Loss of cooperative function of transforming growth factor-β signaling proteins, smad3 with embryonic liver fodrin, a β -spectrin, in primary biliary cirrhosis

Bibhuti Mishra, Yi Tang, Varalakshmi Katuri, Tom Fleury, Anan H. Said, Asif Rashid, Wilma Jogunoori, Lopa Mishra

Research output: Contribution to journalArticlepeer-review

Abstract

Modulation of fibrogenesis, epithelial, and mesenchymal cell fates are prominent effects of transforming growth factor-β (TGF-β) signaling by Smad proteins. We have previously shown that Smad2 and Smad3 insufficiency leads to a loss of bile ducts. In addition, Smad3/4 activity is mediated by embryonic liver fodrin (ELF), a β-Spectrin. In mouse elf-/- mutants and in liver explant cultures, loss of ELF function results in T lymphocytic proliferation and absent intrahepatic bile ducts. A similar phenotype is seen in a number of cholestatic diseases with progressive loss of intrahepatic bile ducts and fibrosis. However, the expression patterns of Smads or role of ELF in cholestatic and fibrotic liver diseases are not yet known. Methods/results: We investigated the role of ELF in primary biliary cirrhosis (PBC, autoimmune hepatitis C, chronic viral hepatitis and in livers from mice deficient in Smad2/Smad3. We generated elf+/- mutant mice and analyzed for chronic liver disease and hepatocellular cancer (HCC) from 6 to 12 months. Perturbations in ELF expression were consistently seen only in PBC tissues. ELF expression was similarly aberrant in tissues from Smad2+/-/Smad3+/- mutant mice. Further studies indicated that ELF mislocalization is correlated with aberrant localization of Smad3 in some PBC tissues. Thirteen of 17 elf+/- mutant mice developed steatosis, fibrosis, hepatic dysplasia, with HCC in two mice. Conclusions: These results suggest that a compromised cytoarchitecture and polarized trafficking of TGF-β signaling molecules, ELF and Smad3 are involved in the pathogenesis of PBC as well as HCC.

Original languageEnglish (US)
Pages (from-to)637-645
Number of pages9
JournalLiver International
Volume24
Issue number6
DOIs
StatePublished - Dec 2004

Keywords

  • Hepatocellular cancer
  • Primary biliary cirrhosis
  • Smad3
  • TGF-β

ASJC Scopus subject areas

  • Hepatology

Fingerprint Dive into the research topics of 'Loss of cooperative function of transforming growth factor-β signaling proteins, smad3 with embryonic liver fodrin, a β -spectrin, in primary biliary cirrhosis'. Together they form a unique fingerprint.

Cite this