Sphingolipids including sphingomyelin have been implicated as potential atherogenic lipids. Studies in apolipoprotein-E (apoE) null mice have revealed that the serine palmitoyl transferase 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 apolipoprotein A-I (apoA-I) synthesis and plasma high density lipoprotein cholesterol levels were also increased in apoE null mice treated with myriocin. Since myriocin is a known inhibitor of ERK 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 mM myriocin for up to 48 hours. Myriocin increased apoA-I mRNA and protein levels, by approximately 3-fold and 2-fold, respectively. Myriocin also increased apoA-I secretion up to 3.5-fold, and decreased ERK phosphorylation by approximately 70%. Similar data 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 MAP kinase kinase inhibitor PD98059 potently inhibited ERK phosphorylation, as expected, and increased primary hepatocyte apoA-I production by 3-fold. These data 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.
Here is the original:
Myriocin-mediated upregulation of hepatocyte apoA-I synthesis is associated with ERK inhibition
Tags: a-indicate-that, a-this-pathway-, experiments
Related posts:
- Countervailing vascular effects of rosiglitazone in high cardiovascular risk mice: Role of oxidative stress and PRMT-1
- Ethanol -induced vasoconstriction is mediated via redox-sensitive, cyclooxygenase-dependent mechanisms.
- The development of hepatic fibrosis occurs normally in AMPK deficient mice
- Fenofibrate improves endothelial function in the brachial artery and forearm resistance arterioles of statin-treated type 2 diabetic patients
- Angiotensin II infusion promotes ascending aortic aneurysms: attenuation by CCR2 deficiency in apoE -/- mice
Related posts brought to you by Yet Another Related Posts Plugin.
