The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages
Open accessAbstract
Hypertriglyceridemia is an important risk factor for atherosclerosis, especially in obesity. Macrophages are one of the primary cell types involved in atherogenesis and are thought to contribute to lesion formation through both lipid accumulation and proinflammatory gene expression. In this study, we sought to determine the direct impact of triglyceride (TG)-rich VLDL-induced lipid accumulation on macrophage proinflammatory processes. Incubation of mouse peritoneal macrophages with 100 microg/ml VLDL for 6 h led to 2.8- and 3.7-fold increases in intracellular TGs and FFAs, respectively (P < 0.05). The inflammatory proteins tumor necrosis factor-alpha, interleukin-1beta, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinase 3 (MMP3), and macrophage inflammatory protein-1alpha (MIP-1alpha) were all upregulated by at least 2-fold (P < 0.05) in a dose-dependent manner in VLDL-treated macrophages. The increase in inflammatory gene expression coincided with the phosphorylation of the mitogen-activated protein kinase (MAPK) pathway members extracellular signal-regulated kinase (ERK) 1/2, stress-activated protein kinase/c-Jun NH2-terminal kinase, and p38 MAPK and was ameliorated by U0126, an inhibitor of ERK1/2. Inhibition of extracellular TG hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of intracellular TG and FFA accumulation and was accompanied by the amelioration of ERK1/2 phosphorylation and MIP-1alpha gene expression. These data indicate that VLDL hydrolysis, and the subsequent accumulation of intracellular FFAs and TGs, plays a substantive role in mediating the proinflammatory effects of VLDL. These data have important implications for the direct proatherogenic effects of VLDL on macrophage-driven atherosclerosis.
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The hydrolysis of remnant TGs by lipoprotein lipase at the endothelial surface or within the subendothelial space generates a host of proinflammatory mediators.
“the hydrolysis of remnant TGs by lipoprotein lipase at the endothelial surface or within the subendothelial space generates a host of proinflammatory mediators (25).”
From Triglycerides and residual atherosclerotic risk (2021) · cites this paper as [25]
Direct incubation of mouse peritoneal macrophages with TRL increases macrophage cell triglyceride and fatty acid content and increases expression of macrophage inflammatory proteins.
“For example, direct incubation of mouse peritoneal macrophages with TRL increases macrophage cell triglyceride and fatty acid content; more importantly, this incubation increases expression of macrophage inflammatory proteins, including tumor necrosis factor-␣, interleukin-1, monocyte chemotactic protein-1, intercellular adhesion molecule-1, and matrix metalloproteinase-3. 83,84”
From Triglycerides and Cardiovascular Disease: A Scientific Statement From the American Heart Association (2011) · cites this paper as [84]
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- Authors
- Saraswathi, V., & Hasty, A. H.
- Affiliations
- Vanderbilt University Medical Center (US)
- Vanderbilt University (US)
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 47
- Issue
- 7
- Pages
- 1406-1415
- ISSN
- 0022-2275 (ISSN-L)
- OpenAlex
- W2141939352
- Cited by
- 95
- References
- 50
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 3 · 2022: 8 · 2021: 4 · 2020: 6 · 2019: 3 · 2018: 5 · 2017: 5 · 2016: 4 · 2015: 6 · 2014: 5 · 2013: 9 · 2012: 8
- FWCI
- 2.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Diabetes Association (1-04-JF-20)
- American Heart Association (0330011N)
- Vanderbilt University
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-26657, DK59637, DK 20593, P30DK026657)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- VLDL, lipolysis, triglyceride-rich lipoproteins, peritoneal macrophages, macrophage inflammation, atherosclerosis, hypertriglyceridemia, free fatty acids, TNF-α, IL-1β, MCP-1, ICAM-1, matrix metalloproteinase-3, macrophage inflammatory protein-1alpha, ERK1/2 phosphorylation, MAPK signaling, orlistat, proatherogenic effects
- MeSH terms
- Animals, Esterification, Female, Humans, Hydrolysis, Lipolysis, Lipoproteins, VLDL, Mice, Inbred C57BL, Phosphorylation, Triglycerides, Gene Expression, Macrophages, Peritoneal, Inflammation Mediators, Macrophage Inflammatory Proteins, MAP Kinase Signaling System, Lipid Metabolism, Mice, Chemokine CCL3, Chemokine CCL4, In Vitro Techniques
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