title: Cell-to-cell heterogeneity in lipid droplets suggests a mechanism to reduce lipotoxicity.
abstract: 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, nonalcoholic fatty liver disease is the most common cause of abnormal hepatic function among adults [4, 5]. Lipotoxicity gradually promotes cellular ballooning and disarray, megamitochondria, 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 and 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.
authors.affiliation: Equip de Proliferació i Senyalització Cel·lular, Institut d'Investigacions Biomèdiques August Pi i Sunyer IDIBAPS, 08036 Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Herms
authors.forename: Marta
authors.initials: M
authors.lastname: Bosch
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ariotti
authors.forename: Babu J N
authors.initials: BJ
authors.lastname: Reddy
authors.forename: Alba
authors.initials: A
authors.lastname: Fajardo
authors.forename: Andrea
authors.initials: A
authors.lastname: Fernández-Vidal
authors.forename: Anna
authors.initials: A
authors.lastname: Alvarez-Guaita
authors.forename: Manuel Alejandro
authors.initials: MA
authors.lastname: Fernández-Rojo
authors.forename: Carles
authors.initials: C
authors.lastname: Rentero
authors.forename: Francesc
authors.initials: F
authors.lastname: Tebar
authors.forename: Carlos
authors.initials: C
authors.lastname: Enrich
authors.forename: María-Isabel
authors.initials: MI
authors.lastname: Geli
authors.forename: Robert G
authors.initials: RG
authors.lastname: Parton
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gross
authors.forename: Albert
authors.initials: A
authors.lastname: Pol
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005434:Flow Cytometry; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry* / Q000502:physiology; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D001896:Boron Compounds; D005227:Fatty Acids; D008055:Lipids; D017382:Reactive Oxygen Species