Document Detail

JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis.
MedLine Citation:
PMID:  19638343     Owner:  NLM     Status:  MEDLINE    
Free fatty acids (FFA) induce hepatocyte lipoapoptosis by a c-Jun N-terminal kinase (JNK)-dependent mechanism. However, the cellular processes by which JNK engages the core apoptotic machinery during lipotoxicity, especially activation of BH3-only proteins, remain incompletely understood. Thus, our aim was to determine whether JNK mediates induction of BH3-only proteins during hepatocyte lipoapoptosis. The saturated FFA palmitate, but not the monounsaturated FFA oleate, induces an increase in PUMA mRNA and protein levels. Palmitate induction of PUMA was JNK1-dependent in primary murine hepatocytes. Palmitate-mediated PUMA expression was inhibited by a dominant negative c-Jun, and direct binding of a phosphorylated c-Jun containing the activator protein 1 complex to the PUMA promoter was identified by electrophoretic mobility shift assay and a chromatin immunoprecipitation assay. Short hairpin RNA-targeted knockdown of PUMA attenuated Bax activation, caspase 3/7 activity, and cell death. Similarly, the genetic deficiency of Puma rendered murine hepatocytes resistant to lipoapoptosis. PUMA expression was also increased in liver biopsy specimens from patients with non-alcoholic steatohepatitis as compared with patients with simple steatosis or controls. Collectively, the data implicate JNK1-dependent PUMA expression as a mechanism contributing to hepatocyte lipoapoptosis.
Sophie C Cazanave; Justin L Mott; Nafisa A Elmi; Steven F Bronk; Nathan W Werneburg; Yuko Akazawa; Alisan Kahraman; Sean P Garrison; Gerard P Zambetti; Michael R Charlton; Gregory J Gores
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-07-28
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-21     Completed Date:  2009-11-06     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  26591-602     Citation Subset:  IM    
Miles and Shirley Fitterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
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MeSH Terms
Anthracenes / pharmacology
Apoptosis / drug effects,  genetics,  physiology*
Apoptosis Regulatory Proteins / genetics,  metabolism*
Cell Line, Tumor
Dose-Response Relationship, Drug
Fatty Liver / genetics,  metabolism,  pathology
Gene Expression / drug effects
Hepatocytes / cytology,  drug effects,  metabolism*
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Fluorescence
Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors,  genetics,  metabolism*
Palmitates / pharmacology
Phosphorylation / drug effects
Proto-Oncogene Proteins / genetics,  metabolism*
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Proteins / genetics,  metabolism
bcl-2-Associated X Protein / metabolism
Grant Support
Reg. No./Substance:
0/Anthracenes; 0/Apoptosis Regulatory Proteins; 0/BBC3 protein, human; 0/PUMA protein, mouse; 0/Palmitates; 0/Proto-Oncogene Proteins; 0/Tumor Suppressor Proteins; 0/anthra(1,9-cd)pyrazol-6(2H)-one; 0/bcl-2-Associated X Protein; EC Protein Kinase 8

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