The story about how research on cellular fat clumps led to the discovery of a newabnormality in Niemann-Pick disease type C
Nagoya University Graduate School of Medicine
Professor Toyoshi Fujimoto
Most cells in the human body contain fatty clumps called lipid droplets.

We conducted

research aimed at clarifying the mechanism by which lipid droplets are dissolved. As a result, we
happened to obtain results related to the intractable hereditary disease called Niemann-Pickdisease type C. This was something very unexpected and the pleasure of basic research. Hereis a brief history of our study.
Lipid droplets store fat that is not necessary for the moment as esters. For more than adecade, our research has focused on how lipid droplets are made and broken down and what theymean to cells.
In this study, we used yeast to investigate the mechanism of lipid droplet breakdown.
Yeast is a useful material for this kind of research because they have a similar structure to humancells and can be genetically manipulated easily. When yeast cells are placed in a nutrient-richsolution, they proliferate by repeating division, but after a few days, the nutrients in the solution
are depleted, and they stop dividing and enter a state called the "stationary phase.” Yeast in
this state can be regarded as a model for human central nervous cells, which do not divide either.
In the stationary phase of yeast, lipid droplets are engulfed by a bag-like structure called avacuole, which is made of a single membrane, and are broken down by digestive enzymes inside
the vacuole.

As a result, fatty acids are released from lipid esters contained in the lipid

droplets and used as a energy source for theyeast. Sterols (equivalent to cholesterol inChanges in vacuoles as captured
by electron microscopy

human cells) are also released from thelipid droplets, and these sterols are

Vacuolesincorporated to the membrane of thevacuole. By electron microscopy, we
found that, when the sterol content of thevacuolar membrane increases, thevacuolar membrane begins to show afootball-like polygonal shape, and that
lipid droplets are surrounded by theYeast in the proliferation
phase

Yeast in the stationaryphasepolygonal membrane.
The result up to this point was somewhat expected from previous studies, but what isinteresting is as follows. As I mentioned earlier, those sterols were incorporated into the vacuole
membrane, but in fact, this does not happen spontaneously. This process requires a protein (NPC

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Lipid droplet
Sterol released from lipid dropletprotein) mutated in patients of NiemannPick disease type C. If the NPC protein is
not functioning correctly, lipid droplet uptakeVacuoles

gradually decreases, and yeast will slowly diedue to insufficient energy supply.

TheNPC protein changes the properties of thevacuole membrane by transferring free sterols
NPC
proteinfrom the lipid droplets to the vacuole
membrane, allowing more fat droplets to be

A deformed vacuole engulfs
lipid droplets more efficiently

Sterols are delivered to thevacuolar membrane by NPC
proteins

taken up and digested. This enables yeast to
survive longer because it can efficiently
obtain fatty acids as a source of energy.

Although NPC proteins have been known to be involved in sterol transport, it has beenbelieved that the transported sterols are immediately transported to other parts of the cell.

The

present results reveal for the first time that sterols transported by NPC proteins are required forthe function of the vacuole (equivalent to lysosomes in human cells) membrane itself (i.e., lipid
droplet uptake).
The enlarged liver and spleen seen in patients with Niemann-Pick disease type C are thought
to be caused by inadequate functioning of the NPC protein, which results in the accumulation ofcholesterol in lysosomes. On the other hand, it is less well understood why the abnormalities
occur in the CNS of NPC patients. We presume that the reduced uptake of lipid droplets, as
shown in this study, may cause CNS abnormalities, although it will need to be studied in humancells.
The results of this research were published in the international journal eLife (Tsuji et al, eLife
6, e25960, 2017; https://elifesciences.org/articles/25960) and in the eLife digest section, which
introduces the contents to the general public.

The journal is freely accessible without asubscription fee, so please look if you are interested.

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