Key result
Recombinant ANGPTL3 boosts macrophage TNFα expression ~2.5-fold and increases intracellular lipid accumulation.
Why the study?
Because integrins are involved in inflammation and atherosclerotic plaque initiation, the study evaluated the potential direct pro-inflammatory action of ANGPTL3 via interaction of its fibrinogen-like domain and integrin αVβ3.
Does human recombinant ANGPTL3 induce pro-inflammatory responses and alter lipid metabolism in THP-1 macrophages?
Does human recombinant ANGPTL3 induce pro-inflammatory responses and alter lipid metabolism in THP-1 macrophages?
Effect estimate: 2.49-fold increase
Absolute Event Rate: 2.49% vs 1%
ANGPTL3 exerts direct pro-inflammatory effects and promotes lipid accumulation in macrophages, suggesting a potential pro-atherogenic role beyond its systemic lipid-regulating functions.
In vitro macrophage data suggest pro-atherogenic effects; hypothesis-generating and leaves open in vivo relevance for ANGPTL3-targeted therapies.
Background and aim: ANGPTL3 is a hepatokine acting as a negative regulator of lipoprotein lipase (LPL) through its N-terminal domain. Besides this activity, the C-terminal domain of ANGPTL3 interacts with integrin αVβ3. Since integrins are involved in inflammation and in the initiation of atherosclerotic plaque, the aim of our study was to evaluate the potential direct pro-inflammatory action of ANGPTL3 through the interaction of the fibrinogen-like domain and integrin αVβ3. Methods: We utilized cultured THP-1 human-derived macrophages and evaluated their pro-inflammatory phenotype in response to treatment with human recombinant ANGPTL3 (hANGPTL3). By Western blot, RT-qPCR, biochemical analysis, and ELISA assays, we determined the expression of genes and proteins involved in lipid metabolism and inflammatory response as well as intracellular cholesterol and triglyceride levels. In addition, we evaluated the effect of hANGPTL3 on the cellular cholesterol efflux process. Results: Incubation of THP-1-derived macrophages with 100 ng/mL of hANGPTL3 increased the mRNA expression of the pro-inflammatory cytokines IL-1β, IL-6, and TNFα (respectively, 1.87 ± 0.08-fold, 1.35 ± 0.11-fold, and 2.49 ± 0.43-fold vs. control). The secretion of TNFα, determined by an ELISA assay, was also induced by hANGPTL3 (1.98 ± 0.4-fold vs. control). The pro-inflammatory effect of hANGPTL3 was partially counteracted by co-treatment with the integrin αVβ3 inhibitor RGD peptide, reducing the mRNA levels of IL-1β (3.35 ± 0.35-fold vs. 2.54 ± 0.25-fold for hANGPTL3 vs. hANGPTL3 + RGD, respectively). Moreover, hANGPTL3 reduced cholesterol efflux to apoA-I, with a parallel increase in the intracellular triglyceride and cholesterol contents by 31.2 ± 2.8% and 20.0 ± 4.1%, respectively, compared to the control. Conclusions: ANGPTL3 is an important liver-derived regulator of plasma lipoprotein metabolism, and overall, our results add a new important pro-inflammatory activity of this circulating protein. This new function of ANGPTL3 could also be related to triglyceride and cholesterol accumulation into macrophages.
No takes yet. Share an insight, caveat, or question.
Milani et al. (2025) studied Cultured THP-1 human-derived macrophages. Human recombinant ANGPTL3 (hANGPTL3) vs. Control (untreated) was evaluated on mRNA expression of TNFα (2.49-fold increase). Incubation of THP-1-derived macrophages with hANGPTL3 increased the mRNA expression of TNFα by 2.49-fold and increased intracellular triglyceride and cholesterol contents.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: