Abstract
Maintaining cellular lipid homeostasis is crucial to oxidative tissues, and it becomes compromised in obesity. Lipid droplets (LD) play a central role in lipid homeostasis by mediating fatty acid (FA) storage in the form of triglyceride, thereby lowering intracellular levels of lipids that mediate cellular lipotoxicity. LDs and mitochondria have interconnected functions, and anecdotal evidence suggests they physically interact. However, the mechanisms of interaction have not been identified. Perilipins are LD-scaffolding proteins and potential candidates to play a role in their interaction with mitochondria. We examined the contribution of LD perilipin composition to the physical and metabolic interactions between LD and mitochondria using multiple techniques: confocal imaging, electron microscopy (EM), and lipid storage and utilization measurements. Using neonatal cardiomyocytes, reconstituted cell culture models, and rodent heart tissues, we found that perilipin 5 (Plin5) recruits mitochondria to the LD surface through a C-terminal region. Compared with control cells, Plin5-expressing cells show decreased LD hydrolysis, decreased palmitate β-oxidation, and increased palmitate incorporation into triglycerides in basal conditions, whereas in stimulated conditions, LD hydrolysis inhibition is lifted and FA released for β-oxidation. These results suggest that Plin5 regulates oxidative LD hydrolysis and controls local FA flux to protect mitochondria against excessive exposure to FA during physiological stress.
Highlights
Maintaining cellular lipid homeostasis is crucial to oxidative tissues, and it becomes compromised in obesity
Because of difficulty in obtaining isolated lipid droplets from heart tissue, the subcellular distribution of mitochondria and Lipid droplets (LD) was investigated in neonatal cardiac myocytes, a cell culture model that expresses detectable levels of endogenous perilipin 5 (Plin5) at the LD surface in response to fatty acid incubation (Fig. 2)
At the metabolic level, we show that Plin5 stabilizes LDs by inhibiting hydrolysis and channeling fatty acid (FA) to triglyceride stores at the expense of FA oxidation by the mitochondria, and Plin5 releases FA to mitochondria -oxidation when adenyl cyclase is activated with forskolin
Summary
Maintaining cellular lipid homeostasis is crucial to oxidative tissues, and it becomes compromised in obesity. This article must be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Cellular energy homeostasis of oxidative tissue relies on a critical balance between fatty acid (FA) uptake from the environment and consumption by mitochondria oxidation These processes are controlled by complex regulatory mechanisms that ensure energy needs are met while preventing buildup of toxic lipid intermediates and/or oxidized lipids. RNA interference (RNAi) functional screens in Drosophila and mammalian cells have identified several biochemical pathways regulating LD biogenesis and utilization [4, 5] These studies established that the LD compartment is not just a passive sink storing intracellular FAs, but rather, it is a highly regulated, metabolically active organelle with a wide range of functions involving lipid flux, protein trafficking, and interaction with other organelles, including mitochondria [4,5,6]. Functional and physical interactions between these two essential components of cellular energy homeostasis are well accepted, the genes and mechanisms regulating this pathway have not been identified
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