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M504609200v1
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Papers In Press, published online ahead of print May 26, 2005
J. Biol. Chem, 10.1074/jbc.M504609200
Submitted on April 27, 2005
Revised on May 25, 2005
Accepted on May 26, 2005

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

Physiology Dept., UT-Southwestern Medical Center, Dallas, TX 75390-8854

Corresponding Author: joyce.repa{at}utsouthwestern.edu

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-knockout mice. Deletion of CAV1 does not result in either a compensatory increase of CAV2 or CAV3 in intestine. In addition, Cav1-knockout mice display normal mRNA and protein levels of Annexin-2 and 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-knockout 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, Hydroxy-methylglutaryl 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.


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