Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis

Harmeet M Malhi, Steven F. Bronk, Nathan W. Werneburg, Gregory James Gores

Research output: Contribution to journalArticle

462 Citations (Scopus)

Abstract

Elevated serum free fatty acids (FFAs) and hepatocyte lipoapoptosis are features of non-alcoholic fatty liver disease. However, the mechanism by which FFAs mediate lipoapoptosis is unclear. Because JNK activation is pivotal in both the metabolic syndrome accompanying non-alcoholic fatty liver disease and cellular apoptosis, we examined the role of JNK activation in FFA-induced lipoapoptosis. Multiple hepatocyte cell lines and primary mouse hepatocytes were treated in culture with monounsaturated fatty acids and saturated fatty acids. Despite equal cellular steatosis, apoptosis and JNK activation were greater during exposure to saturated versus monounsaturated FFAs. Inhibition of JNK, pharmacologically as well as genetically, reduced saturated FFA-mediated hepatocyte lipoapoptosis. Cell death was caspase-dependent and associated with mitochondrial membrane depolarization and cytochrome c release indicating activation of the mitochondrial pathway of apoptosis. JNK-dependent lipoapoptosis was associated with activation of Bax, a known mediator of mitochondrial dysfunction. As JNK can activate Bim, a BH3 domain-only protein capable of binding to and activating Bax, its role in lipoapoptosis was also examined. Small interfering RNA-targeted knock-down of Bim attenuated both Bax activation and cell death. Collectively the data indicate that saturated FFAs induce JNK-dependent hepatocyte lipoapoptosis by activating the proapoptotic Bcl-2 proteins Bim and Bax, which trigger the mitochondrial apoptotic pathway.

Original languageEnglish (US)
Pages (from-to)12093-12101
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number17
DOIs
StatePublished - Apr 28 2006

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Nonesterified Fatty Acids
Hepatocytes
Chemical activation
Monounsaturated Fatty Acids
Fatty Acids
Cell death
Apoptosis
Liver
Cell Death
bcl-2-Associated X Protein
Depolarization
Mitochondrial Membranes
Caspases
Cytochromes c
Protein Binding
Small Interfering RNA
Proteins
Cells
Membranes
Cell Line

ASJC Scopus subject areas

  • Biochemistry

Cite this

Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. / Malhi, Harmeet M; Bronk, Steven F.; Werneburg, Nathan W.; Gores, Gregory James.

In: Journal of Biological Chemistry, Vol. 281, No. 17, 28.04.2006, p. 12093-12101.

Research output: Contribution to journalArticle

Malhi, Harmeet M ; Bronk, Steven F. ; Werneburg, Nathan W. ; Gores, Gregory James. / Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 17. pp. 12093-12101.
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