Lipid-induced up-regulation of human acyl-CoA synthetase 5 promotes hepatocellular apoptosis |
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Authors: | Andrea Reinartz Josef Ehling Andrea Leue Christian Liedtke Ursula Schneider Jürgen Kopitz Thomas Weiss Claus Hellerbrand Ralf Weiskirchen Ruth Knüchel Nikolaus Gassler |
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Institution: | 1. Institute of Pathology, RWTH Aachen University, Aachen, Germany;2. Department of Medicine III, RWTH Aachen University, Aachen, Germany;3. Institute of Pathology, University of Heidelberg, Heidelberg, Germany;4. Department of Surgery, University of Regensburg, Regensburg, Germany;5. Department of Internal Medicine I, University of Regensburg, Regensburg, Germany;6. Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University, Aachen, Germany |
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Abstract: | In the pathogenesis of nonalcoholic fatty liver disease, accumulation of lipids in hepatocytes and hepatocyte apoptosis are strongly implicated in disease progression from the potentially reversible condition of steatosis to severe acute and chronic liver injury. Acyl-CoA synthetase 5, a member of the ACSL gene family that catalyzes the activation of long-chain fatty acids for lipid biosynthesis, is the only ACSL isoform that is both, located on mitochondria and functionally involved in enterocyte apoptosis. In this study, the regulation of human ACSL5 in hepatocellular fatty acid degeneration and its involvement in hepatocyte apoptosis was investigated using models of in vitro and in vivo steatosis as well as plasmid-mediated stable gene transfer and RNAi-mediated gene silencing. ACSL5 mRNA and protein were strongly increased by uptake of dietary derived fatty acids in primary human hepatocytes, HepG2 cells and human steatotic liver. Over-expression of ACSL5 decreased HepG2 cell viability and increased susceptibility to TRAIL- and TNFα-, but not FAS- induced apoptosis, whereas knock down of ACSL5 reduced apoptosis susceptibility. High ACSL5 activity resulted in enhanced caspase-3/7 activity, but was not accompanied by up-regulation of death receptors, DR4, DR5 or TNF-R1. This study gives evidence that hepatocyte steatosis is associated with ACSL5 up-regulation resulting in increased susceptibility to hepatic cell death. We propose that ACSL5 could play a role in promoting fatty acid-induced lipoapoptosis in hepatocytes as important mechanism in fatty liver-related disorders. |
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Keywords: | ACSL5 acyl-CoA synthetase long chain isoform 5 TNFα Tumor necrosis factor alpha TRAIL TNFα related apoptosis inducing ligand NAFLD non-alcoholic fatty liver disease NASH non-alcoholic steatohepatitis CMV cytomegalievirus CamR chloramphenicol resistance qRT-PCR quantitative real time polymerase chain reaction HRP horseradish peroxidase SDS sodium dodecyl sulphate mAb monoclonal antibody FasL Fas (TNF receptor superfamily member 6) ligand PHH primary human hepatocytes |
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