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J Biol Chem. 2009 Sep 25;284(39):26591-602. doi: 10.1074/jbc.M109.022491. Epub 2009 Jul 28.

JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis.

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1
Miles and Shirley Fitterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.

Abstract

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.

PMID:
19638343
PMCID:
PMC2785347
DOI:
10.1074/jbc.M109.022491
[Indexed for MEDLINE]
Free PMC Article

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