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J. Biol. Chem., Vol. 279, Issue 50, 52772-52780, December 10, 2004

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Cholesterol and 25-Hydroxycholesterol Inhibit Activation of SREBPs by Different Mechanisms, Both Involving SCAP and Insigs^*

Christopher M. Adams, Julian Reitz, Jef K. De Brabander¶, Jamison D. Feramisco||, Lu Li, Michael S. Brown**, and Joseph L. Goldstein

From the Departments of Molecular Genetics and ^¶Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046

The current paper demonstrates that cholesterol and its hydroxylated derivative, 25-hydroxycholesterol (25-HC), inhibit cholesterol synthesis by two different mechanisms, both involving the proteins that control sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that activate genes encoding enzymes of lipid synthesis. Using methyl--cyclodextrin as a delivery vehicle, we show that cholesterol enters cultured Chinese hamster ovary cells and elicits a conformational change in SREBP cleavage-activating protein (SCAP), as revealed by the appearance of a new fragment in tryptic digests. This change causes SCAP to bind to Insigs, which are endoplasmic reticulum retention proteins that abrogate movement of the SCAP·SREBP complex to the Golgi apparatus where SREBPs are normally processed to their active forms. Direct binding of cholesterol to SCAP in intact cells was demonstrated by showing that a photoactivated derivative of cholesterol cross-links to the membrane domain of SCAP. The inhibitory actions of cholesterol do not require the isooctyl side chain or the 5-double bond of cholesterol, but they do require the 3-hydroxyl group. 25-HC is more potent than cholesterol in eliciting SCAP binding to Insigs, but 25-HC does not cause a detectable conformational change in SCAP. Moreover, a photoactivated derivative of 25-HC does not cross-link to SCAP. These data imply that cholesterol interacts with SCAP directly by inducing it to bind to Insigs, whereas 25-HC works indirectly through a putative 25-HC sensor protein that elicits SCAP-Insig binding.

Received for publication, September 8, 2004 , and in revised form, September 23, 2004.

^* This work was supported by Grant HL20948 from the National Institutes of Health and grants from the Perot Family Foundation and the W. M. Keck Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the Physician Scientist Training Program of the University of Texas Southwestern Medical Center.

^|| Supported by National Institutes of Health Medical Scientist Training Grant GM-08014.

^** To whom correspondence may be addressed: Dept. of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9046. E-mail: mike.brown{at}utsouthwestern.edu. To whom correspondence may be addressed: Dept. of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9046. E-mail: joe.goldstein{at}utsouthwestern.edu.

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