Coexpression of CLA-1 and human PDZK1 in murine liver modulates HDL cholesterol metabolism.
OBJECTIVE
In rodents scavenger receptor class B type I (SR-BI) is a key molecule for selective uptake of cholesteryl ester from high-density lipoprotein (HDL). This study was aimed to clarify the role of the human SR-BI/CD36 and LIMP-II Analogues-1 (CLA-1) as a molecular target of selective uptake of cholesteryl ester from HDL in vivo.


RESULTS
To clarify the function and regulation of CLA-1 in vivo we produced CLA-1 BAC transgenic mice. In spite of abundant hepatic RNA expression of CLA-1, CLA-1 BAC transgenic mice had no significant effect on mouse HDL cholesterol. Although coexpression of a human scaffolding protein PDZK1 along with CLA-1 enhanced hepatic CLA-1 expression, it did not affect mouse HDL cholesterol levels, either. However, in the presence of human apoA-1, HDL cholesterol level and size were significantly reduced in CLA-1 transgenic mice, and its reduction was more pronounced in CLA-1/human PDZK1 double transgenic mouse.


CONCLUSIONS
We established a mouse model to study human reverse cholesterol transport by expressing CLA-1, human PDZK1, and human apoA-I gene. Our results imply that enhancing CLA-1 expression by human PDZK1 in the liver can modulate HDL cholesterol metabolism and possibly enhance reverse cholesterol transport to prevent the progression of atherosclerosis in human.
Komori
Hidenori
H
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Arai
Hidenori
H
Kashima
Terumi
T
Huby
Thierry
T
Kita
Toru
T
Ueda
Yukihiko
Y
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism*; D022202:Chromosomes, Artificial, Bacterial; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*
C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D002352:Carrier Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008565:Membrane Proteins; C484659:PDZK1 protein, human; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B