Transintestinal cholesterol excretion is an active metabolic process modulated by PCSK9 and statin involving ABCB1.
Arterioscler Thromb Vasc Biol
; 33(7): 1484-93, 2013 Jul.
Article
em En
| MEDLINE
| ID: mdl-23559630
ABSTRACT
OBJECTIVE:
Transintestinal cholesterol excretion (TICE) is an alternate pathway to hepatobiliary secretion. Our study aimed at identifying molecular mechanisms of TICE. APPROACH ANDRESULTS:
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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Lovastatina
/
Serina Endopeptidases
/
Colesterol
/
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
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Inibidores de Hidroximetilglutaril-CoA Redutases
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Subfamília B de Transportador de Cassetes de Ligação de ATP
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Pró-Proteína Convertases
/
Jejuno
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Assunto da revista:
ANGIOLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
França