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J. Biol. Chem., Vol. 281, Issue 39, 28975-28980, September 29, 2006

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PDZK1 Is Required for Maintaining Hepatic Scavenger Receptor, Class B, Type I (SR-BI) Steady State Levels but Not Its Surface Localization or Function^*

Ayce Yesilaltay, Olivier Kocher, Rinku Pal, Andrea Leiva^¶, Verónica Quiñones^¶, Attilio Rigotti^¶, and Monty Krieger¹

From the Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Department of Pathology, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and ^¶Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Marcoleta 367, 833-0024 Santiago, Chile

PDZK1 is a multi-PDZ domain-containing adaptor protein that binds to the C terminus of the high density lipoprotein receptor, scavenger receptor, class B, type I (SR-BI), and controls the posttranscriptional, tissue-specific expression of this lipoprotein receptor. In the absence of PDZK1 (PDZK1(-/-) mice), murine hepatic SR-BI protein levels are very low (<5% of control). As a consequence, abnormal plasma lipoprotein metabolism (1.5-1.7-fold increased total plasma cholesterol carried in both normal size and abnormally large high density lipoprotein particles) resembles, but is not as severely defective as, that in SR-BI(-/-) mice. Here we show that the total plasma cholesterol levels and size distribution of lipoproteins are virtually identical in SR-BI(-/-) and SR-BI(-/-)/PDZK1(-/-) mice, indicating that most, if not all of the effects of PDZK1 on lipoprotein metabolism are likely because of the effects of PDZK1 on SR-BI. Hepatic overexpression of wild-type SR-BI in PDZK1(-/-) mice restored near or greater than normal levels of cell surface-expressed, functional SR-BI protein levels in the livers of SR-BI(-/-)/PDZK1(-/-) mice and consequently restored apparently normal lipoprotein metabolism in the absence of PDZK1. Thus, PDZK1 is important for maintaining adequate steady state levels of SR-BI in the liver but is not essential for cell surface expression or function of hepatic SR-BI.

Received for publication, April 20, 2006 , and in revised form, July 10, 2006.

^* This work was supported by National Institutes of Health Grants HL64737, HL66105 (to M. K.), and TW006153 (to M. K. and A. R.), a grant from the Beth Israel Deaconess Medical Center Pathology Foundation, Inc. (to O. K.), and Grant 1030416 from the Fondo Nacional de Desarrollo Científico y Tecnológico (to A. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biology, Massachusetts Institute of Technology, Rm. 68-483, 77 Massachusetts Ave., Cambridge, MA 02139. Tel.: 617-253-6793; Fax. 617-258-5851; E-mail: krieger{at}mit.edu.

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