Free Fatty Acids Induce JNK-dependent Hepatocyte Lipoapoptosis*
By H. Malhi, S. Bronk, N. Werneburg, G. Gores. Journal of Biological Chemistry, 2006
710 citations recorded by the source corpus.
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.
Subfields: Epidemiology, Immunology
View Paper: https://www.semanticscholar.org/paper/7c2df6fde1373903ae03ba1d02b674402eb32858
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Citations in the corpus
- Lipotoxicity and the gut-liver axis in NASH pathogenesis. (2018, neutral): “resistance and FA-induced lipotoxicity [37].”
- Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages (2018, positive): “We first confirmed that culturing AML12 cells in medium supplemented with palmitic and oleic acids at a high, but sub-toxic (Malhi et al., 2006), dose (500 μM) led to accumulation of visible lipid droplets within 24 to 48 hr (Figures 5A–5C).”
- Fatty Acid and Endotoxin Activate Inflammasomes in Mouse Hepatocytes that Release Danger Signals to Stimulate Immune Cells (2011, neutral): “FFAs can be recognized as endogenous danger molecules and induce inflammatory signaling and activation of nuclear factor kappa B and c-Jun N-terminal kinase–activator protein 1 pathways leading to cytokine and chemokine production.(25,26) Although TLRs detect ligands either on the cell surface or in”
- Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites (2010, background): “Apoptotic cell death appears to be central to the pathogenesis of lipotoxic injury in the liver(14,158) as it is in other tissues(12) and activation of caspases,(50) and JNK may be major effectors of this process.(10,27,159,160) Exciting progress is being made in understanding the response of the li”
- Endoplasmic Reticulum Stress in Liver Disease (2010, background): “Apoptosis and inflammation are key features of progressive NASH, and are both linked to the UPR as well.”