Dietary cholesterol does not normalize low plasma cholesterol levels but induces hyperbilirubinemia and hypercholanemia in Mdr2 P-glycoprotein-deficient mice

Background/Aims: Mdr2 P-glycoprotein deficiency in mice (Mdr2((-/-))) leads to formation of cholesterol/cholesterol-depleted bile and reduced plasma HDL cholesterol. We addressed the questions: (1) does HDL in Mdr2((-/-)) mice normalize upon phospholipid and/or cholesterol feeding, and (2): is the Mdr2((-/-)) liver capable of handling excess dietary cholesterol.Methods: Male and female Mdr2((-/-)) and Mdr2((+/+)) mice were fed diets with or without additional phosphatidylcholine and/or cholesterol, Plasma, hepatic and biliary lipids as well as liver function parameters and expression of transport proteins involved in bile formation were analyzed.Results: Feeding excess phospholipids and/or cholesterol did not affect lipoprotein levels in Mdr2((+/+)) or Mdr2((-/+)) mice. Dietary cholesterol caused hyperbilirubinemia (male +100%; female +500%) and elevated plasma bile salts (male +200 %; female +1250 %) in Mdr2((-/-)) mice only, independent of phospholipids. Bile flow nor biliary bile salt and bilirubin secretion were affected in cholesterol-fed Mdr2((-/-)) mice. Elevated plasma bile salts may be related to cholesterol-induced reduction of hepatic Nac-taurocholate cotransporting protein expression in Mdr2((-/-)) mice.Conclusion: Excess dietary phospholipids and cholesterol do not normalize low HDL associated with Mdr2 P-glycoprotein-deficiency. Induction of hyperbilirubinemia and hypercholanemia by dietary cholesterol in Mdr2((-/-)) mice delineates the important role of biliary lipid secretion in normal hepatic functioning. (C) 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.