Saturated free fatty acids induce cholangiocyte lipoapoptosis
| العنوان: | Saturated free fatty acids induce cholangiocyte lipoapoptosis |
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| المؤلفون: | Sathish Kumar Natarajan, Anuttoma Ray, Mary Anne Phillippi, Justin L. Mott, Sohini Roy, Ashley M. Mohr, Sophie C. Cazanave, Sally A. Ingham, Cody J. Wehrkamp |
| المصدر: | Hepatology. 60:1942-1956 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | medicine.medical_specialty, Palmitates, Apoptosis, Caspase 3, Fatty Acids, Nonesterified, Cholangiocyte, Cell Line, Tumor, Proto-Oncogene Proteins, Internal medicine, Puma, medicine, Humans, Caspase, Hepatology, biology, Forkhead Box Protein O3, Fatty liver, Forkhead Transcription Factors, biology.organism_classification, medicine.disease, Enzyme Activation, Fatty Liver, Bile Ducts, Intrahepatic, Endocrinology, Lipotoxicity, Caspases, biology.protein, FOXO3, Mitogen-Activated Protein Kinases, Steatohepatitis, Apoptosis Regulatory Proteins |
| الوصف: | Recent studies have identified a cholestatic variant of nonalcoholic fatty liver disease (NAFLD) with portal inflammation and ductular reaction. Based on reports of biliary damage, as well as increased circulating free fatty acids (FFAs) in NAFLD, we hypothesized the involvement of cholangiocyte lipoapoptosis as a mechanism of cellular injury. Here, we demonstrate that the saturated FFAs palmitate and stearate induced robust and rapid cell death in cholangiocytes. Palmitate and stearate induced cholangiocyte lipoapoptosis in a concentration-dependent manner in multiple cholangiocyte-derived cell lines. The mechanism of lipoapoptosis relied on the activation of caspase 3/7 activity. There was also a significant up-regulation of the proapoptotic BH3-containing protein, PUMA. In addition, palmitate-induced cholangiocyte lipoapoptosis involved a time-dependent increase in the nuclear localization of forkhead family of transcription factor 3 (FoxO3). We show evidence for posttranslational modification of FoxO3, including early (6 hours) deacetylation and dephosphorylation that coincide with localization of FoxO3 in the nuclear compartment. By 16 hours, nuclear FoxO3 is both phosphorylated and acetylated. Knockdown studies confirmed that FoxO3 and its downstream target, PUMA, were critical for palmitate- and stearate-induced cholangiocyte lipoapoptosis. Interestingly, cultured cholangiocyte-derived cells did not accumulate appreciable amounts of neutral lipid upon FFA treatment. Conclusion: Our data show that the saturated FFAs palmitate and stearate induced cholangiocyte lipoapoptosis by way of caspase activation, nuclear translocation of FoxO3, and increased proapoptotic PUMA expression. These results suggest that cholangiocyte injury may occur through lipoapoptosis in NAFLD and nonalcoholic steatohepatitis patients. (Hepatology 2014;60:1941–1955) |
| تدمد: | 1527-3350 0270-9139 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d0d786645a2609aba9a5294735bb088 https://doi.org/10.1002/hep.27175 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....7d0d786645a2609aba9a5294735bb088 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15273350 02709139 |
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