Knock-down of 24-dehydrocholesterol Reductase Suppresses SREBP2: A Novel Approach to Reduce PCSK9 in vivo

Introduction: Current therapeutic approaches to suppress the actions of proprotein convertase subtilisin/kexin type 9 (PCSK9) primarily involve monoclonal antibody. An alternative approach could be to suppress the SREBP2 pathway. Inhibition of sterol regulatory element-binding protein cleacage-activating protein (SCAP) will prevent SREBP mediated transcription of sterol biogenesis genes and PCSK9.24-dehydrocholesterol reductase (DHCR24) catalyzes the last step of cholesterol synthesis, converting desmosterol to cholesterol. Desmosterol is a strong LXR agonist and an inhibitor of SCAP. Hypothesis: We tested our hypothesis that reduction of DHCR24 expression would result in an increase in desmosterol, resulting in the suppression of SCAP and reduction of PCSK9 in vivo. Methods: In these studies, we used AAVshRNA to knock-down DHCR24 in the livers of CETP transgenic mice and WT mice. Results: Animals injected with AAVshRNA-DHCR24 resulted in 85% knockdown of DHCR24, with a concomitant 75% suppression of cholesterol synthesis, as measured by deuterium incorporation into newly made cholesterol. Knock-down of DHCR24 was also associated with up-regulation of fatty acid oxidation genes and suppression of fatty acid biosynthetic and SREBP-2 cholesterol biosynthetic pathways. Interestingly, DHCR24 knockdown was associated with a 60% decrease in plasma PCSK9 levels in CETP Tg mice (n=10, P Conclusions: To our knowledge, this is the first in vivo study to demonstrate that PCSK9 levels can be decreased via suppression of DHCR24 in vivo . These results suggest that DHCR24 might represent a novel therapeutic target for reducing LDL-cholesterol.