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

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 −/− ) and Ldlr −/− (control) mouse adipose tissue showed elevated SR-BI protein levels, but significantly reduced HDL-C uptake. 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.

Pcpe2: A New Partner for the Scavenger Receptor Class B Type I in High-Density Lipoprotein Selective Lipid Uptake

“…6 This is similar to the effects of a lack of Pcpe2 on hepatic HDL cholesterol uptake reported previously by Sorci-Thomas and coworkers in which they demonstrated impaired HDL reverse cholesterol transport and increased atherosclerosis development in LDLR (lowdensity lipoprotein receptor)-deficient mice that also lacked Pcolce2 gene expression. 8 Xu et al 6 now report that loss of Pcpe2 in LDLR-deficient mice was accompanied by reductions in the sizes of different adipose tissue depots including visceral, subcutaneous, and brown adipose tissue and increased glucose tolerance in both male and female mice that had been fed a high-fat, high-cholesterol diet. Despite the reductions in the sizes of adipose tissue depots, the sizes of adipocytes, at least in visceral adipose tissue, were increased in Pcpe2 compared with control mice.…”

“…6 Furthermore, the levels of Pcolce2 gene expression were correlated with the amount of visceral fat in a mouse genetic diversity panel and with body mass index, percentage of fat, and plasma insulin levels in obese subjects slated for bariatric surgery. 6 Together, these findings point to an important role for Pcpe2 in the regulation of adipose tissue cholesterol levels, obesity, and insulin resistance in both model laboratory mice and in humans. But just how does Pcpe2 deficiency bring about this regulation in adipocyte cholesterol homeostasis?…”

“…A number of studies have reported that SR-B1 partially localizes in plasma membrane subdomains including lipid rafts, caveolae, and microvillar channels. [9][10][11] Xu et al found that in adipose tissue from control mice, with intact Pcpe2 gene expression, SR-B1 was found in both lipid raft and nonlipid raft fractions, whereas in adipose tissue from Pcpe2-deficient mice, very little SR-B1 was found in the lipid raft fraction, 6 suggesting that Pcpe2 may be required for the partial lipid raft localization of SR-B1 in the plasma membrane. Could this redistribution of SR-B1 out of lipid rafts explain the inability of SR-B1 to mediate selective HDL lipid uptake in the Pcpe2-deficient adipocytes?…”

“…[9][10][11][12][13][14][15] Other potential mechanisms by which Pcpe2 protein promoted selective HDL lipid uptake by SR-B1 were suggested by Xu et al First, Pcpe2 might bind to HDL and facilitate HDL binding to SR-B1 in a manner that allows for selective HDL lipid uptake. 6 Second, Pcpe2 might interact with SR-B1 to facilitate SR-B1 oligomerization. 6 In support of the first possibility, Pcpe2 is known to bind to apolipoprotein A1, 16,17 HDL's major protein constituent, although its binding to SR-B1 does not appear to have been tested.…”

SR-B1’s Next Top Model: Structural Perspectives on the Functions of the HDL Receptor

“…SR-B1’s localization and clustering in sphingolipid-rich microdomains [ 2 ] and ability to interact with itself or other proteins likely impacts receptor function. For example, the extracellular matrix protein procollagen C-endopeptidase enhancer protein 2 (PCPE2) has recently been shown to enhance SR-B1’s cholesterol transport functions in hepatocytes [ 98 ] and adipocytes [ 99 ]. SR-B1 has been reported to serve as a co-factor to facilitate SARS-CoV-2 entry into cells [ 58 •].…”