Abstract 261: Liver-specific Pcsk9 Knockout And Transgenic Mice (original) (raw)

2007

Abstract

Background: PCSK9 is primarily expressed in liver and intestine and was recently identified as the third locus implicated in autosomal dominant hypercholesterolemia, after LDLR and APOB. PCSK9 transits through the secretory pathway, associates with LDLR and triggers its degradation in endodomal/lysosomal compartments. Hypothesis: Mice lacking PCSK9 specifically in liver or intestine will define the tissue-specific contribution of PCSK9 to cholesterol homeostasis, and whether the latter is exclusively dependent on LDLR. Methods: Conditional Pcsk9 knockout mice in which the proximal promoter and exon 1 were framed with loxP sites were obtained. Using Cre-expressing mice, we generated complete (Pcsk9−/ −), hepatocyte ( Alb-cre )- or enterocyte ( Vil-cre )-specific knockouts. We also generated double knockout mice lacking both LDLR and PCSK9 and transgenic mice overexpressing mouse V5-tagged PCSK9 in hepatocytes. Results: PCSK9-deficient mice were hypocholesterolemic (−42% in plasma cho...

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