Pcpe2, a Novel Extracellular Matrix Protein, Regulates Adipocyte SR-BI-Mediated High-Density Lipoprotein Uptake

Arterioscler Thromb Vasc Biol. 2021 Nov;41(11):2708-2725. doi: 10.1161/ATVBAHA.121.316615. Epub 2021 Sep 23.

Abstract

Objective: To investigate the role of adipocyte Pcpe2 (procollagen C-endopeptidase enhancer 2) in SR-BI (scavenger receptor class BI)-mediated HDL-C (high-density lipoprotein cholesterol) uptake and contributions to adipose lipid storage.

Approach and results: Pcpe2, a glycoprotein devoid of intrinsic proteolytic activity, is believed to participate in extracellular protein-protein interactions, supporting SR-BI- mediated HDL-C uptake. In published studies, Pcpe2 deficiency increased the development of atherosclerosis by reducing SR-BI-mediated HDL-C catabolism, but the biological impact of this deficiency on adipocyte SR-BI-mediated HDL-C uptake is unknown. Differentiated cells from Ldlr-/-/Pcpe2-/- (Pcpe2-/-) mouse adipose tissue showed elevated SR-BI protein levels, but significantly reduced HDL-C uptake compared to Ldlr-/- (control) adipose tissue. SR-BI-mediated HDL-C uptake was restored by preincubation of cells with exogenous Pcpe2. In diet-fed mice lacking Pcpe2, significant reductions in visceral, subcutaneous, and brown adipose tissue mass were observed, despite elevations in plasma triglyceride and cholesterol concentrations. Significant positive correlations exist between adipose mass and Pcpe2 expression in both mice and humans.

Conclusions: Overall, these findings reveal a novel and unexpected function for Pcpe2 in modulating SR-BI expression and function as it relates to adipose tissue expansion and cholesterol balance in both mice and humans.

Keywords: HDL; Pcolce2; adipose tissue; cholesterol; diet; extracellular matrix; lipoprotein; metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism*
  • Adipocytes / pathology
  • Adipogenesis
  • Adiposity
  • Adult
  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • CHO Cells
  • Caveolin 1 / metabolism
  • Cholesterol, HDL / metabolism*
  • Cricetulus
  • Diet, High-Fat
  • Disease Models, Animal
  • Energy Metabolism
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Humans
  • Inflammation Mediators / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Membrane Microdomains / genetics
  • Membrane Microdomains / metabolism*
  • Membrane Microdomains / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism
  • Scavenger Receptors, Class B / genetics
  • Scavenger Receptors, Class B / metabolism*
  • Subcutaneous Fat / metabolism*
  • Subcutaneous Fat / pathology

Substances

  • Cav1 protein, mouse
  • Caveolin 1
  • Cholesterol, HDL
  • Extracellular Matrix Proteins
  • Glycoproteins
  • Inflammation Mediators
  • Intracellular Signaling Peptides and Proteins
  • PCOLCE2 protein, human
  • Pcolce2 protein, mouse
  • Receptors, LDL
  • Scarb1 protein, mouse
  • Scavenger Receptors, Class B