Transintestinal Cholesterol Excretion Is an Active Metabolic Process Modulated by PCSK9 and Statin Involving ABCB1
| Autor: | E. Letessier, Philippe Costet, Anne Lespine, J.-M. Berger, Bruno Pillot, Xavier Collet, Bertrand Cariou, M. Mahmood Hussain, Cédric Le May, Xavier Prieur |
|---|---|
| Přispěvatelé: | Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Dept Cell Biol, Leiden University, Université Fédérale Toulouse Midi-Pyrénées, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ProdInra, Migration, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
Time Factors Biopsy [SDV]Life Sciences [q-bio] 030204 cardiovascular system & hematology transintestinal cholesterol excretion PCSK9 Mice chemistry.chemical_compound 0302 clinical medicine ComputingMilieux_MISCELLANEOUS IN-VIVO Mice Knockout 0303 health sciences Serine Endopeptidases lipoprotein PLASMA-CHOLESTEROL P-GLYCOPROTEIN [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism Recombinant Proteins [SDV] Life Sciences [q-bio] DENSITY-LIPOPROTEIN RECEPTOR Cholesterol Jejunum low-density lipoprotein receptor lipids (amino acids peptides and proteins) Proprotein Convertases Proprotein Convertase 9 Cardiology and Cardiovascular Medicine medicine.medical_specialty ATP Binding Cassette Transporter Subfamily B Statin medicine.drug_class COMPLETE BILE DIVERSION Biology LDL RECEPTOR 03 medical and health sciences [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system Internal medicine MULTIDRUG TRANSPORTER medicine [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] Animals Humans Secretion BILIARY STEROL SECRETION ATP Binding Cassette Transporter Subfamily B Member 1 Lovastatin Metabolic Process 030304 developmental biology ATP-binding cassette transporter B1 Cholesterol HDL [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology Cholesterol LDL Cholesterol excretion Mice Inbred C57BL Endocrinology Receptors LDL chemistry LDL receptor Hydroxymethylglutaryl-CoA Reductase Inhibitors CONVERTASE SUBTILISIN/KEXIN TYPE-9 KNOCKOUT MICE Lipoprotein |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology Arteriosclerosis, Thrombosis, and Vascular Biology, American Heart Association, 2013, 33 (7), pp.1484-1493. ⟨10.1161/ATVBAHA.112.300263⟩ Arteriosclerosis, Thrombosis, and Vascular Biology, 2013, 33 (7), pp.1484-1493. ⟨10.1161/ATVBAHA.112.300263⟩ |
| ISSN: | 1079-5642 1524-4636 |
| DOI: | 10.1161/ATVBAHA.112.300263⟩ |
| Popis: | Objective— Transintestinal cholesterol excretion (TICE) is an alternate pathway to hepatobiliary secretion. Our study aimed at identifying molecular mechanisms of TICE. Approach and 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|