Transcriptional reprogramming in murine liver defines the physiologic consequences of biliary obstruction

Campbell, Kathleen; Sabla, Gregg; Bezerra, Jorge A.

doi:10.1016/j.jhep.2003.09.025

Cited by 16 publications

(15 citation statements)

References 38 publications

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“…We then mined the platform by using the Drawable Gene function of the software to select genes uniquely up-regulated at each time before and after CCl 4 injection, with baseline levels at all other time points in Plg ϩ and Plg o mice. This approach allows for the identification of genes expressed exclusively at single time points and has been successfully used to determine the molecular signatures and predominant physiologic consequences of hepatobiliary obstruction (11).…”

Section: Methodsmentioning

confidence: 99%

Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice

Shanmukhappa

Mourya

Sabla

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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In multiple systems, impaired proteolysis associated with the loss of the hemostatic factor plasminogen (Plg) results in fibrin-dependent defects in tissue repair. However, repair within the liver is known to be defective in Plg-deficient (Plg o ) mice independent of fibrin clearance and appears to be compromised in part by the poor clearance of necrotic cells. Based on these findings, we examined the hepatic transcriptome after injury in search of transcriptional programs that are sensitive to the Plg͞fibrinogen system. To this end, we generated biotinylated cRNA pools from livers of Plg o mice and controls before and after a single dose of the hepatotoxin carbon tetrachloride and hybridized them against high-density oligonucleotide arrays. Analysis of the gene expression platform identified an unexpected transcriptional signature within challenged livers of Plg o mice for pancreatic gene products, including trypsinogen-2, amylase-2, elastase-1, elastase-2, and cholesterylester lipase. Validation studies found that this transcriptional program also contained products of the endocrine pancreas (Reg-1 and insulin genes) and the expression of the pancreatic transcription factors p48 and PDX-1. By using a LacZ transgene to trace the cellular source of pancreatic gene expression, we found that PDX-1 was expressed in albumin-positive cells that were morphologically indistinguishable from hepatocytes, and in albumin-negative epithelioid cells within zones of pericentral injury. More detailed studies revealed that the mechanisms of heterotopic gene expression in Plg o mice required fibrin(ogen). Collectively, these data reveal a regulatory role for the hemostatic factors plasmin(ogen) and fibrin(ogen) in cellular plasticity within adult tissues of the digestive system. development ͉ differentiation ͉ regeneration

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Section: Methodsmentioning

confidence: 99%

Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice

Shanmukhappa

Mourya

Sabla

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…In 1 study, the functional classification of genes differentially expressed at different times after the ligation of extrahepatic bile ducts identified a transcriptional reprogramming that correlated with predominant physiologic consequences of bile flow. 86 In the second study, the liver overexpressed plasminogen activator inhibitor-1 (PAI-1) following duct ligation. 87 The investigators then subjected PAI-1-deficient mice to bile duct ligation and showed that the loss of PAI-1 protected the liver from cholestasis-induced liver cell necrosis.…”

Section: New Insights Into the Etiology And Pathogenesismentioning

confidence: 99%

Screening and outcomes in biliary atresia

et al. 2007

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Biliary atresia is the most common cause of end-stage liver disease in the infant and is the leading pediatric indication for liver transplantation in the United States. Earlier diagnosis (<30-45 days of life) is associated with improved outcomes following the Kasai portoenterostomy and longer survival with the native liver. However, establishing this diagnosis is problematic because of its rarity, the much more common indirect hyperbilirubinemia that occurs in the newborn period, and the schedule for routine infant health care visits in the United States. The pathogenesis of biliary atresia appears to involve immune-mediated fibro-obliteration of the extrahepatic and intrahepatic biliary tree in most patients and defective morphogenesis of the biliary system in the remainder. The determinants of the outcome of portoenterostomy include the age at surgery, the center's experience, the pres-

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“…Bezerra gave several examples of his own work that emphasizes the power of this approach; he and his colleagues initially applied high-density microarrays to determine the consequences of biliary obstruction on liver gene expression. 63 Using the model of bile duct ligation in adult mice, he examined the level of expression of approximately 12,000 genes and generated a molecular footprint reflecting the activation of three biological processes that manifest in a sequential and time-restricted fashion. Initial changes were identified in genes involved in sterol metabolism.…”

Section: Genomics: Uncovering Clues Of Biology and Phenotypementioning

confidence: 99%

“…The initial hypothesis tested was that there would be differences in gene regulation in the two clinical forms of biliary atresia: the embryonic form and the acquired form. 63 Analysis of liver samples at the time of diagnosis successfully identified a highly distinctive gene expression profile. In the embryonic form, a coordinated expression of regulatory genes was observed, including those in chromatin integrity/ function.…”

Section: Genomics: Uncovering Clues Of Biology and Phenotypementioning

confidence: 99%

Intrahepatic Cholestasis: Summary of an American Association for the Study of Liver Diseases Single-Topic Conference *

et al. 2005

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Transcriptional reprogramming in murine liver defines the physiologic consequences of biliary obstruction

Cited by 16 publications

References 38 publications

Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice

Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice

Screening and outcomes in biliary atresia

Intrahepatic Cholestasis: Summary of an American Association for the Study of Liver Diseases Single-Topic Conference *

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