A Novel Process Maintaining Glycerophospholipid Homeostasis in Mammalian Cells

Abstract

Glycerophospholipid (GPL) homeostasis in eukaryotic cells is thought to be maintained via biosynthesis, degradation and acyl chain remodeling. Here we provide evidence for an additional process termed "head-group remodeling" where other GPLs, when in excess, are rapidly converted to phosphatidylcholine and triacylglycerol. Mass spectrometric studies showed the formation of diacylglycerol, but not phosphatidic acid, from the exogenous GPL thus indicating that the first step is catalyzed by a phospholipase C-type enzyme. Consistently, triacylglycerol formation was significantly inhibited by the knock-down of several PLCs, but not phospholipase Ds. Second, we found that each exogenous GPL strongly inhibited the synthesis of the corresponding endogenous GPL class. Based on these and previous data we hypothesize how mammalian cells could coordinate the multiple processes contributing to GPL homeostasis in mammalian cells. In conclusion, this study provides the first evidence that head group remodeling plays an important role in GPL homeostasis in mammalian cells.

Hypothesis: Chemical activity regulates and coordinates the processes maintaining glycerophospholipid homeostasis in mammalian cells

“…Recently, we have shown that loading of any common GPL to HeLa, BHK-21, or CHO cells strongly inhibited the synthesis of the corresponding GPL class. 22,23 The GPL molecules in excess in a membrane should have an increased chemical activity, which should promote their binding to the active or a regulatory site of the synthetizing enzyme thus inhibiting its activity. Alternatively, the molecules in excess could, for example, in case of CTT, inhibit membrane association and thus the activity of the synthetizing enzyme.…”

“…Extensive knock-down studies indicated that different enzymes (including PLCs or similar enzymes) catalyze the initial, committed step of the interconversion or "head group remodeling". 23 Since loading of an exogenous GPL to the cells should greatly increase the chemical activity of the respective GPL class, it is most likely that chemical activity drives head group remodeling. A particular benefit of this novel homeostatic process is that it requires far less cellular energy than biosynthesis de novo, simply because the fatty acids need not to be activated to CoA derivatives.…”

“…Due to the shortcomings indicated above as well as recent novel data of the synthesis and degradation of GPLs we hypothesize here that the chemical activity of the different GPLs regulate and coordinate their metabolism thus maintaining the GPL homeostasis. We propose (a) that when the mole fraction of one GPL class deviates from an optimal value, its chemical activity changes abruptly due to weakened interactions with the proximal molecules (Figure ) and (b) such abrupt changes in the chemical activity of the different GPLs regulate and coordinate multiple homeostatic process including synthesis, degradation, interconversion (head group remodeling), and interorganelle translocation of GPLs (Figure ).…”

“…Early studies have also indicated that, beside PS and PC, the synthesis of PI may also be regulated by a feed‐back mechanism in rat pituitary cells, but the details of this process remain unclear. Recently, we have shown that loading of any common GPL to HeLa, BHK‐21, or CHO cells strongly inhibited the synthesis of the corresponding GPL class . The GPL molecules in excess in a membrane should have an increased chemical activity, which should promote their binding to the active or a regulatory site of the synthetizing enzyme thus inhibiting its activity.…”

“…We have recently found that exogenous PE, PS, PI, PG, and PA are rapidly and effectively converted to PC when loaded to HeLa cells . Notably, blocking of fatty acyl‐CoA formation with Triacsin C had no effect on the conversion to PC thus excluding the possibility that deacylation of the GPL precursor, followed by incorporation of released fatty acids to PC via synthesis de novo is involved in the process.…”