Evaluation of the Contribution of the ATP Binding
Cassette Transporter, P‑glycoprotein, to <i>in Vivo</i> Cholesterol
Homeostasis
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Abstract
P-glycoprotein
(Pgp, encoded by <i>ABCB1</i>, commonly
known as MDR1), an ATP-dependent transporter with a broad range of
hydrophobic drug substrates, has been associated with the <i>in vitro</i> intracellular transport of cholesterol; however,
these findings have not been confirmed <i>in vivo</i>. In
this manuscript we tested the contributions of Pgp to <i>in vivo</i> cholesterol homeostasis by comparing the cholesterol phenotype of
wild type mice with mice lacking both murine isoforms of Pgp (<i>Abcb1a</i><sup>–/–</sup>/<i>1b</i><sup>–/–</sup>) 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 two key transcription factors involved in maintaining cholesterol
balance, the Liver X Receptor and SREBP-2, which may have maintained
the wild type phenotype in the knockout mice. 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 the mole fraction of 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