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Attenuated lipotoxicity and apoptosis is linked to exogenous and endogenous augmenter of liver regeneration by different pathways.
PLoS One. 2017; 12(9):e0184282.Plos

Abstract

Nonalcoholic fatty liver disease (NAFLD) covers a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Free fatty acids (FFA) induce steatosis and lipo-toxicity and correlate with severity of NAFLD. In this study we aimed to investigate the role of exogenous and endogenous ALR (augmenter of liver regeneration) for FFA induced ER (endoplasmatic reticulum) -stress and lipoapoptosis. Primary human hepatocytes or hepatoma cells either treated with recombinant human ALR (rhALR, 15kDa) or expressing short form ALR (sfALR, 15kDa) were incubated with palmitic acid (PA) and analyzed for lipo-toxicity, -apoptosis, activation of ER-stress response pathways, triacylglycerides (TAG), mRNA and protein expression of lipid metabolizing genes. Both, exogenous rhALR and cytosolic sfALR reduced PA induced caspase 3 activity and Bax protein expression and therefore lipotoxicity. Endogenous sfALR but not rhALR treatment lowered TAG levels, diminished activation of ER-stress mediators C-Jun N-terminal kinase (JNK), X-box binding protein-1 (XBP1) and proapoptotic transcription factor C/EBP-homologous protein (CHOP), and reduced death receptor 5 protein expression. Cellular ALR exerts its lipid lowering and anti-apoptotic actions by enhancing FABP1, which binds toxic FFA, increasing mitochondrial β-oxidation by elevating the mitochondrial FFA transporter CPT1α, and decreasing ELOVL6, which delivers toxic FFA metabolites. We found reduced hepatic mRNA levels of ALR in a high fat diet mouse model, and of ALR and FOXA2, a transcription factor inducing ALR expression, in human steatotic as well as NASH liver samples, which may explain increased lipid deposition and reduced β-oxidation in NASH patients. Present study shows that exogenous and endogenous ALR reduce PA induced lipoapoptosis. Furthermore, cytosolic sfALR changes mRNA and protein expression of genes regulating lipid metabolism, reduces ER-stress finally impeding progression of NASH.

Authors+Show Affiliations

Children's University Hospital, University of Regensburg, Regensburg, Germany. Center for Liver Cell Research, University of Regensburg Hospital, Regensburg, Germany.Children's University Hospital, University of Regensburg, Regensburg, Germany.Children's University Hospital, University of Regensburg, Regensburg, Germany.Department of Internal Medicine, University of Regensburg Hospital, Regensburg, Germany.Children's University Hospital, University of Regensburg, Regensburg, Germany.Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuernberg, Erlangen, Germany.Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany.Children's University Hospital, University of Regensburg, Regensburg, Germany.Children's University Hospital, University of Regensburg, Regensburg, Germany. Department of Biochemistry and Microbiology, Faculty of Pharmacy, Damascus University, Damascus, Syria.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28877220

Citation

Weiss, Thomas S., et al. "Attenuated Lipotoxicity and Apoptosis Is Linked to Exogenous and Endogenous Augmenter of Liver Regeneration By Different Pathways." PloS One, vol. 12, no. 9, 2017, pp. e0184282.
Weiss TS, Lupke M, Ibrahim S, et al. Attenuated lipotoxicity and apoptosis is linked to exogenous and endogenous augmenter of liver regeneration by different pathways. PLoS One. 2017;12(9):e0184282.
Weiss, T. S., Lupke, M., Ibrahim, S., Buechler, C., Lorenz, J., Ruemmele, P., Hofmann, U., Melter, M., & Dayoub, R. (2017). Attenuated lipotoxicity and apoptosis is linked to exogenous and endogenous augmenter of liver regeneration by different pathways. PloS One, 12(9), e0184282. https://doi.org/10.1371/journal.pone.0184282
Weiss TS, et al. Attenuated Lipotoxicity and Apoptosis Is Linked to Exogenous and Endogenous Augmenter of Liver Regeneration By Different Pathways. PLoS One. 2017;12(9):e0184282. PubMed PMID: 28877220.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Attenuated lipotoxicity and apoptosis is linked to exogenous and endogenous augmenter of liver regeneration by different pathways. AU - Weiss,Thomas S, AU - Lupke,Madeleine, AU - Ibrahim,Sara, AU - Buechler,Christa, AU - Lorenz,Julia, AU - Ruemmele,Petra, AU - Hofmann,Ute, AU - Melter,Michael, AU - Dayoub,Rania, Y1 - 2017/09/06/ PY - 2017/05/02/received PY - 2017/08/21/accepted PY - 2017/9/7/entrez PY - 2017/9/7/pubmed PY - 2017/10/24/medline SP - e0184282 EP - e0184282 JF - PloS one JO - PLoS One VL - 12 IS - 9 N2 - Nonalcoholic fatty liver disease (NAFLD) covers a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Free fatty acids (FFA) induce steatosis and lipo-toxicity and correlate with severity of NAFLD. In this study we aimed to investigate the role of exogenous and endogenous ALR (augmenter of liver regeneration) for FFA induced ER (endoplasmatic reticulum) -stress and lipoapoptosis. Primary human hepatocytes or hepatoma cells either treated with recombinant human ALR (rhALR, 15kDa) or expressing short form ALR (sfALR, 15kDa) were incubated with palmitic acid (PA) and analyzed for lipo-toxicity, -apoptosis, activation of ER-stress response pathways, triacylglycerides (TAG), mRNA and protein expression of lipid metabolizing genes. Both, exogenous rhALR and cytosolic sfALR reduced PA induced caspase 3 activity and Bax protein expression and therefore lipotoxicity. Endogenous sfALR but not rhALR treatment lowered TAG levels, diminished activation of ER-stress mediators C-Jun N-terminal kinase (JNK), X-box binding protein-1 (XBP1) and proapoptotic transcription factor C/EBP-homologous protein (CHOP), and reduced death receptor 5 protein expression. Cellular ALR exerts its lipid lowering and anti-apoptotic actions by enhancing FABP1, which binds toxic FFA, increasing mitochondrial β-oxidation by elevating the mitochondrial FFA transporter CPT1α, and decreasing ELOVL6, which delivers toxic FFA metabolites. We found reduced hepatic mRNA levels of ALR in a high fat diet mouse model, and of ALR and FOXA2, a transcription factor inducing ALR expression, in human steatotic as well as NASH liver samples, which may explain increased lipid deposition and reduced β-oxidation in NASH patients. Present study shows that exogenous and endogenous ALR reduce PA induced lipoapoptosis. Furthermore, cytosolic sfALR changes mRNA and protein expression of genes regulating lipid metabolism, reduces ER-stress finally impeding progression of NASH. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/28877220/Attenuated_lipotoxicity_and_apoptosis_is_linked_to_exogenous_and_endogenous_augmenter_of_liver_regeneration_by_different_pathways_ L2 - https://dx.plos.org/10.1371/journal.pone.0184282 DB - PRIME DP - Unbound Medicine ER -