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Evaluation of the contribution of the ATP binding cassette transporter, P-glycoprotein, to in vivo cholesterol homeostasis.


Mol Pharm. 2013 Jun 10;


Authors: Lee SD, Thornton SJ, Sachs-Barrable K, Kim JH, Wasan KM


Abstract

P glycoprotein (Pgp, encoded by ABCB1), an ATP-dependent transporter with a broad range of hydrophobic drug substrates, has been associated with the in vitro intracellular transport of cholesterol; however these findings have not been confirmed in vivo. In this manuscript we tested the contributions of Pgp to in vivo cholesterol homeostasis by comparing the cholesterol phenotype of wild type mice with mice lacking both murine isoforms of Pgp (Abcb1a-/-/1b-/-) by measuring cholesterol absorption, circulating cholesterol, and lipoprotein cholesterol profiles. The mice were fed diets containing normal or high levels of dietary fat (25% vs. 45% kcal from fat) and cholesterol (0.02% vs. 0.20% w/w) for 8 weeks to challenge their capacity to maintain homeostasis. There were no significant differences in cholesterol absorption, circulating cholesterol levels, and lipoprotein profiles between Pgp knockout and wild type mice fed matching diets. Compensatory shifts were observed in the activation of the Liver X Receptor and SREBP-2 transcription factors in the jejunum and liver of the knockout mice, which may have maintained the wild type phenotype. Deletion of Pgp affected the molar composition of gallbladder bile when the mice were fed diets containing high levels of dietary fat, cholesterol, or both. The mole fraction of bile salts was reduced in the gallbladder bile of Pgp knockout mice while cholesterol was increased. In this paper, we provide evidence that Pgp knockout mice maintain cholesterol homeostasis, even when challenged with high cholesterol diets. We suggest that the specific shifts in cholesterol regulatory networks identified in the jejunum and liver of the knockout mice may have compensated for the lack of Pgp. Our finding that Pgp knockout mice were unable to maintain gallbladder bile composition when challenged with high dietary fat and/or cholesterol compliments recent reports that Pgp may be a secondary bile salt export pump.

PMID: 23750858 [PubMed - as supplied by publisher]