Cell-to-Cell Heterogeneity in Lipid Droplets Suggests a Mechanism to Reduce Lipotoxicity

Abstract

Summary Lipid droplets (LDs) are dynamic organelles that collect, store, and supply lipids [1]. LDs have a central role in the exchange of lipids occurring between the cell and the environment, and provide cells with substrates for energy metabolism, membrane synthesis, and production of lipid-derived molecules such as lipoproteins or hormones. However, lipid-derived metabolites also cause progressive lipotoxicity [2]; accumulation of reactive oxygen species (ROS), endoplasmic reticulum stress, mitochondrial malfunctioning, and cell death [2]. Intracellular accumulation of LDs is a hallmark of prevalent human diseases including obesity, steatosis, diabetes, myopathies, and arteriosclerosis [3]. Indeed, non-alcoholic fatty liver disease is the most common cause of abnormal hepatic function among adults [4, 5]. Lipotoxicity gradually promotes cellular ballooning and disarray, megamitochondria, and accumulation of Mallory’s hyaline in hepatocytes and inflammation, fibrosis, and cirrhosis in the liver. Here, using confocal microscopy, serial-block-face scanning electron microscopy, and flow-cytometry we show that LD accumulation is heterogeneous within a cell population and follows a positive skewed distribution. Lipid availability and fluctuations in biochemical networks controlling lipolysis, fatty acid oxidation, and protein synthesis, contribute to cell-to-cell heterogeneity. Critically, this reversible variability generates a subpopulation of cells that effectively collect and store lipids. This high-lipid subpopulation accumulates more LDs, more ROS, and reduces the risk of lipotoxicity to the population without impairing overall lipid homeostasis, since high-lipid cells can supply stored lipids to the other cells. In conclusion, we demonstrate fat storage compartmentalization within a cell population and propose that this is a protective social organization to reduce lipotoxicity.

Lipid droplet functions beyond energy storage

“…Both the LD protein PLIN2 (Lsd-2) and the last enzyme in triglyceride biosynthesis, DGAT1, are required specifically in glial cells for LDs and also to dampen ROS levels and mitigate oxidative damage in glia and in neuroblasts [27]. The notion that only a subpopulation of cells may need to accumulate LDs in order to protect the entire tissue has also been proposed for non-alcoholic fatty liver disease, where LD abundance is very variable from one hepatocyte to another [125]. In Drosophila , one of the beneficial roles of glial LDs is to store the abundant PUFA linoleate as triglyceride, thus sequestering it away from the membrane phospholipid pool [27].…”

Phospholipase A2 regulation of lipid droplet formation

“…It has recently been shown in hepatocytes that the LDs within a given cell or among cells of the same tissue show a remarkable heterogeneity [18]. Thus it has been suggested that the existence of cells containing high lipid levels within a cell population could potentially reduce lipotoxicity to the average cell without impairing overall lipid homeostasis [18].…”

The why, when and how of lipid droplet diversity

“…Everyone who has ever looked at the lipid droplets of different cell lines or tissues quickly realizes that lipid droplets vary within and between cell types in terms of their spatial organization, number and size ( Fig. 2) (for example, see Gocze and Freeman, 1994;Herms et al, 2013;Szymanski et al, 2007). Drosophila S2 cells, for example, carry many small lipid droplets of equal size (Krahmer et al, 2011) (Fig.…”