Caveolin-1 is not required for murine intestinal cholesterol transport.
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.
Valasek
Mark A
MA
Department of Physiology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Weng
Jian
J
Shaul
Philip W
PW
Anderson
Richard G W
RG
Repa
Joyce J
JJ
D064286:ATP Binding Cassette Transporter 1; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D017306:Annexin A2 / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001384:Azetidines / Q000494:pharmacology; D001692:Biological Transport; D015152:Blotting, Northern; D015153:Blotting, Western; D051242:Caveolin 1; D051243:Caveolin 2; D051244:Caveolin 3; D022461:Caveolins / Q000378:metabolism / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism*; D003902:Detergents / Q000494:pharmacology; D004386:Duodenum / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism; D000069438:Ezetimibe; D017353:Gene Deletion; D005838:Genotype; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013261:Sterols / Q000378:metabolism
C577836:ABCA1 protein, human; C462600:ABCG5 protein, mouse; C472822:ANXA2 protein, human; D064286:ATP Binding Cassette Transporter 1; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters; D017306:Annexin A2; D000924:Anticholesteremic Agents; D001384:Azetidines; C495541:Cav1 protein, mouse; C495548:Cav3 protein, mouse; D051242:Caveolin 1; D051243:Caveolin 2; D051244:Caveolin 3; D022461:Caveolins; D003902:Detergents; D008074:Lipoproteins; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D012333:RNA, Messenger; D013261:Sterols; D012313:RNA; D000255:Adenosine Triphosphate; D002784:Cholesterol; D000069438:Ezetimibe