Sometimes cholesterol is happy just to hang with its phospholipid partners and mellow them out. But when levels of membrane cholesterol start to rise, lipid crowding creates a cadre of cholesterol with activist tendencies.  Anna Sokolov and Arun Radhakrishan have used a mutated, soluble form of the cholesterol-binding toxin perfringolysin-O (PFO) as a probe to measure the levels of this free or active cholesterol in ER membranes and correlate these levels with the activation of the cholesterol-sensing system in the ER (1).  This study builds on earlier work that Dr. Radhakrishan performed in the Brown and Goldstein lab demonstrating that there is a sharp threshold of cholesterol levels in the ER, above which the activation of SREBP-2 by the SCAP/Insig control mechanism is triggered (2).  Sokolov and Radhakrishnan’s new work indicates that this sharp threshold results from the appearance of a pool of cholesterol that has broken free from a complex, probably with phospholipid.  This new, free pool of cholesterol is then able to interact with SCAP and Insig to prevent the trafficking of SREBP-2 to the Golgi where the activating proteolysis of SREBP-2 occurs.  These observations are in line with a long-standing model promoted by Lang and Steck.  They have demonstrated, in the plasma membrane, that there is a similar dichotomy between two pools of cholesterol.  One pool of cholesterol seems to be primarily complexed with phospholipids and is inert with respect to interaction with cholesterol trafficking and metabolism.  The second pool appears when cholesterol levels are elevated.  This second pool of cholesterol is free to move within the cell, particularly to the ER, to activate the SREBP regulatory system (3).  One interesting aspect of Sokolov and Radhakrishan’s work is that, whereas in model liposome systems with a standard phospholipid (16:0/18:1 phosphatidylcholine), the free pool of cholesterol only appears at very high cholesterol levels (above 30 Mol%), in lipids extracted from the ER this pool appears at the low levels of cholesterol normally found in the ER (5 Mol%).  Thus, the lipid composition of the ER is ideally suited to allow the detection of very subtle changes in cholesterol levels.

1. Sokolov A, Radhakrishnan A. Accessibility of cholesterol in endoplasmic reticulum (ER) membranes and activation of SREBP-2 switch abruptly at a common cholesterol threshold. J Biol Chem. 2010 Jun 23. [Epub ahead of print]
2. Radhakrishnan A, Goldstein JL, McDonald JG, Brown MS Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance. Cell Metab. 2008 Dec;8(6):512-21

3. Lange Y, Steck TL. Cholesterol homeostasis and the escape tendency (activity) of plasma membrane cholesterol.  Prog Lipid Res. 2008 Sep;47(5):319-32.

Reviewed by: Binks Wattenberg, University of Louisville
Posted on: 15 July 2010