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Tacrolimus (FK506) prevents early stages of ethanol induced hepatic fibrosis by targeting LARP6 dependent mechanism of collagen synthesis.

Title: Tacrolimus (FK506) prevents early stages of ethanol induced hepatic fibrosis by targeting LARP6 dependent mechanism of collagen synthesis.
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Name(s): Manojlovic, Zarko, author
Blackmon, John, author
Stefanovic, Branko, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2013-06-03
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Tacrolimus (FK506) is a widely used immunosuppressive drug. Its effects on hepatic fibrosis have been controversial and attributed to immunosuppression. We show that in vitro FK506, inhibited synthesis of type I collagen polypeptides, without affecting expression of collagen mRNAs. In vivo, administration of FK506 at a dose of 4 mg/kg completely prevented development of alcohol/carbon tetrachloride induced liver fibrosis in rats. Activation of hepatic stellate cells (HSCs) was absent in the FK506 treated livers and expression of collagen α2(I) mRNA was at normal levels. Collagen α1(I) mRNA was increased in the FK506 treated livers, but this mRNA was not translated into α1(I) polypeptide. No significant inflammation was associated with the fibrosis model used. FK506 binding protein 3 (FKBP3) is one of cellular proteins which binds FK506 with high affinity. We discovered that FKBP3 interacts with LARP6 and LARP6 is the major regulator of translation and stability of collagen mRNAs. In the presence of FK506 the interaction between FKBP3 and LARP6 is weakened and so is the pull down of collagen mRNAs with FKBP3. We postulate that FK506 inactivates FKBP3 and that lack of interaction of LARP6 and FKBP3 results in aberrant translation of collagen mRNAs and prevention of fibrosis. This is the first report of such activity of FK506 and may renew the interest in using this drug to alleviate hepatic fibrosis.
Identifier: FSU_pmch_23755290 (IID), 10.1371/journal.pone.0065897 (DOI), PMC3670911 (PMCID), 23755290 (RID), 23755290 (EID), PONE-D-13-06089 (PII)
Grant Number: F31 AA019845, 5R01DK059466-08, AA019845-01A1
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670911.
Subject(s): Animals
Autoantigens/genetics
Autoantigens/metabolism
Carbon Tetrachloride
Collagen Type I/antagonists & inhibitors
Collagen Type I/biosynthesis
Collagen Type I/genetics
Ethanol
Gene Expression Regulation/drug effects
HEK293 Cells
Hepatic Stellate Cells/drug effects
Hepatic Stellate Cells/metabolism
Hepatic Stellate Cells/pathology
Humans
Immunosuppressive Agents/pharmacology
Liver/drug effects
Liver/metabolism
Liver/pathology
Liver Cirrhosis/chemically induced
Liver Cirrhosis/metabolism
Liver Cirrhosis/pathology
Liver Cirrhosis/prevention & control
Male
Primary Cell Culture
Rats
Rats, Wistar
Ribonucleoproteins/antagonists & inhibitors
Ribonucleoproteins/genetics
Ribonucleoproteins/metabolism
Tacrolimus/pharmacology
Tacrolimus Binding Proteins/genetics
Tacrolimus Binding Proteins/metabolism
Tissue Culture Techniques
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_23755290
Owner Institution: FSU
Is Part Of: PloS one.
1932-6203
Issue: iss. 6, vol. 8

Choose the citation style.
Manojlovic, Z., Blackmon, J., & Stefanovic, B. (2013). Tacrolimus (FK506) prevents early stages of ethanol induced hepatic fibrosis by targeting LARP6 dependent mechanism of collagen synthesis. Plos One. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_23755290