Title
Dietary cholesterol does not normalize low plasma cholesterol levels but induces hyperbilirubinemia and hypercholanemia in Mdr2 P-glycoprotein-deficient mice
Author
Voshol, P.J.
Koopen, N.R.
de Vree, J.M.L.
Havinga, R.
Princen, H.M.G.
Oude Elferink, R.P.J
Groen, A.K.
Kuipers, F.
Gaubius Instituut TNO
Publication year
2001
Abstract
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 Na+-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. © 2001 European Association for the Study of the Liver. Chemicals/CAS: Antigens, CD36; ATP-Binding Cassette Transporters; Bile Acids and Salts; Carrier Proteins; Cholesterol, 57-88-5; Cholesterol, Dietary; DNA Primers; Membrane Proteins; Membrane Transport Proteins; multidrug resistance protein 3; Organic Anion Transporters, Sodium-Dependent; P-Glycoproteins; Receptors, Immunologic; Receptors, Lipoprotein; Receptors, Scavenger; RNA, Messenger; Scarb1 protein, mouse; Scavenger Receptors, Class B; sodium-bile acid cotransporter, 145420-23-1; Symporters
Subject
Animals
Antigens, CD36
ATP-Binding Cassette Transporters
Base Sequence
Bile
Bile Acids and Salts
Carrier Proteins
Cholesterol
Cholesterol, Dietary
DNA Primers
Female
Gene Expression
Hyperbilirubinemia
Liver
Male
Membrane Proteins
Membrane Transport Proteins
Mice
Mice, Knockout
Organic Anion Transporters, Sodium-Dependent
P-Glycoproteins
Receptors, Immunologic
Receptors, Lipoprotein
Receptors, Scavenger
RNA, Messenger
Scavenger Receptors, Class B
Symporters
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DOI
https://doi.org/10.1016/s0168-8278(00)00021-0
TNO identifier
235998
ISSN
0168-8278
Source
Journal of Hepatology, 34 (2), 202-209
Document type
article