Reduced plasma cholesterol and increased fecal sterol loss in multidrug resistance gene 2 P-glycoprotein-deficient mice

Background & Aims: mdr2 P-glycoprotein (Pgp) deficiency in mice leads to the absence of biliary phospholipids and cholesterol in the presence of normal bile salt secretion. The aim of this study was to evaluate the importance of the biliary pathway in cholesterol homeostasis by determining the effects of mdr2 Pgp deficiency on; hepatic and plasma lipid levels and cholesterol kinetics in chow-fed mice. Methods: Hepatic lipid content, enzyme activities, plasma lipoprotein levels, and fecal sterol excretion were measured in wild-type (+/+) and mdr2 Pgp-deficient (-/-) mice. Cholesterol kinetics were determined using radiotracer techniques. Results: No differences in hepatic lipid content were observed between (-/-) and (+/+) mice. Plasma high-density lipoprotein cholesterol and apolipoprotein A-I levels were strongly reduced in (-/-) mice compared with controls, whereas the apolipoprotein B contents of very-low-density lipoprotein and low-density lipoprotein were increased. Hepatic activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase was threefold greater in (-/-) mice than in controls; however, compartmental analysis of plasma cholesterol decay showed no differences in cholesterol synthesis between (-/-) and (+/+) mice. A dual isotope approach for estimating cholesterol absorption yielded similar to 50% lower values in (-/-) mice than in controls. Surprisingly, (-/-) mice showed a fourfold increase in fecal neutral sterol secretion. Conclusions: This study unequivocally establishes the important direct role of biliary lipids in the regulation of plasma lipid levels in mice.