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rdf:type |
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lifeskim:mentions |
umls-concept:C0021467,
umls-concept:C0021469,
umls-concept:C0041904,
umls-concept:C0109317,
umls-concept:C0162493,
umls-concept:C0220781,
umls-concept:C0227525,
umls-concept:C0332281,
umls-concept:C0752312,
umls-concept:C1150579,
umls-concept:C1333340,
umls-concept:C1366882,
umls-concept:C1370600,
umls-concept:C1705767,
umls-concept:C1705791,
umls-concept:C1883254
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pubmed:issue |
12
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pubmed:dateCreated |
2010-3-30
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pubmed:abstractText |
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 muM 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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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/20102334-10799716,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/20102334-9763522
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
1470-8736
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
118
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
727-36
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pubmed:dateRevised |
2010-9-28
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pubmed:meshHeading |
pubmed-meshheading:20102334-Animals,
pubmed-meshheading:20102334-Apolipoprotein A-I,
pubmed-meshheading:20102334-Cells, Cultured,
pubmed-meshheading:20102334-Extracellular Signal-Regulated MAP Kinases,
pubmed-meshheading:20102334-Fatty Acids, Monounsaturated,
pubmed-meshheading:20102334-Hep G2 Cells,
pubmed-meshheading:20102334-Hepatocytes,
pubmed-meshheading:20102334-Humans,
pubmed-meshheading:20102334-Male,
pubmed-meshheading:20102334-Mice,
pubmed-meshheading:20102334-Mice, Knockout,
pubmed-meshheading:20102334-Phosphorylation,
pubmed-meshheading:20102334-Protein Kinase Inhibitors,
pubmed-meshheading:20102334-RNA, Messenger,
pubmed-meshheading:20102334-Up-Regulation
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pubmed:year |
2010
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pubmed:articleTitle |
Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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