Lipid droplet (LD) formation is a hallmark of cellular stress. Cells attempt to combat noxious stimuli by switching their metabolism from oxidative phosphorylation to glycolysis, sparing resources in LDs for generating cellular reducing power and for anabolic biosynthesis. Membrane phospholipids are also a source of LDs. To elucidate the formation of LDs, we exposed mice to hyperoxia, hypoxia, myocardial ischemia, and sepsis induced by cecal ligation and puncture (CLP). All the above-mentioned stressors enhanced the formation of LDs, as assessed by transmission electron microscopy, with severe mitochondrial swelling. Disruption of mitochondria by depleting mitochondrial DNA (ρ0 cells) significantly augmented the formation of LDs, causing transcriptional activation of fatty acid biosynthesis and metabolic reprogramming to glycolysis. Heme oxygenase (HO)-1 counteracts CLP-mediated septic shock in mouse models. In HO-1-deficient mice, LD formation was not observed upon CLP, but a concomitant decrease in “LD-decorating proteins” was observed, implying a link between LDs and cytoprotective activity. Collectively, LD biogenesis during stress can trigger adaptive LD formation, which is dependent on mitochondrial integrity and HO-1 activity; this may be a cellular survival strategy, apportioning energy-generating substrates to cellular defense. 1. Introduction Intracellular lipid droplets (LDs) store neutral lipids, including triacylglycerol and cholesterol esters, in cells [1]. LDs are surrounded by a unique phospholipid monolayer that is decorated with many proteins, among which adipocyte differentiation-related protein (ADRP) and the perilipin family are well characterized [2–4]. Although LDs were initially considered to be static organelles for fat storage, it is becoming increasingly evident that alterations in the regulation of formation and breakdown of LD can affect the risk of metabolic disorders such as diabetes and related diseases [5–8]. Recently, the biology of LDs has gained public interest because of the causal link between excess lipid storage in certain tissues and pathophysiologies related to obesity [9, 10]. In these cases, LDs are likely to interfere with membrane trafficking of the insulin-sensitive glucose transporter, which might account for the insulin resistance common in patients with type 2 diabetes [11]. LDs are formed under two very different environmental conditions that are not mutually exclusive. First, cells accumulate LDs in response to exogenous lipid availability. It is thought that the fatty acids in LDs are stored for
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