Cholesterol Homeostasis and Atherosclerosis Mechanisms

Cholesterol homeostasis is maintained by a balance between influx, synthesis, distribution and efflux of cholesterol within cells and across tissues. Low-density lipoprotein-bound cholesterol enters the arterial wall, where macrophages internalise modified lipoproteins and convert into cholesterol-laden foam cells. Excess intracellular cholesterol triggers inflammatory signalling, oxidative stress and endoplasmic reticulum dysfunction, promoting lesion progression. Reverse cholesterol transport, mediated by transporters such as ABCA1 and acceptors including apolipoprotein A-I, returns cholesterol to the liver for excretion. Endothelial cells regulate vascular tone and barrier integrity in response to shear forces and lipid exposure; dysfunction here initiates monocyte recruitment and smooth muscle cell migration. Vascular smooth muscle cells can undergo phenotypic switching, proliferate and contribute to fibrous cap formation or destabilisation. Inflammatory cytokines, modified lipids and oxidative molecules amplify recruitment of immune cells, perpetuating chronic vascular inflammation. An integrated understanding of lipid flux, cell–cell crosstalk and inflammatory cascades is essential for new strategies to prevent or reverse plaque development and reduce cardiovascular risk.

Research from Nature Portfolio

Recent studies have elucidated how macrophage-derived cholesterol metabolites drive vascular inflammation. The cholesterol metabolite 27-hydroxycholesterol fosters crosstalk between macrophages and endothelial cells by engaging endothelial oestrogen receptor α, triggering NF-κB activation and monocyte adhesion, thus accelerating lesion formation. Inhibition of the enzyme responsible for 27-hydroxycholesterol synthesis reduces endothelial activation and monocyte recruitment without compromising host defence, highlighting a novel anti-inflammatory target. Earlier foundational work demonstrated that myeloid-derived apolipoprotein E governs dendritic cell plasma-membrane cholesterol content, enhancing MHC-II antigen presentation and T-cell activation. Isoform-specific differences in apoE influence adaptive immune responses, revealing an immunometabolic axis by which cholesterol transport proteins modulate both lipid homeostasis and immune cell function in atherosclerosis.

Cholesterol Homeostasis and Atherosclerosis Mechanisms publication trend

The graph below shows the total number of articles in cholesterol homeostasis and atherosclerosis mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

27-hydroxycholesterol (27HC): A cholesterol metabolite generated by CYP27A1 that modulates endothelial and immune cell signalling during atherogenesis.

Apolipoprotein E (apoE): A plasma protein involved in lipid transport and immune regulation, with isoform-specific effects on antigen presentation and cholesterol efflux.

ABCA1 (ATP-binding cassette transporter A1): A membrane transporter that mediates cholesterol efflux to apolipoprotein acceptors, crucial for reverse cholesterol transport.

Endothelial nitric oxide synthase (eNOS): An enzyme in endothelial cells producing nitric oxide, a vasodilator and inhibitor of leukocyte adhesion.

Lipid droplets: Intracellular organelles for neutral lipid storage that can influence signalling pathways and cellular functions in vascular cells.

MFN2 (Mitofusin-2): A mitochondrial outer-membrane GTPase essential for mitochondrial fusion, whose downregulation promotes vascular smooth muscle cell proliferation.

DNMT1 (DNA methyltransferase 1): An enzyme that maintains DNA methylation patterns, implicated in epigenetic silencing of anti-proliferative genes in atherosclerosis.

References

1. Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice. Nature Communications (2023).
2. Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation. Journal of Clinical Investigation (2023).
3. Myeloid apolipoprotein E controls dendritic cell antigen presentation and T cell activation. Nature Communications (2018).
4. Aberrant MFN2 transcription facilitates homocysteine‐induced VSMCs proliferation via the increased binding of c‐Myc to DNMT1 in atherosclerosis. Journal of Cellular and Molecular Medicine (2019).
5. ATP-Binding Membrane Cassette Transporter A1 (ABCA1): A Possible Link between Inflammation and Reverse Cholesterol Transport. Molecular Medicine (2010).