Dataset Information

On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects.

ABSTRACT: Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulatory ligand that terminates the lifecycle of the low-density lipoprotein (LDL) receptor (LDLR) thus affecting plasma LDL-cholesterol (LDL-C) levels. Recent evidence shows that in addition to the straightforward mechanism of action, there are more complex interactions between PCSK9, LDLR and plasma lipoprotein levels, including: (a) the presence of both parallel and reciprocal regulation of surface LDLR and plasma PCSK9; (b) a correlation between PCSK9 and LDL-C levels dependent not only on the fact that PCSK9 removes hepatic LDLR, but also due to the fact that up to 40% of plasma PCSK9 is physically associated with LDL; and (c) an association between plasma PCSK9 production and the assembly and secretion of triglyceride-rich lipoproteins. The effect of PCSK9 on LDLR is being successfully utilized toward the development of anti-PCSK9 therapies to reduce plasma LDL-C levels. Current biochemical research has uncovered additional mechanisms of action and interacting partners for PCSK9, and this opens the way for a more thorough understanding of the regulation, metabolism, and effects of this interesting protein.

SUBMITTER: Tavori H

PROVIDER: S-EPMC4562333 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects.

Tavori Hagai H Rashid Shirya S Fazio Sergio S

Atherosclerosis 20141217 2

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulatory ligand that terminates the lifecycle of the low-density lipoprotein (LDL) receptor (LDLR) thus affecting plasma LDL-cholesterol (LDL-C) levels. Recent evidence shows that in addition to the straightforward mechanism of action, there are more complex interactions between PCSK9, LDLR and plasma lipoprotein levels, including: (a) the presence of both parallel and reciprocal regulation of surface LDLR and plasma PCSK9; (b) a corr ...[more]

PMID: 25544176

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Project description:ObjectivesVariants of the secreted glycoprotein, proprotein convertase subtilisin/kexin 9 (PCSK9), associate with both hypo- and hyper-cholesterolemic phenotypes. Herein, we carried out full exonic sequencing of PCSK9 documenting the frequency of single and multiple PCSK9 variations and their effects on serum lipoprotein and PCSK9 levels in Caucasian Canadians.MethodsThe 12 exons of PCSK9 were sequenced in 207 unrelated Caucasian Canadians. Minor allele frequencies of PCSK9 variants were compared amongst LDL cholesterol (LDLC) quintiles. Serum PCSK9 levels were measured by ELISA and lipoproteins by enzymatic methods. Comparisons were made with a Caucasian family cohort (n=51) and first generation African Canadians (n=31).ResultsIn Caucasians, but not African Canadians, the c.61_63insCTG (denoted L10Ins) and A53V PCSK9 variations were linked and their frequency was significantly higher among Caucasian Canadians with LDLC levels in the <25th percentile. In both the unrelated and family Caucasian cohorts those carrying the L10A53V PCSK9 variant had significantly lower LDLC without reduction in plasma PCSK9. The I474V PCSK9 variant associated with significantly lower serum PCSK9 and LDLC. A novel PCSK9 variant was identified; E206K. We found that the frequency of multiple PCSK9 variations was higher in first generation African Canadians.ConclusionsWe showed that the L10A53V and I474V PCSK9 variants were significantly associated with lower LDLC levels in Caucasian Canadians but differed in their effect on serum PCSK9 concentrations, illuminating differences in their mechanism of inaction and indicating that that PCSK9 measurement alone may not always be a good indicator of PCSK9 function.Full exonic sequencing of PCSK9 pointed to factors that may contribute to L10Ins PCSK9 variant loss of function in Canadians of Caucasian but not those of African descent. These included; (1) its tight linkage with the A53V variant in Caucasians and/or (2) for both the L10 and I474V, the combined (and negating) effect of multiple, differing phenotypic PCSK9 variants within individuals of African ancestry for which combinations of PCSK9 variations and their overall frequency was higher. No population studies, to our knowledge, have addressed or accessed the effect of multiple PCSK9 variants on cholesterol profiles. Our results indicate that this should be considered.

Dataset Information

On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects.

Publications

On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects.

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