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J Biol Chem. 2015 Jun 19;290(25):15496-511. doi: 10.1074/jbc.M115.646240. Epub 2015 May 6.

Procollagen C-endopeptidase Enhancer Protein 2 (PCPE2) Reduces Atherosclerosis in Mice by Enhancing Scavenger Receptor Class B1 (SR-BI)-mediated High-density Lipoprotein (HDL)-Cholesteryl Ester Uptake.

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the Section of Molecular Medicine, Department of Internal Medicine and the Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101.
the Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut 06268.
From the Department of Medicine and the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Shire Human Genetic Therapies, Lexington, Massachusetts 02421, and.
the Department of Pediatrics, University of Kentucky, Lexington, Kentucky 40506.
From the Department of Medicine and the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226,


Studies in human populations have shown a significant correlation between procollagen C-endopeptidase enhancer protein 2 (PCPE2) single nucleotide polymorphisms and plasma HDL cholesterol concentrations. PCPE2, a 52-kDa glycoprotein located in the extracellular matrix, enhances the cleavage of C-terminal procollagen by bone morphogenetic protein 1 (BMP1). Our studies here focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2-deficient mice to determine whether they protected against diet-induced atherosclerosis. PCPE2-deficient mice were crossed with LDL receptor-deficient mice to obtain LDLr(-/-), PCPE2(-/-) mice, which had elevated HDL levels compared with LDLr(-/-) mice with similar LDL concentrations. We found that LDLr(-/-), PCPE2(-/-) mice had significantly more neutral lipid and CD68+ infiltration in the aortic root than LDLr(-/-) mice. Surprisingly, in light of their elevated HDL levels, the extent of aortic lipid deposition in LDLr(-/-), PCPE2(-/-) mice was similar to that reported for LDLr(-/-), apoA-I(-/-) mice, which lack any apoA-I/HDL. Furthermore, LDLr(-/-), PCPE2(-/-) mice had reduced HDL apoA-I fractional clearance and macrophage to fecal reverse cholesterol transport rates compared with LDLr(-/-) mice, despite a 2-fold increase in liver SR-BI expression. PCPE2 was shown to enhance SR-BI function by increasing the rate of HDL-associated cholesteryl ester uptake, possibly by optimizing SR-BI localization and/or conformation. We conclude that PCPE2 is atheroprotective and an important component of the reverse cholesterol transport HDL system.


apolipoprotein; atherosclerosis; cholesterol metabolism; extracellular matrix protein; high-density lipoprotein (HDL); scavenger receptor

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