Scientists discover lipid metabolism with simulations and experiments

The schematic illustration exhibits how lipid composition influences lipid droplet formation and the way seipin traps and accumulates triglycerides and diacylglycerols inside its ring-shaped construction. Credit score: Analysis group Stefano Vanni, College of Fribourg

In people and animals, fats cells produce and retailer fats in particular organelles, that are specialised subunits throughout the cell, referred to as lipid droplets. The lipid droplets make up the most important a part of the quantity of those fats cells, often known as adipocytes. Adipocytes fulfill important duties defending our organs, in addition to elements of the physique which can be delicate to chilly, and so they function a supply of reserve power. However after we eat an excessive amount of fat-rich meals, the adipocytes and thus the fats deposits develop excessively, main, within the worst-case state of affairs, to the event of pathologies equivalent to weight problems and obesity-related ailments. In distinction, sure people develop a illness as a result of no lipid droplets are fashioned in any respect. The related medical image is known as lipodystrophy, wherein the affected people are unable to retailer lipids and thus develop into critically in poor health.

Along with adipocytes, each single cell of the human organism incorporates lipid droplets. The organelles serve primarily as power suppliers, for instance throughout cell development, however they’re additionally concerned in lipid metabolism contained in the cells.

“The position of lipid droplets is crucial. And when lipid storage is poorly regulated, pathologies equivalent to weight problems, lipodystrophy and most cancers develop,” says Stefano Vanni, SNSF professor on the College of Fribourg. Correct regulation of lipid storage is subsequently important for each single cell in your complete organism.

Simulating lipid metabolism

Vanni and his analysis crew are investigating how these lipid droplets retailer lipids in cells. The scientists run coarse-grain molecular dynamics simulations—the place chemical teams are represented by particular person beads to simplify the illustration of complicated methods—on the CSCS supercomputer “Piz Daint” to higher perceive the mechanisms concerned in lipid storage on the molecular stage. Their analysis findings on lipid metabolism had been just lately revealed in each eLife and the Proceedings of the Nationwide Academy of Sciences.

Within the first examine, they investigated how lipid droplets are fashioned. As was recognized from earlier research, the droplets kind after accumulation of fats between the 2 leaflets of the endoplasmic reticulum membrane, one other organelle of the cell. The endoplasmic reticulum expands all through your complete cell quantity and, amongst different issues, performs an necessary position in lipid metabolism. Nonetheless, precisely how the formation of lipid droplets is linked to the endoplasmic reticulum and the way the method is regulated was nonetheless unclear.

“One issue in simulating lipid droplets is their magnitude: With a measurement of fifty to 100 nanometers, they’re giant objects in comparison with particular person proteins,” says Vanni. Because of this very giant computing sources are wanted for his or her simulations, however, in flip, the outcomes obtained could be immediately in contrast with in vivo observations of the organelles beneath the microscope. The scientists subsequently in contrast their conclusions from the simulations of how lipid droplets are fashioned to the outcomes of an experimental analysis group additionally based mostly on the College of Fribourg. Particularly, the experimental group investigated the impact of gene-modification on lipid droplet formation in yeast cells, noticed in vivo utilizing fluorescence microscopy.

Several types of lipids guarantee correct lipid droplet formation

By combining in silico and in vivo experiments, the researchers had been capable of present that the so-called phospholipids, the lipids that represent the membranes of the endoplasmic reticulum, both promote or stop the aggregation of triglycerides, that are the principle type of fats in lipid droplets. In response to the outcomes, phospholipids with monounsaturated fatty acids of their construction appear to favor the formation of lipid droplets. Nonetheless, the other occurs when quick saturated fatty acids are current within the phospholipids: Much less lipid droplets are fashioned, and the free triglycerides transfer into the endoplasmic reticulum membrane as a substitute of accumulating in lipid droplets.

Primarily based on their findings, the researchers conclude that lipid droplet formation removes stress from the endoplasmic reticulum: By driving free triglycerides from the 2 leaflets of the endoplasmic reticulum membrane into lipid droplets, the cells are protected against excessive fatty acid ranges (lipotoxicity) that might in the end result in cell loss of life.

How the protein seipin controls lipid droplets constructing

With additional simulations, Vanni and his co-workers additionally investigated the position of the protein seipin, since current works have proven that lipid droplets formation at all times happens on the websites the place this protein is current. The precise position of seipin within the technique of lipid droplets formation continues to be unclear—the protein was found solely twenty years in the past in reference to the above-mentioned lipodystrophy, says Vanni, as particular mutations within the protein may cause the illness. Certainly one of seipin’s mysteries, in response to Vanni, is that when the protein is knocked out the lipid droplets don’t merely disappear. Somewhat, both very giant or very small lipid droplets are fashioned, making it obscure the protein’s perform.

The simulations that Vanni’s group carried out present that seipin traps and accumulates triglycerides inside its ring-shaped construction and—surprisingly for the researchers—additionally the precursors of a lot of these fat, particularly diacylglycerols. Nonetheless, if mutations are launched within the particular seipin area that traps triglycerides, the formation of the lipid droplets is hindered. The examine additionally means that the protein seipin remodels sure websites of the endoplasmic reticulum, making ready them for the formation of lipid droplets. With a greater understanding of the mechanisms underlying fats metabolism, researchers hope to clarify why, for instance, polyunsaturated fat are more healthy than unsaturated fat, and why the latter ought to be decreased in our weight loss plan. As well as, the outcomes may assist to enhance the understanding of metabolic ailments associated to fats storage and thus assist within the growth of medicine or dietary merchandise.

Lipid droplets assist defend kidney cells from harm

Extra info:
Valeria Zoni et al, Pre-existing bilayer stresses modulate triglyceride accumulation within the ER versus lipid droplets, eLife (2021). DOI: 10.7554/eLife.62886

Valeria Zoni et al, Seipin accumulates and traps diacylglycerols and triglycerides in its ring-like construction, Proceedings of the Nationwide Academy of Sciences (2021). DOI: 10.1073/pnas.2017205118

Scientists discover lipid metabolism with simulations and experiments (2021, June 9)
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