title: Transintestinal cholesterol excretion is an active metabolic process modulated by PCSK9 and statin involving ABCB1.
abstract: OBJECTIVE
  Transintestinal cholesterol excretion (TICE) is an alternate pathway to hepatobiliary secretion. Our study aimed at identifying molecular mechanisms of TICE.
  
  
  RESULTS
  We studied TICE ex vivo in mouse and human intestinal explants, and in vivo after bile diversion and intestinal cannulation in mice. We provide the first evidence that both low-density lipoprotein (LDL) and high-density lipoprotein deliver cholesterol for TICE in human and mouse jejunal explants at the basolateral side. Proprotein convertase subtilisin kexin type 9 (PCSK9)(-/-) mice and intestinal explants show increased LDL-TICE, and acute injection of PCSK9 decreases TICE in vivo, suggesting that PCSK9 is a repressor of TICE. The acute repression was dependent on the LDL receptor (LDLR). Further, TICE was increased when mice were treated with lovastatin. These data point to an important role for LDLR in TICE. However, LDLR(-/-) mice showed increased intestinal LDL uptake, contrary to what is observed in the liver, and tended to have higher TICE. We interpret these data to suggest that there might be at least 2 mechanisms contributing to TICE; 1 involving LDL receptors and other unidentified mechanisms. Acute modulation of LDLR affects TICE, but chronic deficiency is compensated for most likely by the upregulation of the unknown mechanisms. Using mice deficient for apical multidrug active transporter ATP-binding cassette transporter B1 a and b, and its inhibitor, we show that these apical transporters contribute significantly to TICE.
  
  
  CONCLUSIONS
  TICE is operative in human jejunal explants. It is a metabolically active process that can be acutely regulated, inversely related to cholesterolemia, and pharmacologically activated by statins.
authors.affiliation: INSERM, UMR 1087, CNRS UMR 6291, Nantes F-44000, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Le May
authors.forename: Jean Mathieu
authors.initials: JM
authors.lastname: Berger
authors.forename: Anne
authors.initials: A
authors.lastname: Lespine
authors.forename: Bruno
authors.initials: B
authors.lastname: Pillot
authors.forename: Xavier
authors.initials: X
authors.lastname: Prieur
authors.forename: Eric
authors.initials: E
authors.lastname: Letessier
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
authors.forename: Xavier
authors.initials: X
authors.lastname: Collet
authors.forename: Bertrand
authors.initials: B
authors.lastname: Cariou
authors.forename: Philippe
authors.initials: P
authors.lastname: Costet
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001706:Biopsy; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007583:Jejunum / Q000187:drug effects* / Q000201:enzymology; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D011994:Recombinant Proteins; D002784:Cholesterol; C095122:multidrug resistance protein 3; D008148:Lovastatin; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C507084:Abcb1b protein, mouse
keywords: ATP-binding cassette transporter B1; PCSK9; lipoprotein; low-density lipoprotein receptor; transintestinal cholesterol excretion