P-glycoprotein Dysfunction Contributes to Hepatic Steatosis and Obesity in Mice

被引:26
作者
Foucaud-Vignault, Magali [1 ]
Soayfane, Zeina [1 ,2 ,3 ]
Menez, Cecile [1 ]
Bertrand-Michel, Justine [4 ]
Guy, Pascal [1 ]
Martin, Pierre [1 ]
Guillou, Herve [1 ]
Collet, Xavier [2 ,3 ]
Lespine, Anne [1 ]
机构
[1] INRA, TOXALIM, UPS, INP,UMR1331, F-31931 Toulouse, France
[2] NSERM, UMR 1048I, Toulouse, France
[3] Fac Med Toulouse, INSERM, UPS, Inst Malad Metab & Cardiovasc, F-31073 Toulouse, France
[4] IFR150, Toulouse, France
关键词
PREGNANE-X-RECEPTOR; CONSTITUTIVE-ANDROSTANE RECEPTOR; MULTIDRUG-RESISTANCE GENE; MEMBRANE CHOLESTEROL; CYCLOSPORINE-A; IN-VIVO; EXPRESSION; MDR1; POLYMORPHISMS; IVERMECTIN;
D O I
10.1371/journal.pone.0023614
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
Although the main role of P-glycoprotein (Pgp) is to extrude a broad range of xenochemicals and to protect the organism against xenotoxicity, it also transports a large range of endogenous lipids. Using mice lacking Pgp, we have investigated the possible involvement of Pgp in lipid homeostasis in vivo. In a long term study, we have followed the food intake, body status and lipid markers in plasma and liver of wild-type and mdr1ab(-/-) mice over 35 weeks. Pgp-deficient mice showed excess weight, hypertrophy of adipose mass, high insulin and glucose levels in plasma. Some of these metabolic disruptions appeared earlier in Pgp-deficient mice fed high-fat diet. Moreover, hepatosteatosis with increased expression of genes involved in liver detoxification and in de novo lipid synthesis occurred in Pgp-deficient mice. Overall, Pgp deficiency clearly induced obesity in FVB genetic background, which is known to be resistant to diet-induced obesity. These data reinforce the finding that Pgp gene could be a contributing factor and possibly a relevant marker for lipid disorder and obesity. Subsequent to Pgp deficiency, changes in body availabilities of lipids or any Pgp substrates may affect metabolic pathways that favour the occurrence of obesity. This is of special concern because people are often facing simultaneous exposition to many xenochemicals, which inhibits Pgp, and an excess in lipid dietary intake that may contribute to the high prevalence of obesity in our occidental societies.
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页数:9
相关论文
共 47 条
[1]
Transport of lipids by ABC proteins: Interactions and implications for cellular toxicity, viability and function [J].
Aye, Irving L. M. H. ;
Singh, Ambika T. ;
Keelan, Jeffrey A. .
CHEMICO-BIOLOGICAL INTERACTIONS, 2009, 180 (03) :327-339
[2]
BATT RAL, 1978, INT J OBESITY, V2, P303
[3]
BLIGH EG, 1959, CAN J BIOCHEM PHYS, V37, P911
[4]
Hepatic Expression of Thyroid Hormone-Responsive Spot 14 Protein Is Regulated by Constitutive Androstane Receptor (NR1I3) [J].
Breuker, Cyril ;
Moreau, Amelie ;
Lakhal, Laila ;
Tamasi, Viola ;
Parmentier, Yannick ;
Meyer, Urs ;
Maurel, Patrick ;
Lumbroso, Serge ;
Vilarem, Marie-Jose ;
Pascussi, Jean-Marc .
ENDOCRINOLOGY, 2010, 151 (04) :1653-1661
[5]
Phospholipid transfer protein is regulated by liver X receptors in vivo [J].
Cao, GQ ;
Beyer, TP ;
Yang, XP ;
Schmidt, RJ ;
Zhang, YY ;
Bensch, WR ;
Kauffman, RF ;
Gao, H ;
Ryan, TP ;
Liang, Y ;
Eacho, PI ;
Jiang, XC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (42) :39561-39565
[6]
Endosulfan induces CYP2B6 and CYP3A4 by activating the pregnane X receptor [J].
Casabar, Richard C. T. ;
Das, Parikshit C. ;
DeKrey, Gregory K. ;
Gardiner, Catherine S. ;
Cao, Yan ;
Rose, Randy L. ;
Wallace, Andrew D. .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2010, 245 (03) :335-343
[7]
Regulation of cholesterol 7α-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRα) [J].
Chiang, JYL ;
Kimmel, R ;
Stroup, D .
GENE, 2001, 262 (1-2) :257-265
[8]
Flavonoids: A class of modulators with bifunctional interactions at vicinal ATP- and steroid-binding sites on mouse P-glycoprotein [J].
Conseil, G ;
Baubichon-Cortay, H ;
Dayan, G ;
Jault, JM ;
Barron, D ;
Di Pietro, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (17) :9831-9836
[9]
DEVELOPMENT OF OBESITY IN DIABETIC MICE PAIR-FED WITH LEAN SIBLINGS [J].
COX, JE ;
POWLEY, TL .
JOURNAL OF COMPARATIVE AND PHYSIOLOGICAL PSYCHOLOGY, 1977, 91 (02) :347-358
[10]
Liver X Receptor: an oxysterol sensor and a major player in the control of lipogenesis [J].
Ducheix, S. ;
Lobaccaro, J. M. A. ;
Martin, P. G. ;
Guillou, H. .
CHEMISTRY AND PHYSICS OF LIPIDS, 2011, 164 (06) :500-514