Review
Lipid synthesis and transport are coupled to regulate membrane lipid dynamics in the endoplasmic reticulum

https://doi.org/10.1016/j.bbalip.2019.05.005Get rights and content

Highlights

  • •

    Lipid synthesizing enzymes are under product inhibition.

  • •

    Lipid transport from the ER helps maintain lipid synthesis.

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    Inositol lipids control lipid transport between membranes.

Abstract

Structural lipids are mostly synthesized in the endoplasmic reticulum (ER), from which they are actively transported to the membranes of other organelles. Lipids can leave the ER through vesicular trafficking or non-vesicular lipid transfer and, curiously, both processes can be regulated either by the transported lipid cargos themselves or by different secondary lipid species. For most structural lipids, transport out of the ER membrane is a key regulatory component controlling their synthesis. Distribution of the lipids between the two leaflets of the ER bilayer or between the ER and other membranes is also critical for maintaining the unique membrane properties of each cellular organelle. How cells integrate these processes within the ER depends on fine spatial segregation of the molecular components and intricate metabolic channeling, both of which we are only beginning to understand. This review will summarize some of these complex processes and attempt to identify the organizing principles that start to emerge. This article is part of a Special Issue entitled Endoplasmic reticulum platforms for lipid dynamics edited by Shamshad Cockcroft and Christopher Stefan.

Section snippets

Localization of enzymes for de novo phosphatidic acid biosynthesis

The biosynthetic pathways responsible for the synthesis of various phospholipids were already established between the late 1950s and early 1970s and have been thoroughly summarized in many excellent reviews (e.g. [1,2] (Fig. 1)). These intricate metabolic pathways became increasingly complicated in the genomic era after the identification of multiple genes encoding enzymes that seemingly carry out the same enzymatic reaction. While many of these enzymes are located in the ER, as expected, the

Most phospholipid synthesizing enzymes are under feed-back inhibition

While the amounts of the enzymes required for phospholipid synthesis are subject to transcriptional regulation, their activities are also directly controlled by the lipid composition of the very membranes to which they are localized. Selected examples of these regulatory processes will be discussed below.

Lipid transport is critical for the control of lipid synthesis

The picture that emerges from the above examples is that the synthesis of phospholipids must be tightly coupled to the transport processes that prevent accumulation of the lipid products at the site of synthesis. It is entirely possible, that the activity of lipid synthesizing enzymes were found highest in membrane preparations that contained contact sites, because the lipid products can be moved away from the ER in such preparations. Lipids can be transported out from the ER by lipid transfer

Concluding remarks

The specific lipid composition of membranes is critical for defining organelle identity and the proper assembly and function of protein complexes that work on those organelles. Lipid synthesis and distribution are fine-tuned to maintain the unique lipid composition of membranes. The product inhibition characterized in most lipid synthesizing enzymes makes lipid transport processes not only important for lipid distribution, but also for the dynamic regulation of lipid synthesis. Non-vesicular

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Declaration of Competing Interest

The Authors declare no conflict of interest related to this work.

Acknowledgement

We would like to thank Dr. Joshua Pemberton for many fruitful discussions and for his suggestions during the writing of this manuscript. The work of the authors is supported by the intramural research program of the Eunice Kennedy Shriver NICHD, at the National Institutes of Health.

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