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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / analogs & derivatives*
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Acetylcysteine / pharmacology
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Amino Acid Sequence
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Animals
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CD36 Antigens / genetics
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CD36 Antigens / physiology
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Cholesterol, HDL / blood*
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Chromatography, High Pressure Liquid
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Cysteine Endopeptidases
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Electrophoresis, Polyacrylamide Gel
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Enzyme Inhibitors / pharmacology
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Gene Expression
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Gene Expression Regulation
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Humans
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Liver / chemistry
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Liver / metabolism
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Membrane Proteins / analysis
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Membrane Proteins / chemistry
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Membrane Proteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Molecular Sequence Data
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Multienzyme Complexes / antagonists & inhibitors
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Neoplasm Proteins
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Proteasome Endopeptidase Complex
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Receptors, Immunologic*
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Receptors, Lipoprotein*
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Receptors, Scavenger
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Scavenger Receptors, Class B
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Transfection
Substances
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CD36 Antigens
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Cholesterol, HDL
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Enzyme Inhibitors
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Membrane Proteins
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Multienzyme Complexes
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Neoplasm Proteins
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PDZK1IP1 protein, human
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Pdzk1ip1 protein, mouse
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Receptors, Immunologic
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Receptors, Lipoprotein
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Receptors, Scavenger
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SCARB1 protein, human
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Scarb1 protein, mouse
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Scavenger Receptors, Class B
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lactacystin
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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Acetylcysteine