Abstract
BackgroundDyslipidemia 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.ObjectiveThe 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.ResultsLSR, 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.ConclusionsB[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.
Highlights
Obesity has become an increasing problem of public health in the industrialized world [1,2], and represents a significant risk factor for many pathologies including cardiovascular disease and diabetes
The removal of lipoproteins from the circulation is mediated by hepatic lipoprotein receptors, including the low-density lipoprotein (LDL)-receptor (LDL-R), well-known for its key role in the regulation of cholesterol metabolism [5], but which participates in the removal of TGRL
We first sought to determine the effect of benzo[a ]pyrene (B[a ]P) on LSR, LDL-R in mouse Hepa1-6 cells, which have been shown previously to express both of these lipoprotein receptors [8]
Summary
Obesity has become an increasing problem of public health in the industrialized world [1,2], and represents a significant risk factor for many pathologies including cardiovascular disease and diabetes. The lipolysis stimulated lipoprotein receptor (LSR) has recently been shown by our laboratory and others to play an important role in the removal of TGRL during the postprandial phase [6,7,8] If these receptors are deficient (LSR+/2) or lacking (LDL-R-/-) in mice, the animals exhibit changes in plasma lipid levels, and significantly higher weight gain when placed under highfat diets as compared to wild-type littermates [9,10]. 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
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