Targeted Disruption of the PDZK1 Gene in Mice Causes Tissue-specific Depletion of the High Density Lipoprotein Receptor Scavenger Receptor Class B Type I and Altered Lipoprotein Metabolism

Abstract

PDZK1, a multi-PDZ domain containing adaptor protein, interacts with various membrane proteins, including the high density lipoprotein (HDL) receptor scavenger receptor class B type I (SR-BI). Here we show that PDZK1 controls in a tissue-specific and post-transcriptional fashion the expression of SR-BI in vivo. SR-BI protein expression in PDZK1 knock-out (KO) mice was reduced by 95% in the liver, 50% in the proximal intestine, and not affected in steroidogenic organs (adrenal, ovary, and testis). Thus, PDZK1 joins a growing list of adaptors that control tissue-specific activity of cell surface receptors. Hepatic expression of SR-BII, a minor splice variant with an alternative C-terminal cytoplasmic domain, was not affected in PDZK1 KO mice, suggesting that binding of PDZK1 to SR-BI is required for controlling hepatic SR-BI expression. The loss of hepatic SR-BI was the likely cause of the elevation in plasma total and HDL cholesterol and the increase in HDL particle size in PDZK1 KO mice, phenotypes similar to those observed in SR-BI KO mice. PDZK1 KO mice differed from SR-BI KO mice in that the ratio of unesterified to total plasma cholesterol was normal, females were fertile, and cholesteryl ester stores in steroidogenic organs were essentially unaffected. These differences may be due to nearly normal extrahepatic expression of SR-BI in PDZK1 KO mice. The PDZK1-dependent regulation of hepatic SR-BI and, thus, lipoprotein metabolism supports the proposal that this adaptor may represent a new target for therapeutic intervention in cardiovascular disease.

Ras/Mitogen-activated Protein Kinase (MAPK) Signaling Modulates Protein Stability and Cell Surface Expression of Scavenger Receptor SR-BI

“…This study indicates that PPAR␣-inducible SR-BI degradation pathways are triggered by HDL or other ligands that activate the Ras/MAPK pathway. As hepatic SR-BI expression positively correlates with biliary cholesterol secretion (2,(33)(34)(35)(36)(37)(38)(39)(40), one can speculate that HDL-induced activation of Mek1/2 kinases, followed by PPAR␣ phosphorylation and subsequent SR-BI degradation, is a feedback loop to fine-tune cholesterol homeostasis in the liver.…”

“…Because fibrates down-regulate SR-BI, but also PDZK1, which is essential for maintaining hepatic SR-BI levels (2,36,37,40), it was originally speculated that decreased hepatic SR-BI levels upon PPAR␣ activation might be secondary to decreased PDZK1. Also, an atherogenic diet induces post-translational down-regulation of both SR-BI and PDZK1 in mouse liver (68).…”

“…Recently, the PDZ domain containing protein PDZK1 was identified to interact and stabilize SR-BI cell surface expression in mouse hepatocytes (38 -40). Loss of hepatic SR-BI in PDZK1 KO mice suggest that PDZK1 is essential for maintaining hepatic SR-BI levels (40). However, PPAR␣-inducible SR-BI degradation in mouse liver appears independent of PDZK1 (37).…”

Prostacyclin receptors: Transcriptional regulation and novel signalling mechanisms

“…Similar to prostacyclin and the IP, through its activation of SR-B1, HDL also plays an essential protective role within the CV system where it regulates re-endothelialization as well as RCT, maintaining endothelial integrity and protecting against atherosclerosis and restenosis 118,119 . By binding to its C-terminal PDZ ligand, PDZK1 plays an essential role in maintaining SR-BI expression levels in the liver, thereby controlling HDL cholesterol levels, and is now also known to play a key role in HDL/SR-BI-regulation of EC migration, promoting re-endothelialization 117,120,121 …”

Noncanonical Role of the PDZ4 Domain of the Adaptor Protein PDZK1 in the Regulation of the Hepatic High Density Lipoprotein Receptor Scavenger Receptor Class B, Type I (SR-BI)

“…It interacts with several membrane-associated proteins such as cell surface receptors and ion channels (2,6). One of these PDZK1-interacting proteins is the HDL receptor scavenger receptor class B type I (SR-BI) (7)(8)(9). SR-BI is a 509-amino acid cell-surface glycoprotein with a large extracellular loop, two trans-membrane domains, and short cytoplasmic N and C termini (10).…”