Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9

Abstract

PCSK9 encodes proprotein convertase subtilisin͞kexin type 9a (PCSK9), a member of the proteinase K subfamily of subtilases. Missense mutations in PCSK9 cause an autosomal dominant form of hypercholesterolemia in humans, likely due to a gain-of-function mechanism because overexpression of either WT or mutant PCSK9 reduces hepatic LDL receptor protein (LDLR) in mice. Here, we show that livers of knockout mice lacking PCSK9 manifest increased LDLR protein but not mRNA. Increased LDLR protein led to increased clearance of circulating lipoproteins and decreased plasma cholesterol levels (46 mg͞dl in Pcsk9 ؊/؊ mice versus 96 mg͞dl in WT mice). Statins, a class of drugs that inhibit cholesterol synthesis, increase expression of sterol regulatory element-binding protein-2 (SREBP-2), a transcription factor that activates both the Ldlr and Pcsk9 genes. Statin administration to Pcsk9 ؊/؊ mice produced an exaggerated increase in LDLRs in liver and enhanced LDL clearance from plasma. These data demonstrate that PCSK9 regulates the amount of LDLR protein in liver and suggest that inhibitors of PCSK9 may act synergistically with statins to enhance LDLRs and reduce plasma cholesterol.low-density lipoprotein receptor ͉ lipoproteins ͉ proteinase ͉ sterol regulatory element-binding protein

Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

“…However, PCSK9 is implicated in the development of the nervous system [Poirier et al, 2006] and its inactivation results in disordered neuronal development and death in embryos of zebrafish but not in mice [Rashid et al, 2005;Poirier et al, 2006]. Furthermore, since PCSK9 is expressed not only in the liver, gut, and central nervous system, but also in the kidney, other human diseases associated with its mutations could still be undiscovered.…”

“…Similarly to wild type, human mutant PCSK9 (p.S127R and p.F216L) overexpressed in the liver of mice leads to hypercholesterolemia due to a dramatic decrease of hepatic LDL receptor levels through a posttranscriptional mechanism [Park et al, 2004]. Conversely, livers of knockout mice lacking PCSK9 (Pcsk9-/-) display increased LDL receptor (but not mRNA) that leads to a decrease in plasma cholesterol levels of 48% compared to wildtype litter mates [Rashid et al, 2005]. Likewise, an antisense oligonucleotide (ASO) inhibitor targeting murine PCSK9 [Graham et al, 2007] as well as cellular PCSK9 [Benjannet et al, 2004], resulted in an increase in hepatic LDL receptor levels and reduced total cholesterol and LDL-C. Additional information on animal and cellular models is developed in the online Supplementary Information.…”

“…Thus, it was suggested that a combined statin-antiPCSK9 therapeutic regimen could overcome this effect and enhance cholesterol reduction. Initial proof-of-concept was provided by statin administration to Pcsk9(-/-) mice that produced an exaggerated increase in LDL receptors in liver and enhanced LDL clearance from plasma [Rashid et al, 2005].…”

A Novel Loss of Function Mutation of PCSK9 Gene in White Subjects With Low-Plasma Low-Density Lipoprotein Cholesterol

“…[13][14][15] Missense mutations of PCSK9 associated with hypercholesterolemia in humans would increase the capacity of PCSK9 to limit the number of LDL-r, thus representing gain of function mutations. In sharp contrast, mice with targeted inactivation of PCSK9 gene (pcsk9 Ϫ/Ϫ ) have an increased number of LDL-r in the liver, increased removal of plasma LDL, and reduced plasma LDL-C. 16 In 2005 Cohen et al 17 found that 2 inactivating mutations of PCSK9 (Y142X and C679X), present in 2% to 2.6% of blacks of the Dallas Heart Study, were associated with 30% to 40% reduction of plasma LDL-C. They proposed the concept that in human loss of function mutations of PCSK9 would increase the number of liver LDL-r and the receptor mediated uptake and catabolism of plasma LDL, as observed in pcsk9 Ϫ/Ϫ mice.…”

Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population

“…[10][11][12] Conversely, the depletion or removal of PCSK9 protein can substantially increase the level of LDLR and decrease the plasma cholesterol. [13][14][15][16] It is very important that haplotype signatures of prominent SNPs of these three genes are studied in all populations rather than inferring or assuming frequencies from the HAPMAP data, where only a few populations are tested. LDLR is a highly polymorphic gene but how relevant is the CHB (Han Chinese in Beijing) frequencies to other similar races in other locations?…”