Abstract
BackgroundPrevious studies including our group have indicated the effects of ezetimibe on increased plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration, while the rapid expression in different organs and the potential molecular mechanisms for this impact have not been carefully evaluated.MethodsThirty rats were randomly divided into two groups (n = 15 for each), which were orally administrated with ezetimibe (10 mg/kg/day) or normal saline. Blood samples were obtained at day 3 after orally administration, and the PCSK9 levels were determined by ELISA. We further analyzed the mRNA expression of PCSK9, low-density lipoprotein receptor (LDLR), sterol regulator element-binding protein 2 (SREBP2), and hepatocyte nuclear factor 1 alpha (HNF-1α) by real-time PCR, as well as the protein expression by western blot, in liver, intestine and kidney respectively.ResultsEzetimibe significantly increased plasma PCSK9 levels compared with control group, while there was no significant difference between the two groups with regard to lipid profile at day 3. Moreover, ezetimibe remarkably increased the expression of PCSK9, LDLR, SREBP2 and HNF-1α in liver. Enhanced expression of PCSK9, LDLR and SREBP2 protein were found in intestine and kidney, while no changes in the expression of HNF-1α were observed in intestine and kidney of rats with ezetimibe treatment.ConclusionsThe data demonstrated that ezetimibe increased PCSK9 expression through the SREBP2 and HNF-1α pathways in different organs, subsequently resulting in elevated plasma PCSK9 levels prior to the alterations of lipid profile in rats.
Highlights
Proprotein convertase subtilisin/kexin type 9 (PSCK9) is a circulating protein synthesized mainly in the liver, intestine, kidney and brain,which impairs low-density lipoprotein (LDL) clearance by binding directly to the epidermal growth factor repeat A of the LDL receptor (LDLR) and subsequently targeting it for degradation [1,2,3,4]
The data demonstrated that ezetimibe increased proprotein convertase subtilisin/kexin type 9 (PCSK9) expression through the sterol regulator element-binding protein 2 (SREBP2) and HNF-1α pathways in different organs, subsequently resulting in elevated plasma PCSK9 levels prior to the alterations of lipid profile in rats
Changes of PCSK9, LDLR, SREBP2 and HNF-1α mRNA expression after ezetimibe treatment Relative mRNA expression of PCSK9, LDLR, SREBP2 and HNF-1α mRNA were determined in liver, intestine and kidney
Summary
Proprotein convertase subtilisin/kexin type 9 (PSCK9) is a circulating protein synthesized mainly in the liver, intestine, kidney and brain,which impairs low-density lipoprotein (LDL) clearance by binding directly to the epidermal growth factor repeat A of the LDL receptor (LDLR) and subsequently targeting it for degradation [1,2,3,4] This process, subsequently, results in increased LDL-cholesterol (LDL-C) levels in the circulation [5,6]. Previous studies including our group have indicated the effects of ezetimibe on increased plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration, while the rapid expression in different organs and the potential molecular mechanisms for this impact have not been carefully evaluated
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