Yes, our cells contain organelles called lipid droplets. Lipid droplets are connected to a protein called seipin, and disturbances in their relationship may have harmful consequences.

A few years ago, the research group led by Academy Professor Elina Ikonen took on a new field of research when Veijo Salo, then a medical student, began his thesis project in the group by studying lipid droplets and a protein known as seipin.

Lipid droplets are cell organelles that act as reservoirs for excess lipids and release lipids when cells are in need of energy. Fat, or adipose, cells are filled with these droplets, but they can also be found in other eukaryotic cells.

Lipid droplets are generated in the largest endomembrane of the cell – the endoplasmic reticulum – but the mechanisms underlying their formation are not well understood.

“What we do know is that, in addition to lipid metabolism, they are connected to many other intracellular processes, such as autophagy, protein degradation and virus assemby,” says Salo.

“Perturbations in lipid droplet morphology and function are related to many common diseases, such as diabetes, Alzheimer’s disease and fatty liver.”

Salo's research is focused on the membrane protein seipin, which seems to have a particularly important role in the formation and functioning of lipid droplets.

The story of seipin begins in the 1950s when two doctors, one from Norway and the other from Brazil,  took an interest in muscular and otherwise seemingly healthy patients who were, however, suffering from a serious metabolic disorder: their bodies produced no fat tissue at all.

In 2001, French researchers identified the gene mutation underlying the disease. The gene was named seipin after the Norwegian physician who described the disease.

“Mutations in other genes also cause a similar disease, but the clinical features of the disease caused by seipin deficiency are the most severe," Salo points out.

FROM YEAST TO MICE AND MEN

Some years after the mutation was identified, it was found that seipin plays an essential role in the ability of yeast cells to store lipids. Scientists were excited: if that works in yeast cells, why not in animal cells as well? Researchers studying seipin started to use animal models, such as mice and fruit flies.

In 2011, researchers realised – thanks to research in fruit fly – that seipin has a cell-specific effect on the formation of lipid droplets.

“Seipin research was going full speed ahead when we came along,” says Ikonen. “We thought that the protein still had a lot of interesting unexplored aspects and wanted to investigate it in more detail in human cells."

The effort paid off. In November 2016, the EMBO Journal published the article “Seipin regulates ER–lipid droplet contacts and cargo delivery” by Ikonen’s group.

“We still don’t know what seipin exactly does, but we have made significant progress in finding out. An important molecular-level mechanism where seipin is involved was described in the article published by EMBO.”

HIGH PRECISION MICROSCOPY

High resolution microscopy is key to seipin research, much like in many other membrane studies. The best resolution is obtained with electron microscopy in which the group cooperates closely with Eija Jokitalo's group at the Institute of Biotechnology, University of Helsinki. At Ikonen’s laboratory, living cells can be imaged with high precision.

“We have high-quality equipment – not the best in the world, but very good nonetheless – and Veijo has become very adept at using these devices and methods," enthuses Ikonen.

“The critical factor was the ability to examine what lipid droplets go through right after their formation in cells with seipin deficiency," explains Salo. “In order to do this, we needed cells where the gene that encodes seipin was disrupted.”

“Another important factor is the growth environment of cells; we grew them in a completely lipid-free environment. We acutely added lipids into this environment and observed the results. This way, we were able to observe the earliest moments when the problems began.”

DROPLET AND ANCHOR

What happened next in seipin deficient cells? Lipid droplets formed inside the cell, but they looked peculiar.

“The droplets were abnormally small, and their mobility was much higher than usual. Furthermore, they did not grow in size normally, even when lipids were added to the cell,” says Salo.

The results suggest that seipin regulates the contacts between the endoplasmic reticulum and lipid droplets; the protein may serve as an anchor attaching the droplets to the reticulum, thus facilitating lipid and protein cargo transfer between these two organelles.

“To make a long story short, you could say that seipin keeps the droplets connected to the reticulum in order for the cells to effectively store lipids,” Salo sums up.

 

SEIPIN

Seipin is an endoplasmic reticulum (ER network) membrane protein whose mutations cause three rare genetic diseases in humans:

  • A recessively inherited, severe form of congenital generalised lipodystrophy (BSCL2). Patients develop no fat tissue at all, which causes, among other things, a severe metabolic syndrome.
  • A dominantly inherited motor neuron disease, a type of hereditary spastic paraplegia (HSP).
  • Fatal and early onset neurodegenerative disease (“Celia’s encephalopathy”). The disease is identified by a progressive developmental disorder and short life expectancy (6–8 years).