title: Inhibitory action of benzo[α]pyrene on hepatic lipoprotein receptors in vitro and on liver lipid homeostasis in mice.
abstract: BACKGROUND
  Dyslipidemia associated with obesity often manifests as increased plasma LDL and triglyceride-rich lipoprotein levels suggesting changes in hepatic lipoprotein receptor status. Persistent organic pollutants have been recently postulated to contribute to the obesity etiology by increasing adipogenesis, but little information is available on their potential effect on hepatic lipoprotein metabolism.
  
  
  OBJECTIVE
  The objective of this study was to investigate the effect of the common environmental pollutant, benzo[α]pyrene (B[α]P) on two lipoprotein receptors, the LDL-receptor and the lipolysis-stimulated lipoprotein receptor (LSR) as well as the ATP-binding cassette transporter A1 (ABCA1) using cell and animal models.
  
  
  RESULTS
  LSR, LDL-receptor as well as ABCA1 protein levels were significantly decreased by 26-48% in Hepa1-6 cells incubated (<2 h) in the presence of B[α]P (≤1 µM). Real-time PCR analysis and lactacystin studies revealed that this effect was due primarily to increased proteasome, and not lysosomal-mediated degradation rather than decreased transcription. Furthermore, ligand blots revealed that lipoproteins exposed to 1 or 5 µM B[α]P displayed markedly decreased (42-86%) binding to LSR or LDL-receptor. B[α]P-treated (0.5 mg/kg/48 h, i.p. 15 days) C57BL/6J mice displayed higher weight gain, associated with significant increases in plasma cholesterol, triglycerides, and liver cholesterol content, and decreased hepatic LDL-receptor and ABCA1 levels. Furthermore, correlational analysis revealed that B[α]P abolished the positive association observed in control mice between the LSR and LDL-receptor. Interestingly, levels of other proteins involved in liver cholesterol metabolism, ATP-binding cassette transporter G1 and scavenger receptor-BI, were decreased, while those of acyl-CoA:cholesterol acyltransferase 1 and 2 were increased in B[α]P-treated mice.
  
  
  CONCLUSIONS
  B[α]P demonstrates inhibitory action on LSR and LDL-R, as well as ABCA1, which we propose leads to modified lipid status in B[α]P-treated mice, thus providing new insight into mechanisms underlying the involvement of pollutants in the disruption of lipid homeostasis, potentially contributing to dyslipidemia associated with obesity.
authors: Unité de Recherche Animal et Fonctionnalités des Produits Animaux EA3998, Université de Lorraine, Vandœuvre-lès-Nancy, France; Institut National de Recherche Agronomique USC 0340, Vandœuvre-lès-Nancy, France.
authors: Hamed
authors: H
authors: Layeghkhavidaki
authors: Unité de Recherche Animal et Fonctionnalités des Produits Animaux EA3998, Université de Lorraine, Vandœuvre-lès-Nancy, France; Institut National de Recherche Agronomique USC 0340, Vandœuvre-lès-Nancy, France.
authors: Marie-Claire
authors: MC
authors: Lanhers
authors: Unité de Recherche Animal et Fonctionnalités des Produits Animaux EA3998, Université de Lorraine, Vandœuvre-lès-Nancy, France; Institut National de Recherche Agronomique USC 0340, Vandœuvre-lès-Nancy, France.
authors: Samina
authors: S
authors: Akbar
authors: Unité de Recherche Animal et Fonctionnalités des Produits Animaux EA3998, Université de Lorraine, Vandœuvre-lès-Nancy, France; Institut National de Recherche Agronomique USC 0340, Vandœuvre-lès-Nancy, France.
authors: Lynn
authors: L
authors: Gregory-Pauron
authors: Unité de Recherche Animal et Fonctionnalités des Produits Animaux EA3998, Université de Lorraine, Vandœuvre-lès-Nancy, France; Institut National de Recherche Agronomique USC 0340, Vandœuvre-lès-Nancy, France.
authors: Thierry
authors: T
authors: Oster
authors: Laboratory of Analytical Human Biomonitoring, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg.
authors: Nathalie
authors: N
authors: Grova
authors: Laboratory of Analytical Human Biomonitoring, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg.
authors: Brice
authors: B
authors: Appenzeller
authors: Laboratoire d'Ingenérie des Biomolécules, Université de Lorraine, Vandœuvre-lès-Nancy, France.
authors: Jordane
authors: J
authors: Jasniewski
authors: Unité de Recherche Animal et Fonctionnalités des Produits Animaux EA3998, Université de Lorraine, Vandœuvre-lès-Nancy, France; Institut National de Recherche Agronomique USC 0340, Vandœuvre-lès-Nancy, France.
authors: Cyril
authors: C
authors: Feidt
authors: Unité de Recherche Animal et Fonctionnalités des Produits Animaux EA3998, Université de Lorraine, Vandœuvre-lès-Nancy, France; Institut National de Recherche Agronomique USC 0340, Vandœuvre-lès-Nancy, France.
authors: Catherine
authors: C
authors: Corbier
authors: Unité de Recherche Animal et Fonctionnalités des Produits Animaux EA3998, Université de Lorraine, Vandœuvre-lès-Nancy, France; Institut National de Recherche Agronomique USC 0340, Vandœuvre-lès-Nancy, France; Institut National de la Santé et de la Recherche Médicale, Vandœuvre-lès-Nancy, France.
authors: Frances T
authors: FT
authors: Yen
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D066298:In Vitro Techniques; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011973:Receptors, LDL / Q000378:metabolism*; D018110:Receptors, Lipoprotein / Q000378:metabolism*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001564:Benzo(a)pyrene; D002784:Cholesterol; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; C000592022:LSR protein, mouse