Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism.
Secretion of 27-hydroxycholesterol (27OHC) from macrophages is considered as an alternative to HDL-mediated reverse transport of excess cholesterol. We investigated 27OHC-concentrations in plasma of humans and mice with monogenic disorders of HDL metabolism. As compared to family controls mutations in the genes for apolipoprotein A-I, ATP binding cassette transporter (ABC) A1 and lecithin:cholesterol acylstransferase (LCAT) were associated with reduced concentrations of both HDL-cholesterol and HDL-27OHC whereas mutations in the genes for cholesterylester transfer protein (CETP), scavenger receptor type BI and hepatic lipase were associated with elevated HDL concentrations of either sterol. Compared to family controls and relative to the concentrations of total 27OHC and cholesterol, lower 27OHC-ester but normal cholesterylester levels were found in HDL of heterozygous LCAT mutation carriers and nonHDL of heterozygous CETP mutation carriers. In family controls, LCAT activity and CETP mass were more strongly correlated with 27OHC-ester than cholesterylester concentrations in HDL and nonHDL, respectively. These findings suggest that the formation and transfer of 27OHC-esters are more sensitive to reduced activities of LCAT and CETP, respectively, than the formation and transfer of cholesterylesters. 27OHC plasma levels were also decreased in apoA-I-, ABCA1- or LCAT-knockout mice but increased in SR-BI-knockout mice. Transplantation of ABCA1- and/or ABCG1-deficient bone marrow into LDL receptor deficient mice decreased plasma levels of 27OHC. In conclusion, mutations or absence of HDL genes lead to distinct alterations in the quantity, esterification or lipoprotein distribution of 27OHC. These findings argue against the earlier suggestion that 27OHC-metabolism in plasma occurs independently of HDL.
Institute of Clinical Chemistry, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Ratna
R
Karuna
Adriaan G
AG
Holleboom
Mohammad M
MM
Motazacker
Jan Albert
JA
Kuivenhoven
Ruth
R
Frikke-Schmidt
Anne
A
Tybjaerg-Hansen
Spiros
S
Georgopoulos
Miranda
M
van Eck
Theo J C
TJ
van Berkel
Arnold
A
von Eckardstein
Katharina M
KM
Rentsch
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood*; D005260:Female; D005838:Genotype; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood*; D008049:Lipase / Q000235:genetics; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood* / Q000235:genetics; D008074:Lipoproteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000235:genetics; D055815:Young Adult
C577836:ABCA1 protein, human; C487540:ABCG1 protein, mouse; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D015415:Biomarkers; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006888:Hydroxycholesterols; C504173:LIPC protein, human; D008074:Lipoproteins; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C076996:27-hydroxycholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D008049:Lipase