SM (squalene mono-oxygenase) catalyses the first oxygenation step in cholesterol synthesis, immediately before the formation of the steroid backbone at lanosterol. SM is an important control point in the pathway, and is regulated at the post-translational level by accelerated cholesterol-dependent ubiquitination and proteasomal degradation, which is associated with the accumulation of squalene. Using model cell systems, we report that SM is stabilized by unsaturated fatty acids. Treatment with unsaturated fatty acids such as oleate, but not saturated fatty acids, increased protein levels of SM or SM-N100–GFP (the first 100 amino acids of SM fused to GFP) at the post-translational level and partially overcame cholesterol-dependent degradation, as well as reversing cholesterol-dependent squalene accumulation. Maximum stabilization required activation of fatty acids, but not triacylglycerol or phosphatidylcholine synthesis. The mechanism of oleate-mediated stabilization appeared to occur through reduced ubiquitination by the E3 ubiquitin ligase MARCH6. Stabilization of a cholesterol biosynthetic enzyme by unsaturated fatty acids may help maintain a constant cholesterol/phospholipid ratio.
Skip Nav Destination
Article navigation
August 2014
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
July 10 2014
Squalene mono-oxygenase, a key enzyme in cholesterol synthesis, is stabilized by unsaturated fatty acids
Julian Stevenson;
Julian Stevenson
*School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
Search for other works by this author on:
Winnie Luu;
Winnie Luu
*School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
Search for other works by this author on:
Ika Kristiana;
Ika Kristiana
*School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
Search for other works by this author on:
Andrew J. Brown
Andrew J. Brown
1
*School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
1To whom correspondence should be addressed (email aj.brown@unsw.edu.au).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
October 28 2013
Revision Received:
April 25 2014
Accepted:
May 20 2014
Accepted Manuscript online:
May 20 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 461 (3): 435–442.
Article history
Received:
October 28 2013
Revision Received:
April 25 2014
Accepted:
May 20 2014
Accepted Manuscript online:
May 20 2014
Citation
Julian Stevenson, Winnie Luu, Ika Kristiana, Andrew J. Brown; Squalene mono-oxygenase, a key enzyme in cholesterol synthesis, is stabilized by unsaturated fatty acids. Biochem J 1 August 2014; 461 (3): 435–442. doi: https://doi.org/10.1042/BJ20131404
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.