Between 30 and 40% of the population have, or are leading
toward getting, nonalcoholic fatty liver disease. In a recent Science Advances article, Mayo Clinic
researchers show how hungry human liver cells find energy.
done in rat and human liver cells, reports on the role of a small
regulatory protein that acts like a beacon to help cells locate lipids
and provides new information to support the development of therapies for
fatty liver disease.
‘When a protein Rab10 is switched on, it will bind to a lipid droplet and cause the autophagosome to dock on the droplet surface, recruit other proteins, and digest the lipid into a free fatty acid energy source.’
While the mechanisms involved in fat accumulation are the usual
targets of research for fatty liver disease, clarifying the cell's
mechanism for breaking down fat also could provide valuable information
to fuel the discovery of breakthrough treatments in the future.
Fueling the hungry cell
In a well-fed cell, fat deposits, called lipid droplets, are
nutritional insurance. They are ignored by the cell as it fuels growth
and division via its normal pathway. But, in a starving cell, the normal
pathway switches off, and a recycling process, called autophagy,
switches on. Autophagy is a way for cells to break down macromolecules,
such as protein and fat, into their component parts to be used in cell
Under starvation conditions, the cell's recycling pathway directs
specialized vessels to engulf lipid droplets. These vessels, called
autophagosomes, then link with another organelle, called a lysosome,
which is filled with acidic enzymes. When these two merge, the resulting
structure is called an autolysosome. Within the autolysosome, the
enzymes break apart the fat droplet free fatty acids.
How does a hungry cell find the fat? It follows the beacon
Zhipeng Li, first author and a student at Mayo Clinic Graduate
School of Biomedical Sciences, noticed that, within the hungry cells,
one protein, called Rab10, was intimately associated with many of the
lipid droplets. Rab proteins operate like switches; when bound to a
substance, they switch on and facilitate interactions in the cell. There
are more than 60 different Rab switches, or small regulatory GTPases,
in the human genome.
"In this paper, we show that, when Rab10 is switched on, it will
bind to a lipid droplet and cause the autophagosome to dock on the
droplet surface, recruit other proteins, and digest the lipid into a
free fatty acid energy source," says Li.
Dr. Mark McNiven, senior author on the paper and director of Mayo Clinic's Center
for Biomedical Discovery explains that cells have sensors that detect low energy levels and respond.
"Rab10 switches on and builds up around the lipid droplet," says Dr. McNiven. "Then, the cell activates its lysosomes that then targets
these lipid droplets and goes after them. So this was an important step
that we provided between the sensing mechanism of starvation and how
that is signaling to this switch to go after lipid droplets."