Differential effects of scavenger receptor BI deficiency on lipid metabolism in cells of the arterial wall and in the liver.
Scavenger receptor class B, type I (SRBI) is a key regulator of high density lipoprotein (HDL) metabolism. It facilitates the efflux of cholesterol from cells in peripheral tissues to HDL and mediates the selective uptake of cholesteryl esters from HDL in the liver. We investigated the effects of SRBI deficiency in the arterial wall and in the liver using SRBI-deficient mice and wild-type littermates fed a Western-type diet. The SRBI-deficient mice showed massive accumulation of cholesterol-rich HDL in the circulation, reflecting impaired delivery to the liver. Strikingly, SRBI deficiency did not alter hepatic cholesterol (ester) content nor did it affect the expression of key regulators of hepatic cholesterol homeostasis, including HMG-CoA reductase, the low density lipoprotein receptor, and cholesterol 7alpha-hydroxylase. However, a approximately 40% reduction in biliary cholesterol content was observed, and the expression of ABCG8 and ABCG5, ATP half-transporters implicated in the transport of sterols from the liver to the bile, was attenuated by 70 and 35%, respectively. In contrast to the situation in the liver, SRBI deficiency did result in lipid deposition in the aorta and atherosclerosis. Vascular mRNA analysis showed increased expression of inflammatory markers as well as of genes involved in cellular cholesterol homeostasis. Our data show that, although hepatic cholesterol homeostasis is maintained upon feeding a Western-type diet, SRBI deficiency is associated with de-regulation of cholesterol homeostasis in the arterial wall that results in an increased susceptibility to atherosclerosis.
Van Eck
Miranda
M
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.m.eck@LACDR.LeidenUniv.nl
Twisk
Jaap
J
Hoekstra
Menno
M
Van Rij
Brechje T
BT
Van der Lans
Christian A C
CA
Bos
I Sophie T
IS
Kruijt
J Kar
JK
Kuipers
Folkert
F
Van Berkel
Theo J C
TJ
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000166:cytology / Q000473:pathology*; D001161:Arteriosclerosis / Q000209:etiology; D018955:CD36 Antigens / Q000235:genetics / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism*; D004036:Diet, Atherogenic; D005786:Gene Expression Regulation; D022781:Hepatocytes; D050356:Lipid Metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B
D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D008076:Cholesterol, HDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D002784:Cholesterol