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Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition

Sphingolipids including sphingomyelin have been implicated as potential atherogenic lipids. Studies in apoE (apolipoprotein E)-null mice have revealed that the serine palmitoyltransferase inhibitor myriocin reduces plasma levels of sphingomyelin, ceramide, sphingosine-1-phosphate and glycosphingolip...

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Autores principales: Glaros, Elias N., Kim, Woojin S., Garner, Brett
Formato: Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860698/
https://www.ncbi.nlm.nih.gov/pubmed/20102334
http://dx.doi.org/10.1042/CS20090452
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author Glaros, Elias N.
Kim, Woojin S.
Garner, Brett
author_facet Glaros, Elias N.
Kim, Woojin S.
Garner, Brett
author_sort Glaros, Elias N.
collection PubMed
description Sphingolipids including sphingomyelin have been implicated as potential atherogenic lipids. Studies in apoE (apolipoprotein E)-null mice have revealed that the serine palmitoyltransferase inhibitor myriocin reduces plasma levels of sphingomyelin, ceramide, sphingosine-1-phosphate and glycosphingolipids and that this is associated with potent inhibition of atherosclerosis. Interestingly, hepatic apoA-I (apolipoprotein A-I) synthesis and plasma HDL (high-density lipoprotein)-cholesterol levels were also increased in apoE-null mice treated with myriocin. Since myriocin is a known inhibitor of ERK (extracellular-signal-related kinase) phosphorylation, we assessed the possibility that myriocin may be acting to increase hepatic apoA-I production via this pathway. To address this, HepG2 cells and primary mouse hepatocytes were treated with 200 μM myriocin for up to 48 h. Myriocin increased apoA-I mRNA and protein levels by approx. 3- and 2-fold respectively. Myriocin also increased apoA-I secretion up to 3.5-fold and decreased ERK phosphorylation by approx. 70%. Similar findings were obtained when primary hepatocytes were isolated from apoE-null mice that were treated with myriocin (intraperitoneal injection at a dose of 0.3 mg/kg body weight). Further experiments revealed that the MEK (mitogen-activated protein kinase/ERK kinase) inhibitor PD98059 potently inhibited ERK phosphorylation, as expected, and increased primary hepatocyte apoA-I production by 3-fold. These results indicate that ERK phosphorylation plays a role in regulating hepatic apoA-I expression and suggest that the anti-atherogenic mechanism of action for myriocin may be linked to this pathway.
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spelling pubmed-28606982010-05-06 Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition Glaros, Elias N. Kim, Woojin S. Garner, Brett Clin Sci (Lond) Research Article Sphingolipids including sphingomyelin have been implicated as potential atherogenic lipids. Studies in apoE (apolipoprotein E)-null mice have revealed that the serine palmitoyltransferase inhibitor myriocin reduces plasma levels of sphingomyelin, ceramide, sphingosine-1-phosphate and glycosphingolipids and that this is associated with potent inhibition of atherosclerosis. Interestingly, hepatic apoA-I (apolipoprotein A-I) synthesis and plasma HDL (high-density lipoprotein)-cholesterol levels were also increased in apoE-null mice treated with myriocin. Since myriocin is a known inhibitor of ERK (extracellular-signal-related kinase) phosphorylation, we assessed the possibility that myriocin may be acting to increase hepatic apoA-I production via this pathway. To address this, HepG2 cells and primary mouse hepatocytes were treated with 200 μM myriocin for up to 48 h. Myriocin increased apoA-I mRNA and protein levels by approx. 3- and 2-fold respectively. Myriocin also increased apoA-I secretion up to 3.5-fold and decreased ERK phosphorylation by approx. 70%. Similar findings were obtained when primary hepatocytes were isolated from apoE-null mice that were treated with myriocin (intraperitoneal injection at a dose of 0.3 mg/kg body weight). Further experiments revealed that the MEK (mitogen-activated protein kinase/ERK kinase) inhibitor PD98059 potently inhibited ERK phosphorylation, as expected, and increased primary hepatocyte apoA-I production by 3-fold. These results indicate that ERK phosphorylation plays a role in regulating hepatic apoA-I expression and suggest that the anti-atherogenic mechanism of action for myriocin may be linked to this pathway. Portland Press Ltd. 2010-03-30 /pmc/articles/PMC2860698/ /pubmed/20102334 http://dx.doi.org/10.1042/CS20090452 Text en © 2010 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited http://creativecommons.org/licenses/by-nc/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Glaros, Elias N.
Kim, Woojin S.
Garner, Brett
Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition
title Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition
title_full Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition
title_fullStr Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition
title_full_unstemmed Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition
title_short Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition
title_sort myriocin-mediated up-regulation of hepatocyte apoa-i synthesis is associated with erk inhibition
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860698/
https://www.ncbi.nlm.nih.gov/pubmed/20102334
http://dx.doi.org/10.1042/CS20090452
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