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Differential effects of activation of liver X receptor on plasma lipid homeostasis in wild-type and lipoprotein clearance-deficient mice.

ABSTRACT: The effects of liver X receptor (LXR) agonists on plasma lipid homeostasis, especially triglyceride metabolism are controversial. Here we examined the effect of long-term activation of LXR on plasma lipid homeostasis in wild-type C57BL/6 and LDL receptor deficient (LDLR-/-) mice given the LXR agonist T0901317 for 4 weeks. LXR agonist treatment of wild-type mice decreased plasma total triglycerides by 35% due to a significant reduction of plasma VLDL triglycerides. In contrast, in LDLR-/- mice T0901317 treatment increased plasma total cholesterol and triglycerides. An increase in the level of smaller VLDL particles was also observed in T0901317-treated LDLR-/- mice. The changes in circulating lipoprotein profiles in response to T0901317 treatment in these two animal models reflect the balance between synthesis and secretion on the one hand and lipolysis and clearance on the other. In both models there was both an increase in VLDL production and secretion and in an increase in LPL production and activity in T0901317-treated animals. In wild-type mice lipolysis and clearance predominates, while in the absence of the LDLR, which plays a major role in the clearance of apoB-containing lipoproteins, the increased output predominates. The generation of elevated levels of small VLDL particles due to increased lipolysis may represent an additional risk factor for atherosclerosis.

SUBMITTER: Peng D

PROVIDER: S-EPMC2813337 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Differential effects of activation of liver X receptor on plasma lipid homeostasis in wild-type and lipoprotein clearance-deficient mice.

Peng Dacheng D Hiipakka Richard A RA Xie Jing-Tian JT Reardon Catherine A CA Getz Godfrey S GS Liao Shutsung S

Atherosclerosis 20090708 1

The effects of liver X receptor (LXR) agonists on plasma lipid homeostasis, especially triglyceride metabolism are controversial. Here we examined the effect of long-term activation of LXR on plasma lipid homeostasis in wild-type C57BL/6 and LDL receptor deficient (LDLR-/-) mice given the LXR agonist T0901317 for 4 weeks. LXR agonist treatment of wild-type mice decreased plasma total triglycerides by 35% due to a significant reduction of plasma VLDL triglycerides. In contrast, in LDLR-/- mice T0 ...[more]

PMID: 19632679

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Project description: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.

Dataset Information

Differential effects of activation of liver X receptor on plasma lipid homeostasis in wild-type and lipoprotein clearance-deficient mice.

Publications

Differential effects of activation of liver X receptor on plasma lipid homeostasis in wild-type and lipoprotein clearance-deficient mice.

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