Disruption of the murine lecithin:cholesterol acyltransferase gene causes impairment of adrenal lipid delivery and up-regulation of scavenger receptor class B type I.
Lecithin:cholesterol acyltransferase (LCAT) is the major determinant of the cholesteryl ester (CE) content of high density lipoprotein (HDL) in plasma. The selective uptake of HDL-CE is postulated to participate in delivery of tissue-derived cholesterol both to the liver and steroidogenic tissues. Recent studies comparing mice with similarly low levels of HDL, due to the absence of either of the two major HDL-associated apolipoproteins apoA-I and apoA-II, suggest that apoA-I is crucial in modulating this process, possibly through interaction with scavenger receptor class B type I (SR-BI). Because of the central role of LCAT in determining the size, lipid composition, and plasma concentration of HDL, we have created LCAT-deficient mice by gene targeting to examine the effect of LCAT deficiency on HDL structure and composition and adrenal cholesterol delivery. The HDL in the LCAT-deficient mice was reduced in its plasma concentration (92%) and CE content (96%). The HDL particles were heterogeneous in size and morphology and included numerous discoidal particles, mimicking those observed in LCAT-deficient humans. The adrenals of the male Lcat (-/-) mice were severely depleted of lipid stores, which was associated with a 2-fold up-regulation of the adrenal SR-BI mRNA. These studies demonstrate that LCAT deficiency, similar to apoA-I deficiency, is associated with a marked decrease in adrenal cholesterol delivery and supports the hypothesis that adrenal SR-BI expression is regulated by the adrenal cholesterol.
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D S
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Human Genome Center, Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA.
Francone
O L
OL
Forte
T M
TM
Zhang
J
J
Haghpassand
M
M
Rubin
E M
EM
D000311:Adrenal Glands / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood; D015139:Blotting, Southern; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002788:Cholesterol Esters / Q000097:blood; D018390:Gene Targeting; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000378:metabolism*; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008854:Microscopy, Electron; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D015854:Up-Regulation
D016632:Apolipoprotein A-I; D018955:CD36 Antigens; D002788:Cholesterol Esters; D008055:Lipids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D007862:Phosphatidylcholine-Sterol O-Acyltransferase