Abstract 665: Human PDZK1 Expression Enhanced the Human SR-BI (CLA-1) Expression in the Liver of CLA-1 Transgenic Mouse
[Background] SR-BI is an HDL receptor that mediates the selective cholesterol uptake from HDL. We have reported that human SR-BI (CLA-1) does not influence the HDL cholesterol metabolism in CLA-1 transgenic mouse. PDZK1 is an associate protein with SR-BI in the liver stabilizing the receptor in the membrane. To clarify the regulatory mechanism of CLA-1’s expression in the liver, we generated human PDZK1 BAC transgenic mouse.
[Results & Conclusion] In CLA-1 transgenic mouse CLA-1 is transcribed in the liver with a corresponding level to that of the endogenous SR-BI. However, the protein level of CLA-1 was low in the liver compared with that of the endogenous mouse SR-BI. As a result CLA-1 transgene does not impact on the plasma total / HDL cholesterol levels. On the other hand, CLA-1 is expressed in the macrophages and facilitates cholesterol efflux from the cell to HDL. Nonetheless, CLA-1 transgene stimulated the atherosclerotic lesion formation in CLA-1 transgenic mouse fed with the atherogenic diet. This observation suggests the anti-atherogenic magnitude of SR-BI in the liver facilitating the removal of HDL-cholesterol not in the macrophages. To investigate the regulatory mechanism of the molecule’s expression in the liver CLA-1 transgenic mouse with SR-BI−/− background was crossbred with human PDZK1 BAC transgenic mouse. Whereas the PDZK1 transgene does not impact on the mRNA levels of CLA-1 nor of endogenous SR-BI, human PDZK1 increases the protein expression of CLA-1 in the liver (figure⇓). PDZK1 is proved to be an important molecule regulating the CLA-1 expression in the liver impacting on the HDL mediated reverse cholesterol transport in human.