Fat Prospects for Cellular Recycling


Fatty molecules are made-to-order when a piece of essential cellular machinery is needed

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Prof. Zvulun Elazar and his team have revealed a new role for fat molecules in the cell

 Accumulating fat may not sound like a good idea, but it all depends where this fat is stored. Weizmann Institute scientists have revealed that fat molecules found in microscopic sacs called lipid droplets play an essential role in the life of the cell. These take part in the formation of cellular machinery that performs autophagy, a recycling process that maintains body tissues in good order, breaking down unwanted cellular components and maintaining adequate energy levels in times of need. Disruptions in this process can lead to cancer, neurological or inflammatory disorders and numerous other diseases.
The molecular machinery for autophagy is formed on demand. A membrane is created inside the cell, enwrapping part of the cell’s contents, elongating and ultimately sealing itself off to produce the structure that then enables the cellular recycling. Until now, it was unknown exactly how this membrane formed or even how it procured the materials needed for its construction.
 A green fluorescent-labeled protein serves as a marker for autophagy. Autophagy occurs when the protein accumulates within the relevant organelle (left); when diffused throughout the cell (right), the labeled protein signals that no autophagy is taking place
Prof. Zvulun Elazar of Weizmann Institute’s Biological Chemistry Department has been studying autophagy for more than a decade, but it took him and Dr. Tomer Shpilka, then a graduate student, some detective work to discover that lipid droplets play a role in this process. As reported recently in the Proceedings of the National Academy of Sciences (PNAS), USA, and in the EMBO Journal, the scientists discovered a connection between autophagy and the synthesis of fat molecules called fatty acids. They found that the enzyme responsible for this synthesis was degraded by autophagy, but once this enzyme was fully degraded, the autophagy also stopped. This suggested that the fatty acid synthesis was a self-regulating process. It also suggested that this process was needed for autophagy to take place. 
The researchers further learned that it was complex molecules called phospholipids that were necessary for autophagy to occur, and that these phospholipids had to be newly formed each time from the fatty acids and other ingredients stored within lipid droplets. Like most of the fat in our bodies, the fatty molecules within these droplets has been traditionally viewed mainly as an energy reservoir, but the new study suggests that they perform much more targeted and sophisticated roles, including serving as building blocks for the autophagy machinery.
 A yeast cell genetically engineered not to produce lipid droplets, viewed under an electron microscope. After exposure to certain stressful conditions, the organelle called endoplasmic reticulum (top right corner) has become abnormally enlarged, which suggests a connection between this organelle and lipid droplets
Through a series of experiments that used genetic manipulation and other methods, the researchers were able to show that lipid droplets were indeed essential for autophagy. When the formation of droplets was blocked, autophagy failed to occur. Moreover, for autophagy to proceed successfully, these storage organelles had to be found at the right place at the right time.
The scientists further revealed that the large cellular organelle known as the endoplasmic reticulum appears to contribute to the construction of the autophagy machinery. They found that close contacts between this organelle and lipid droplets were pivotal for the manufacture of the autophagy membrane. The researchers also identified a number of genes responsible for regulating both autophagy and the formation of lipid droplets. 
Electron microscopic images reveal autophagy taking place in specialized structures (marked by *) in regular yeast cells (left), but not in cells that lack lipid droplets (right)
 Elazar’s team also included Dr. Evelyn Welter, Noam Borovsky, Frida Shimron, Dr. Yoav Peleg and Dr. Nira Amar, as well as researchers from The Netherlands.
These studies were performed on yeast, but the mechanism they uncovered is highly relevant to human cells. Autophagy is involved in a large number of biological processes and in a variety of diseases. For example, autophagy helps protect the digestive tract from infectious organisms, but when overzealous, it can contribute to such disorders as Crohn’s disease; in cancer, autophagy helps malignant cells to survive inside certain oxygen-deprived tumors. Thus in the future, new treatments for these diseases might be developed by controlling the process of autophagy.
Prof. Zvulun Elazar’s research is supported by the Wohl Biology Endowment Fund; and Paul and Tina Gardner, College Station, TX. Prof. Elazar is the incumbent of the Harold L. Korda Professorial Chair of Biology.