Searching across hundreds of databases

Our searching services are busy right now. Your search will reload in five seconds.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.

PCSK9 encodes proprotein convertase subtilisin/kexin 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 mg/dl in Pcsk9(-/-) mice versus 96 mg/dl 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.

Pubmed ID: 15805190 RIS Download

Mesh terms: Animal Feed | Animals | Apolipoproteins B | Cells, Cultured | Cholesterol | Drug Synergism | Electrophoresis, Polyacrylamide Gel | Female | Gene Deletion | Hepatocytes | Hydroxymethylglutaryl-CoA Reductase Inhibitors | Liver | Lovastatin | Male | Mice | Mice, Knockout | Phenotype | Proprotein Convertase 9 | Proprotein Convertases | RNA, Messenger | Receptors, LDL | Serine Endopeptidases

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

None found

Associated grants

  • Agency: NHLBI NIH HHS, Id: P01 HL020948
  • Agency: NHLBI NIH HHS, Id: R01 HL038049
  • Agency: NHLBI NIH HHS, Id: HL 20948
  • Agency: NHLBI NIH HHS, Id: HL 38049

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

We have not found any resources mentioned in this publication.