Abstract 191: Adipocyte Procollagen C-endopeptidase Enhancer Protein 2 (PCPE2) Influences Lipid Metabolism Secondary to Changes in Expression and Function of Scavenger Receptor Class B Member 1 (SR-BI)

Abstract

Scavenger receptor class B member 1 (SR-BI) functions as a HDL receptor and stimulates reverse cholesterol transport (RCT) via selective uptake of HDL cholesterol esters (HDL-CE). Procollagen c-endopeptidase enhancer protein 2 (PCPE2) is an extracellular matrix glycoprotein encoded by the PCOLCE2 gene and most highly expressed in adipose tissue, heart, and aorta. PCPE2 has been suggested to be atheroprotective secondary to mechanisms involved in lipid metabolism. Our lab previously reported that SR-BI mediated cholesterol ester uptake is reduced in the absence of PCPE2 despite its increased expression levels. Subsequent HDL turnover studies suggested an overall reduction in catabolism, consistent with larger HDL particles observed, is responsible for the paradox. More recently, human data from the TwinsUK study showed strong correlations between PCOLCE2 and adipose tissue distribution with BMI included as a covariate. Furthermore, despite similar overall body weights, our lab observed a significant reduction in visceral fat pad development in PCPE2-deficient mice fed a Western diet for 25 weeks when compared to wild type mice. In addition, our lab has generated PCPE2 knockout cell lines from murine preadipocyte 3T3-L1 cells (PCPE2 -/- 3T3-L1) and Chinese hamster ovary (CHO) cells using CRISPR-Cas9 and siRNA technology, respectfully. In addition to both cell lines showing increased SR-BI expression, differentiated PCPE2 -/- 3T3-L1 cells have impaired lipid droplet formation. To elucidate the relationship between PCPE2 and SR-BI function and their effects on adipose tissue development, we performed RNA sequencing on visceral adipose tissue from PCPE2-deficient male mice fed a Western diet for 12 weeks. Genes exhibiting significant expression alterations (FDR <0.026) compared to wild type were further analyzed via Ingenuity Pathway Analysis (IPA). Differential expression analysis of diseases and functions related to changes in SR-BI expression highlighted permutations of a number of lipid modulating genes. Overall, changes in SR-BI related metabolic pathways secondary to PCPE2 deficiency appear to play a crucial role linking SR-BI mediated cholesterol ester uptake to adipocyte biology.