Journal
BIOCHEMICAL JOURNAL
Volume 461, Issue -, Pages 435-442Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20131404
Keywords
cholesterol; lipid homoeostasis; MARCH6; squalene mono-oxygenase; ubiquitination; unsaturated fatty acids
Categories
Funding
- National Health and Medical Research Council [1008081, 1060515]
- National Heart Foundation of Australia [G11S5757]
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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.
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