Crosstalk Between Cholesterol, ABC Transporters, and PIP2 in Inflammation and Atherosclerosis.

The lowering of plasma low-density lipoprotein cholesterol (LDL-C) is an easily achievable and highly reliable modifiable risk factor for preventing cardiovascular disease (CVD), as validated by the unparalleled success of statins in the last three decades. However, the 2021 American Heart Association (AHA) statistics show a worrying upward trend in CVD deaths, calling into question the widely held belief that statins and available adjuvant therapies can fully resolve the CVD problem. Human biomarker studies have shown that indicators of inflammation, such as human C-reactive protein (hCRP), can serve as a reliable risk predictor for CVD, independent of all traditional risk factors. Oxidized cholesterol mediates chronic inflammation and promotes atherosclerosis, while anti-inflammatory therapies, such as an anti-interleukin-1 beta (anti-IL-1β) antibody, can reduce CVD in humans. Cholesterol removal from artery plaques, via an athero-protective reverse cholesterol transport (RCT) pathway, can dampen inflammation. Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a role in RCT by promoting adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux from arterial macrophages. Cholesterol crystals activate the nod-like receptor family pyrin domain containing 3 (Nlrp3) inflammasome in advanced atherosclerotic plaques, leading to IL-1β release in a PIP2-dependent fashion. PIP2 thus is a central player in CVD pathogenesis, serving as a critical link between cellular cholesterol levels, ATP-binding cassette (ABC) transporters, and inflammasome-induced IL-1β release.