title: P-glycoprotein dysfunction contributes to hepatic steatosis and obesity in mice.
abstract: 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.
authors.affiliation: UMR1331, INP, UPS, TOXALIM, INRA, Toulouse, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Foucaud-Vignault
authors.forename: Zeina
authors.initials: Z
authors.lastname: Soayfane
authors.forename: Cécile
authors.initials: C
authors.lastname: Ménez
authors.forename: Justine
authors.initials: J
authors.lastname: Bertrand-Michel
authors.forename: Pascal Guy Pierre
authors.initials: PG
authors.lastname: Martin
authors.forename: Hervé
authors.initials: H
authors.lastname: Guillou
authors.forename: Xavier
authors.initials: X
authors.lastname: Collet
authors.forename: Anne
authors.initials: A
authors.lastname: Lespine
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics*; D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D000072467:Cytochrome P450 Family 2; D059305:Diet, High-Fat; D004435:Eating; D064429:Fatty Acid Synthases / Q000235:genetics; D005234:Fatty Liver / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000032:analysis / Q000097:blood; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001189:Aryl Hydrocarbon Hydroxylases; D001786:Blood Glucose; D000072467:Cytochrome P450 Family 2; D064429:Fatty Acid Synthases; D007328:Insulin; D008055:Lipids; D013230:Stearoyl-CoA Desaturase; D013250:Steroid Hydroxylases; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3; C101679:Cyp2b10 protein, mouse; C490333:Scd1 protein, mouse