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J. Biol. Chem., Vol. 282, Issue 48, 34994-35004, November 30, 2007

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Plasma Membrane Rafts Complete Cholesterol Synthesis by Participating in Retrograde Movement of Precursor Sterols^*

Yoshio Yamauchi^¶1, Patrick C. Reid², Jeffrey B. Sperry^||, Koichi Furukawa^¶, Motohiro Takeya, Catherine C. Y. Chang, and Ta-Yuan Chang³

From the Departments of Biochemistry and ^||Chemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, the Department of Cell Pathology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan, and the ^¶Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

Mammalian cells synthesize significant amounts of precursor sterols, in addition to cholesterol, at the endoplasmic reticulum (ER). The newly synthesized sterols rapidly move to the plasma membrane (PM). The mechanism by which precursor sterols move back to the ER for their enzymatic processing to cholesterol is essentially unknown. Here we performed pulse-chase experiments and showed that the C29/C30 sterols rapidly move from the PM to the ER and are converted to cholesterol. The retrograde precursor sterol transport is largely independent of the Niemann-Pick type C proteins, which play important roles in late endosomal cholesterol transport. In contrast, disrupting lipid rafts significantly retards the conversion of C29/C30 and C28 sterols to cholesterol, causing the accumulation of precursor sterols at the PM. Our results reveal a previously undisclosed function of the PM lipid rafts: they bring cholesterol biosynthesis to completion by participating in the retrograde movement of precursor sterols back to the ER.

Received for publication, May 2, 2007 , and in revised form, September 7, 2007.

^* This work was supported by National Institutes of Health grant HL36709 (to T. Y. C.), by American Heart Association Postdoctoral Fellowship (to Y. Y.), and by Japan Society for Promotion of Science (to Y. Y.). 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.

¹ Present address: Dept. of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan.

² Present address: PeptiDream Inc., Tokyo, 153-8904, Japan.

³ To whom correspondence should be addressed: Dept. of Biochemistry, Dartmouth Medical School, 7200 Vail Bldg., Rm. 304, Hanover, NH 03755. Tel.: 603-650-1622; Fax: 603-650-1128; E-mail: Ta.Yuan.Chang{at}Dartmouth.edu.

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