Journal of Lipid Research (Apr 2015)

The terminal enzymes of cholesterol synthesis, DHCR24 and DHCR7, interact physically and functionally[S]

  • Winnie Luu,
  • Gene Hart-Smith,
  • Laura J. Sharpe,
  • Andrew J. Brown

Journal volume & issue
Vol. 56, no. 4
pp. 888 – 897

Abstract

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Cholesterol is essential to human health, and its levels are tightly regulated by a balance of synthesis, uptake, and efflux. Cholesterol synthesis requires the actions of more than twenty enzymes to reach the final product, through two alternate pathways. Here we describe a physical and functional interaction between the two terminal enzymes. 24-Dehydrocholesterol reductase (DHCR24) and 7-dehydrocholesterol reductase (DHCR7) coimmunoprecipitate, and when the DHCR24 gene is knocked down by siRNA, DHCR7 activity is also ablated. Conversely, overexpression of DHCR24 enhances DHCR7 activity, but only when a functional form of DHCR24 is used. DHCR7 is important for both cholesterol and vitamin D synthesis, and we have identified a novel layer of regulation, whereby its activity is controlled by DHCR24. This suggests the existence of a cholesterol #x201C;metabolon#x201D;, where enzymes from the same metabolic pathway interact with each other to provide a substrate channeling benefit. We predict that other enzymes in cholesterol synthesis may similarly interact, and this should be explored in future studies.

Keywords