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J. Biol. Chem., Vol. 280, Issue 30, 28103-28109, July 29, 2005

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Caveolin-1 Is Not Required for Murine Intestinal Cholesterol Transport^*

Mark A. Valasek, Jian Weng¶, Philip W. Shaul||, Richard G. W. Anderson¶, and Joyce J. Repa**

From the Departments of Physiology, ^**Internal Medicine, ^||Pediatrics and ^¶Cell Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390

Caveolin-1 (CAV1) is the structural protein of the filamentous coat that decorates the cytoplasmic surface of each caveola. Cell culture studies have implicated CAV1 in playing an important role in intracellular cholesterol trafficking. In addition, it has been reported that CAV1 forms a detergent-resistant protein complex with Annexin-2 in enterocytes that can be disrupted by the cholesterol absorption inhibitor ezetimibe, suggesting a possible role for CAV1 in cholesterol absorption. In this report, we have evaluated cholesterol homeostasis in Cav1 knock-out mice. Deletion of CAV1 does not result in either a compensatory increase of CAV2 or CAV3 in intestine. In addition, Cav1 knock-out mice display normal mRNA and protein levels of Annexin-2 or the putative cholesterol transport protein Niemann-Pick C1-like 1 (NPC1L1) in proximal intestinal mucosa. Fractional cholesterol absorption and fecal neutral sterol excretion are statistically similar in Cav1 knock-out mice and their wild-type littermates. Moreover, oral administration of ezetimibe is equally effective in decreasing cholesterol absorption in Cav1 null mice and wild-type controls. The mRNA expression levels of genes sensitive to intracellular cholesterol concentration (ATP-binding cassette transporters ABCA1 and ABCG5, hydroxymethylglutaryl-CoA synthase and the LDL receptor) are similarly altered in the proximal intestinal mucosa of Cav1 null and wild-type mice following ezetimibe treatment. These results demonstrate that CAV1 is not required for cholesterol absorption or ezetimibe sensitivity in the mouse.

Received for publication, April 27, 2005 , and in revised form, May 25, 2005.

^* This work was supported by grants from the American Heart Association-Texas Affiliate (to J. J. R.), Grants GM07062 (to M. A. V.), HL20948 (to R. G. W. A.), GM52016 (to R. G. W. A.), and HL58888 (to P. W. S.) from the National Institutes of Health, The Perot Family Foundation (to R. G. W. A.), and the Cecil H. Green Distinguished Chair in Cellular and Molecular Biology (to R. G. W. A.). 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Depts. of Physiology and Internal Medicine, Touchstone Center for Diabetes Research, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8854. Tel.: 214-648-9431; Fax: 214-648-9191; E-mail: joyce.repa{at}utsouthwestern.edu.

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