Lipid Droplets as Signaling Platforms Linking Metabolic and Cellular Functions

Arrese, Estela L.; Saudale, Fredy Z.; Soulages, José L.

doi:10.4137/lpi.s11128

Cited by 48 publications

(36 citation statements)

References 182 publications

(322 reference statements)

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“…More recently, LDs have emerged as 45 a dynamic organelle that frequently interact with other organelles and are involved in protein 46 sequestration and transfer between organelles. LDs have also been demonstrated to act as a 47 scaffolding platform to regulate signalling cascades, highlighting their diverse functions [1][2][3][4] . was able to significantly enhance the production of IFN-β and IFN-λ protein by as much as 182 2.6 and 3.6-fold in the presence of dsRNA and 2.0 and 2.1-fold in the presence of dsDNA.…”

Section: Introductionmentioning

confidence: 99%

Intracellular Lipid Droplet Accumulation Occurs Early Following Viral Infection and Is Required for an Efficient Interferon Response

Monson

Duan

Chen

et al. 2020

Preprint

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27Lipid droplets (LDs) are increasingly recognized as critical organelles in signalling events, 28 transient protein sequestration and inter-organelle interactions. However, the role LDs play in 29 antiviral innate immune pathways remains unknown. Here we demonstrate that induction of 30 LDs occurs as early as 2 hours post viral infection, is transient, and returns to basal levels by 31 72 hours. This phenomenon occurred following viral infections, both in vitro and in vivo. 32 Virally driven LD induction was type-I interferon (IFN) independent, however, was 33 dependent on EGFR engagement, offering an alternate mechanism of LD induction in 34 comparison to our traditional understanding of their biogenesis. Additionally, LD induction 35 corresponded with enhanced cellular type-I and -III IFN production in infected cells, with 36 enhanced LD accumulation decreasing viral replication of both HSV-1 and Zika virus 37 (ZIKV). Here, we demonstrate for the first time, that LDs play vital roles in facilitating the 38 magnitude of the early antiviral immune response specifically through the enhanced 39 modulation of IFN following viral infection, and control of viral replication. By identifying 40 LDs as a critical signalling organelle, this data represents a paradigm shift in our 41 understanding of the molecular mechanisms which coordinate an effective antiviral response. 42 48The role of LDs in an infection setting has not been well studied, however, it has been 49 demonstrated that LDs accumulate in leukocytes during inflammatory processes, and they are 50 also induced in human macrophages during bacterial infections 2 . Multiple bacterial strains, 51 including Mycobacterium spp., Chlamydia spp., Klebsiella spp. and Staphylococcus spp. are 52 known to upregulate LDs very early following bacterial infection in both primary and cell 53 culture macrophage models, and this has also been seen for a number of bacterial species in 54 rodent macrophage cell lines 5-7 . Interestingly, Trypanosoma cruzi infection of macrophages 55 also induces LDs, however, this response takes 6-12 days to occur following infection 8 . 56Bacterial-induced LD induction in immune cells has been shown to depend on toll-like 57 receptor engagement, mainly via TLR2 and TLR4, however, the role of LDs in the outcome 58 of bacterial infection remains largely unknown, and the exact mechanisms for controlling LD 59 induction remain elusive 9,10 . It has been suggested in recent work in the zebrafish model that 60 embryos with higher levels of LDs are more protected from bacterial infections 11 and work 61 in the Drosophila embryo has demonstrated that LDs can bind to histones which are released 62 upon detection of intracellular bacterial LPS and act in a bactericidal manner 12 . 63 Interestingly, LD induction has been demonstrated to be a direct result of immune activation 64 of macrophages by IFN-ߛ in a HIF-1 dependent signalling pathway 13 . M. tuberculosis 65 acquires host lipids in the absence of LDs under normal conditions, however, IFN-ߛ ...

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Section: Introductionmentioning

confidence: 99%

Intracellular Lipid Droplet Accumulation Occurs Early Following Viral Infection and Is Required for an Efficient Interferon Response

Monson

Duan

Chen

et al. 2020

Preprint

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“…4,5 Structurally, LDs are natural micelles composed of a hydrophobic core containing triglycerides, cholesterol esters and a corona made of phospholipids that can serve as lipid storage sites and as a platform for the recruitment of signalling molecules. 6,7 Perilipin associated proteins (PAT) coat and stabilize the surface of LD by reducing lipases access to the lipid core. Perilipin-2 (PLIN2) is the main housekeeping LD protein that is ubiquitously expressed and used as a marker for LDs in many human and animal tissues.…”

Section: Introductionmentioning

confidence: 99%

Type 2 diabetes is associated with suppression of autophagy and lipid accumulation in β‐cells

Petropavlovskaia

Khatchadourian

et al. 2019

J Cellular Molecular Medi

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Both type 2 diabetes (T2D) and obesity are characterized by excessive hyperlipidaemia and subsequent lipid droplet (LD) accumulation in adipose tissue. To investigate whether LDs also accumulate in β‐cells of T2D patients, we assessed the expression of PLIN2, a LD‐associated protein, in non‐diabetic (ND) and T2D pancreata. We observed an up‐regulation of PLIN2 mRNA and protein in β‐cells of T2D patients, along with significant changes in the expression of lipid metabolism, apoptosis and oxidative stress genes. The increased LD buildup in T2D β‐cells was accompanied by inhibition of nuclear translocation of TFEB, a master regulator of autophagy and by down‐regulation of lysosomal biomarker LAMP2. To investigate whether LD accumulation and autophagy were influenced by diabetic conditions, we used rat INS‐1 cells to model the effects of hyperglycaemia and hyperlipidaemia on autophagy and metabolic gene expression. Consistent with human tissue, both LD formation and PLIN2 expression were enhanced in INS‐1 cells under hyperglycaemia, whereas TFEB activation and autophagy gene expression were significantly reduced. Collectively, these results suggest that lipid clearance and overall homeostasis is markedly disrupted in β‐cells under hyperglycaemic conditions and interventions ameliorating lipid clearance could be beneficial in reducing functional impairments in islets caused by glucolipotoxicity.

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“…Storage lipids are packaged into specialized organelles called lipid droplets (LDs; also referred to as oil bodies, lipid bodies, or oleosomes). Originally recognized for their importance in energy storage, LDs also play important roles in many cellular processes, including lipid transport and membrane synthesis, protein storage and degradation, lipid signaling, and stress response (Chapman and Trelease, 1991;Chapman et al, 2012;Murphy, 2012;Arrese et al, 2014;Welte and Gould, 2017;Huang, 2018).…”

Section: Introductionmentioning

confidence: 99%

PUX10 Is a CDC48A Adaptor Protein That Regulates the Extraction of Ubiquitinated Oleosins from Seed Lipid Droplets in Arabidopsis

et al. 2018

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Lipid Droplets as Signaling Platforms Linking Metabolic and Cellular Functions

Cited by 48 publications

References 182 publications

Intracellular Lipid Droplet Accumulation Occurs Early Following Viral Infection and Is Required for an Efficient Interferon Response

Intracellular Lipid Droplet Accumulation Occurs Early Following Viral Infection and Is Required for an Efficient Interferon Response

Type 2 diabetes is associated with suppression of autophagy and lipid accumulation in β‐cells

PUX10 Is a CDC48A Adaptor Protein That Regulates the Extraction of Ubiquitinated Oleosins from Seed Lipid Droplets in Arabidopsis

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