In a recent Science Advances article researchers show how hungry human liver cells find energy. This study, 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.

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.

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 processes.

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.

Researchers 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 the first author.

"Rab10 switches on and builds up around the lipid droplet," says the senior author. "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."