Oxysterols in the pathogenesis of major chronic diseases

Abstract

Pathological accumulation of 27-carbon intermediates or end-products of cholesterol metabolism, named oxysterols, may contribute to the onset and especially to the development of major chronic diseases in which inflammation, but also oxidative damage and to a certain extent cell death, are hallmarks and primary mechanisms of progression. Indeed, certain oxysterols exercise strong pro-oxidant and pro-inflammatory effects at concentrations detectable in the lesions typical of atherosclerosis, neurodegenerative diseases, inflammatory bowel diseases, age-related macular degeneration, and other pathological conditions characterized by altered cholesterol uptake and/or metabolism.

Keywords: 24-OH, 24-hydroxycholesterol; 27-OH, 27-hydroxycholesterol; 7-K, 7-ketocholesterol; 7α-OH, 7α-hydroxycholesterol; 7β-OH, 7β-hydroxycholesterol; AMD, Age-related macular degeneration; AP-1, Activator protein-1; Aβ, Amyloid-β; ERK1/2, Extracellular signaling-regulated kinase 1/2; FXR, Farnesoid X receptor; Human chronic diseases; IBD, Inflammatory bowel diseases; ICAM, Intercellular adhesion molecule-1; IL, Interleukin; Inflammation; JNK, c-Jun N-terminal; LDL, Low density lipoprotein; LXR, Liver X receptor; MAPK, Mitogen-activated protein kinase; MCP-1, Monocyte chemotactic protein-1; MIP-1β, Monocyte inflammatory protein-1β; MMP, Matrix metalloproteinase; NF-κB, Nuclear factor-κB; Oxidative stress; Oxysterols; PKC, Protein kinase C; ROS, Reactive oxygen species; TGFβ1, Transforming growth factor β1; TIMP, Tissue inhibitors of metalloproteinases; TNF-α, Tumor necrosis factor-α; VCAM-1, Vascular cell adhesion molecule-1; α-EPOX, 5α,6α-epoxycholesterol; β-EPOX, 5β,6β-epoxycholesterol.

Graphical abstract

Fig. 1

Signaling molecules involved in oxysterol-mediated up-regulation of MMP-9, inflammatory cytokines, and CD36. The involvement of signaling molecules and transcription factors in the up-regulation of MMP-9, inflammatory cytokines, and CD36 has been validated through the transfection or treatment of human promonocytic cells, with specific siRNAs or inhibitors respectively. Rotenone, inhibitor of mitochondrial respiratory chain complex I; DPI, diphenyleneiodonium chloride, inhibitor of NADPH oxidases; PD98059, inhibitor of MEK; SP600125, inhibitor of JNK; parthenolide, inhibitor of NF-κB.