Hypertriglyceridaemia and its multifaceted mechanisms driving atherosclerotic cardiovascular disease

Figures

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  Fig. 1. Macrophage inflammation pathway map. TRL metabolites signal through macrophage pattern-recognition receptors (GPCRs/TLR4/LRPs), activating PKC-MAPK-RAS signaling axes to drive IL-1β/TNF-α secretion. TRLs promote the inflammatory cytokines productions in macrophages through multiple signaling pathways and drive phenotypic polarization toward the pro-inflammatory M1-like state

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  Fig. 2. Hypertriglyceridemia -Driven Monocyte inflammation polarization. Free fatty acids (FFAs) activate insulin receptor (IR) and G protein-coupled receptor 120 (GPR120) on monocytes, driving inflammatory mediator expression via PI3K/AKT and RAS signaling cascades. A HTG environment increases the CD11c+ phenotype of monocytes, promote the aggregation of CD16, p-Syk, and VLA-4 in stable complexes within membrane lipid rafts as well as the phosphorylation of Syk Fc-γ chain, thereby inducing VLA-4 activation, facilitating the connection between VLA-4 and VCAM-1, and stimulating the migration of monocytes to endothelial cells. Furthermore, VLA-4 ligation amplifies inflammatory responses through PI3K/AKT-dependent AP-1 transcriptional activation and HIF-1α stabilization

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  Fig. 3. Pathway map of TRL and its metabolites on endothelial cell, VSMC, and fat tissue. TRLs and their metabolites affect endothelial cells via LOX-1 and integrin receptors. This signaling promotes TNF-α production while inhibiting NO production. FFA-mediated inhibition of mTOR. This inhibition suppresses downstream targets p-mTOR and p70S6K, leading to reduced expression of the mitophagy-related proteins PINK1 and Parkin. Consequently, Parkin enrichment into mitochondria is impaired, preventing the timely clearance of damaged mitochondria. This results in excessive ROS production and promotes endothelial cell aging. FFAs act on the FFAR (Free Fatty Acid Receptor) on vascular smooth muscle cells (VSMCs) and activating the MAPK/p38 signaling pathway. This process promotes the expression of an aging phenotype in VSMCs and suppresses expression of the anti-aging factor SIRT6. FFAs inhibit the AMPK pathway in adipocytes. This inhibition activates GSK-3β and disrupts the Nrf2/Trx1 antioxidant axis, leading to increased ROS levels. The disruption causes Trx1 to dissociate from TXNIP, thereby enhancing the TXNIP-NLRP3 interaction. This interaction stimulates the NLRP3/PYCARD/caspase-1…