Formation and Cellular Impact of Cholesterol Crystals in Health and Disease

Abstract

Cholesterol crystals (CCs) were first discovered in atherosclerotic plaque tissue in the early 1900 and have since been observed and implicated in many diseases and conditions, including myocardial infarction, abdominal aortic aneurism, kidney disease, ocular diseases, and even central nervous system anomalies. Despite the widespread involvement of CCs in many pathologies, the mechanisms involved in their formation and their role in various diseases are still not fully understood. Current knowledge concerning the formation of CCs, as well as the molecular pathways activated upon cellular exposure to CCs, will be explored in this review. As CC formation is tightly associated with lipid metabolism, the role of cellular lipid homeostasis in the formation of CCs is highlighted, including the role of lysosomes. In addition, cellular pathways and processes known to be affected by CCs are described. In particular, CC‐induced activation of the inflammasome and production of reactive oxygen species, along with the role of CCs in complement‐mediated inflammation is discussed. Moreover, the clinical manifestation of embolized CCs is described with a focus on renal and skin diseases associated with CC embolism. Lastly, potential therapeutic measures that target either the formation of CCs or their impact on different cell types and tissues are highlighted.

Lipidomic Profiling of Kidney Cortical Tubule Segments Identifies Lipotypes with Physiological Implications

“…Cellular accumulation of non-esterified cholesterol may play a critical role in kidney injury and progression of associated diseases. 5 , 43 , 44 …”

Inflammation—The new treatment target for ischaemic stroke prevention

“…Mononuclear phagocytes in the circulation differentiate into macrophages within the intima which phagocytose lipid particles becoming foam cells, an early hallmark of atherosclerosis. Cholesterol crystals form within macrophages, further dysregulating intracytoplasmic vesicular membranes, triggering activation of the NLRP3 (nucleotide binding oligomerisation domain like [NOD-like] receptor, pyrin domain containing protein 3) inflammasome, and stimulating the complement system (Baumer et al, 2021). The adaptive immune system also contributes to atherogenesis with T-helper cells and their associated cytokines interferon-gamma (IFNγ), interleukin-12 and interleukin-18 acting in concert with innate immune cells in the intima to stimulate proinflammatory cytokines.…”