-6/STAT3 signaling after bile duct ligation

Nozaki

Lunz

Specht

et al. 2005

Laboratory Investigation

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Small proline-rich proteins 2 (SPRR2) are coordinately expressed with other epidermal differential complex (EDC) genes in the skin. They function as crosslinking proteins that form bridges between other proteins that comprise the cornified cell envelope, which is the major barrier against the environment. IL-6 is invariably produced at sites of biliary tract injury and IL-6-deficient (IL-6 À/À ) mice show impaired barrier function after bile duct ligation (BDL). Screening microarray analysis identified noncoordinate expression of SPRR2 as a candidate gene that is: (a) expressed in biliary epithelial cells (BEC); (b) IL-6 responsive; and (c) potentially related to biliary barrier function. Therefore, we studied in detail the regulation of BEC SPRR2A expression, in vitro; and tested the hypothesis that if BEC SPRR2 expression contributes to biliary barrier function, it should be increased after BDL in IL-6-wild type (IL-6 þ / þ ) mice and not in IL-6 À/À mice. In vitro studies confirmed that IL-6/gp130-signaling, mediated primarily by signal transducer and activator of transcription 3 (STAT3), stimulated noncoordinate BEC SPRR2 expression. In vivo, noncoordinate upregulation of BEC SPRR2 expression after BDL was seen in the IL-6 þ / þ mice and was unrelated to squamous metaplasia. IL-6 À/À mice showed deficient BEC SPRR2 expression after BDL associated with impaired barrier function, as evidenced by smaller diameters of obstructed ducts, decreased bile volume, and an inability to form 'white bile' compared to IL-6 þ / þ mice at 12 weeks after BDL. IL-6 replacement therapy reversed the barrier defect in IL-6 À/À mice after BDL, coincident with recovery of SPRR2A expression. SPRR2 in diseased mouse and human liver localized subjacent to the apical plasma membrane of BEC lining bile ducts, but was more diffusely expressed throughout the cytoplasm of cholangioles. In conclusion, BEC IL-6/gp130/STAT3 signaling noncoordinately upregulates BEC SPRR2 that appears to contribute to modification of the biliary barrier under conditions of stress.

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“…It is also expressed in pancreatic b cells and oxytocin-secreting neurons in the hypothalamus, related to cell growth and learning and memory (Jagla et al, 2000;Fueger et al, 2008;Shi et al, 2012). This peptide is induced in biliary duct epithelial cells in biliary diseases (Srivatsa et al, 2002;Nozaki et al, 2004;Sasaki et al, 2007;Jiang et al, 2010). The TFF3 gene maps to the Obq4 obesity quantitative trait locus, which is highly associated with total calorie intake; indeed, the expression of Obq4 in the intestine is regulated by food intake (Kumar and Smith Richards, 2008;Ge et al, 2015).…”

Section: Crosstalk Of Nrf2 and Estrogen Signaling In Lipid Metabolismmentioning

confidence: 99%

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

Wei

Zou

Lee

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple biologic processes, including hepatic lipid metabolism. Estrogen exerts actions affecting energy homeostasis, including a liver fat-lowering effect. Increasing evidence indicates the crosstalk between these two molecules. The aim of this study was to evaluate whether Nrf2 modulates estrogen signaling in hepatic lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) was induced in wild-type and Nrf2-null mice fed a high-fat diet and the liver fat-lowering effect of exogenous estrogen was subsequently assessed. We found that exogenous estrogen eliminated 49% and 90% of hepatic triglycerides in wild-type and Nrf2-null mice with NAFLD, respectively. This observation demonstrates that Nrf2 signaling is antagonistic to estrogen signaling in hepatic fat metabolism; thus, Nrf2 absence results in striking amplification of the liver fat-lowering effect of estrogen. In addition, we found the association of trefoil factor 3 and fatty acid binding protein 5 with the liver fat-lowering effect of estrogen. In summary, we identified Nrf2 as a novel and potent inhibitor of estrogen signaling in hepatic lipid metabolism. Our finding may provide a potential strategy to treat NAFLD by dually targeting Nrf2 and estrogen signaling.

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Regulation and Function of Trefoil Factor Family 3 Expression in the Biliary Tree

Cited by 43 publications

References 46 publications

GP130-STAT3 Regulates Epithelial Cell Migration and Is Required for Repair of the Bronchiolar Epithelium

GP130-STAT3 Regulates Epithelial Cell Migration and Is Required for Repair of the Bronchiolar Epithelium

Small proline-rich proteins 2 are noncoordinately upregulated by IL-6/STAT3 signaling after bile duct ligation

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

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