Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia
Abstract
Lipid droplets (LDs) are neutral lipid-rich organelles involved in many cellular processes. A well-known example is their accumulation in leukocytes upon activation by pro-inflammatory stimuli such as lipopolysaccharides (LPS) derived from gram-negative bacteria. A role of LDs and LD-associated proteins during inflammation in the brain is unknown, however. We have now studied their dynamics and regulation in microglia, the resident immune cells in the brain. We find that LPS treatment of microglia leads to the accumulation in them of LDs, and enhancement of the size of LDs. This induction of LDs was abolished by triacsin C, an inhibitor of triglyceride biosynthesis. LPS strongly activated c-Jun N-terminal kinase (JNK) and p38 MAPK stress signaling pathways and increased the expression of LD-associated protein perilipin-2 (ADRP) in a time-dependent manner. Immunostaining showed that perilipin-2 in LPS-treated microglia predominantly colocalized with LDs. Inhibitors of p38 α/β (SB203580) and PI3K/Akt pathway (LY294002), but not that of JNK (SP600125), reduced LPS-induced LD accumulation and eliminated the activating effect of LPS on perilipin-2. In addition, cytosolic phospholipase A(2) (cPLA(2)-α), a key enzyme for arachidonic acid release, colocalized with LPS-induced LDs. These observations suggest that LDs may play an important role in eicosanoid synthesis in activated microglia; they provide a novel insight into the regulation of LDs in inflammatory cells of the brain and…
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Treating iMGs with triacsin C effectively decreased BODIPY-labelled LDs.
“Treating iMGs with triacsin C (TrC), an inhibitor of long-chain acyl-CoA synthetase that reduces LD formation10,18,19,39,40, effectively decreased BODIPY-labelled LDs (Extended Data Fig. 7e–i).”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [40]
Inflammatory triggers like lipopolysaccharide, fatty acids, and aging promote lipid droplet accumulation in primary microglial cells and cell lines.
“Inflammatory triggers like lipopolysaccharide (LPS)35,19, fatty acids36, and aging20 promote LD accumulation in primary microglial cells and cell lines.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [35]
PI3K-AKT signaling is a key regulator of lipid metabolism, and PI3K inhibitors block the accumulation of LDs in numerous studies and study models.
“PI3K-AKT signaling is another key regulator of lipid metabolism, and PI3K inhibitors have been shown to efficiently block the accumulation of LDs in numerous studies and in several study models [9, 64, 65].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [64]
LD-accumulating microglia (LDAM) have phagocytosis deficits, produce excessive ROS and pro-inflammatory cytokines, and are implicated in the pathogenesis and progression of neuroinflammatory diseases.
“LD accumulating microglia (LDAM) have phagocytosis deficits, produce excessive amounts of reactive oxygen species (ROS) and pro-inflammatory cytokines, and are increasingly implicated in the pathogenesis and progression of neuroinflammatory diseases [17,18,19].”
From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [19]
LPS-mediated inflammation promotes lipid droplet accumulation in immune cells.
“LPS mediated-inflammation is known to promote LD accumulation in immune cells [19,69,70].”
From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [19]
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References 64 · Cited by 143
- Authors
- Khatchadourian, A., Bourque, S. D., Richard, V. R., Titorenko, V. I., & Maysinger, D.
- Affiliations
- McGill University (CA)
- Concordia University (CA)
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 1821
- Issue
- 4
- Pages
- 607-617
- ISSN
- 1388-1981 (ISSN-L)
- OpenAlex
- W2010212061
- Cited by
- 143
- References
- 64
- Citations by year
- 2026: 6 · 2025: 23 · 2024: 19 · 2023: 14 · 2022: 7 · 2021: 12 · 2020: 12 · 2019: 8 · 2018: 5 · 2017: 9 · 2016: 10 · 2015: 4 · 2014: 6 · 2013: 7 · 2012: 1
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
- PubMed (publishedVersion)
- eScholarship@McGill (McGill) (submittedVersion)
- Funders
- Canadian Institute of Health Research (CIHR)
- Concordia University Chair Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Keywords
- lipid droplets, lipopolysaccharide, microglia, PLIN2, p38 MAPK, JNK, PI3K/Akt signaling, cytosolic phospholipase A2, eicosanoid biosynthesis, triglyceride synthesis, triacsin C, neuroinflammation, lipid droplet dynamics
- MeSH terms
- Perilipin-2, Phosphoinositide-3 Kinase Inhibitors, Animals, Anthracenes, Cells, Cultured, Chromones, Cytoplasmic Granules, Enzyme Activation, Enzyme Inhibitors, Imidazoles, Kinetics, Lipids, Lipopolysaccharides, Membrane Proteins, Models, Biological, Morpholines, Pyridines, Time Factors, Triglycerides, Blotting, Western, Microglia, Microscopy, Confocal, Oleic Acid, Phosphatidylinositol 3-Kinases, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Mice, Group IV Phospholipases A2
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