Abstract
Scavenger receptor class B, type I (SR-BI) is the high density lipoprotein (HDL) receptor essential for hepatic uptake of HDL cholesterol. SR-BI was shown to impact plasma HDL levels and be anti-atherogenic. Thus, the ability to regulate hepatic SR-BI may allow for the modulation of plasma HDL cholesterol and progression of atherosclerosis. However, regulation of SR-BI in liver is not well understood. Recently, the PDZ domain containing protein PDZK1 was shown to interact with SR-BI and may serve an essential role in SR-BI cell surface expression. Here we identify an in vivo PDZK1-interacting protein that we named small PDZK1-associated protein (SPAP; also known as DD96/MAP17). Unexpectedly, we found that hepatic overexpression of SPAP in mice resulted in liver deficiency of PDZK1. The absence of PDZK1 in SPAP transgenic mice resulted in a deficiency of SR-BI in liver and markedly increased plasma HDL. Metabolic labeling experiments showed that the proteasome plays a role in the turnover of newly synthesized PDZK1, but that SPAP overexpression in liver increased PDZK1 turnover in an alternate, proteasome-independent pathway. Thus, SPAP may be an endogenous regulator of cellular PDZK1 levels by regulating PDZK1 turnover.
Highlights
( known as Diphor-1 [11]/CAP70 [12]/NaPi-Cap1 [13]/ CLAMP [14]) was purified from rat liver extracts by affinity chromatography using the carboxyl terminus of SR-BI [14]
Examination of transgenic mice overexpressing SRclass B, type I (SR-BI)1 is a high-density lipoprotein (HDL) BIdel509 in the liver revealed that SR-BIdel509 protein is not receptor that is highly expressed in the liver and steroidogenic at the plasma membrane, and levels were reduced in liver, tissues and at lower levels in the intestine and vasculature in suggesting that the PDZK1-interacting domain of SR-BI is adult mice [2,3,4,5]
small PDZK1-associated protein (SPAP) is of similar size to the previously identified PDZK1-interacting protein DD96/membrane-associated protein 17 kDa (MAP17)
Summary
( known as Diphor-1 [11]/CAP70 [12]/NaPi-Cap1 [13]/ CLAMP [14]) was purified from rat liver extracts by affinity chromatography using the carboxyl terminus of SR-BI [14]. The absence of PDZK1 in SPAP transgenic mice resulted in a deficiency of SR-BI in liver and markedly increased plasma HDL.
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