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

Journal Article


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Abstract


  • 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-I-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 mu M 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.

Authors


  •   Glaros, Elias N. (external author)
  •   Kim, Woojin S. (external author)
  •   Garner, Brett

Publication Date


  • 2010

Citation


  • Glaros, E. N., Kim, W. & Garner, B. (2010). Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition. Clinical Science, 118 (11-12), 727-736.

Scopus Eid


  • 2-s2.0-77954076233

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1569&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/530

Number Of Pages


  • 9

Start Page


  • 727

End Page


  • 736

Volume


  • 118

Issue


  • 11-12

Abstract


  • 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-I-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 mu M 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.

Authors


  •   Glaros, Elias N. (external author)
  •   Kim, Woojin S. (external author)
  •   Garner, Brett

Publication Date


  • 2010

Citation


  • Glaros, E. N., Kim, W. & Garner, B. (2010). Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition. Clinical Science, 118 (11-12), 727-736.

Scopus Eid


  • 2-s2.0-77954076233

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1569&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/530

Number Of Pages


  • 9

Start Page


  • 727

End Page


  • 736

Volume


  • 118

Issue


  • 11-12