Evaluation of the Contribution of the ATP Binding Cassette Transporter, P-glycoprotein, to in Vivo Cholesterol Homeostasis

Abstract

P-glycoprotein (Pgp, encoded by ABCB1, commonly known as MDR1), 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 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

Serum 4β-hydroxycholesterol increases during fluconazole treatment

“…While fluconazole was explicitly denied as an inhibitor of transporters (see the “Introduction” section in [ 39 ]), P-glycoprotein (P-gp) is listed in the DrugBank as inhibited by fluconazole. However, the role of these interactions in the present observations on cholesterol metabolism would contrast with the report that P-gp knockout mice maintain cholesterol homeostasis, although these species differences cannot be excluded [ 40 ]. A more likely interaction could involve the organic anion transporting polypeptide 1B1 (OATP1B1), at which fluconazole inhibited substance uptake [ 41 ].…”

The Role of Canalicular ABC Transporters in Cholestasis

“…Its unusual promiscuity has made it hard to find compounds that are not substrates. Accordingly, ABCB1 has been implicated in the transport of various endogenous compounds, such as cholesterol (Lee et al, 2013) (Jetté et al, 1995;Watchko et al, 2001), and tetrahydroxylated bile acids (Megaraj et al, 2010). Most of these compounds were only investigated in vitro and/or showed a low affinity for ABCB1.…”

Liver X receptors at the intersection of lipid metabolism and atherogenesis

“…The molecular mechanisms involved in TICE are still being elucidated. Deciphering these mechanisms may uncover new cholesterol transport pathways 136, 137 .…”