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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

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 "metabolon", 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.

Original languageEnglish
Pages (from-to)888-897
Number of pages11
JournalJournal of Lipid Research
Volume56
Issue number4
DOIs
Publication statusPublished - Apr 2015
Externally publishedYes

Bibliographical note

Erratum can be found in The Journal of Lipid Research, Vol. 56 (5), pp. 1079, doi: 10.1194/jlr.M056986ERR.

Keywords

  • 24-dehydrocholesterol reductase
  • 7-dehydrocholesterol reductase
  • desmosterol
  • 7-dehydrocholesterol

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