Intermittent hyperlipidaemia accelerates the development of atherosclerosis: cellular and molecular mechanisms

Background: Hyperlipidaemia constitute a major risk factor of atherosclerosis.

Recent overlooked observations indicate that periodic variations in serum cholesterol levels are strongly associated with cardiovascular outcomes. However, the precise mechanisms responsible for this increased risk are not understood. Hypothesis: Periodic fluctuations in serum lipid levels accelerate atherosclerosis.

Methodology and pilot data: Here, we make the unexpected observation that intermittent feeding of mice with a high cholesterol Western-type diet substantially accelerates atherosclerosis compared with continuous feeding (provided that overall cholesterol load is the same).

Our pilot data suggest that intermittent hyperlipidaemia may prevent the establishment of a homeostatic anti-inflammatory state in macrophages (and potentially other cells) and promotes the development of a pro-atherogenic trained immune response.

We propose a comprehensive but focussed programme of research to decipher the cellular and molecular mechanisms behind this interesting and previously unsuspected finding.

Anticipated contribution to the field of research: The results will provide unprecedented insight into the mechanisms through which variability in serum lipid levels mediates vascular inflammation and accelerates the development of atherosclerosis. This knowledge will be critical for the design of novel and effective therapeutic strategies to combat atherosclerosis.