7-Dehydrocholesterol enhances ultraviolet A-induced oxidative stress in keratinocytes: Roles of NADPH oxidase, mitochondria, and lipid rafts

Abstract

Long wavelength solar UVA radiation stimulates formation of reactive oxygen species (ROS) and prostaglandin E 2 (PGE 2 ), which are involved in skin photosensitivity and tumor promotion. High levels of 7-dehydrocholesterol (7-DHC), the precursor to cholesterol, cause exaggerated photosensitivity to UVA in patients with Smith-Lemli-Opitz syndrome (SLOS). Partially replacing cholesterol with 7-DHC in keratinocytes rapidly (<5 min) increased UVA-induced ROS, intracellular calcium, phospholipase A 2 activity, PGE 2 , and NADPH oxidase activity. UVA-induced ROS and PGE 2 production were inhibited in these cells by depleting the Nox1 subunit of NADPH oxidase using siRNA or using a mitochondrial radical quencher, MitoQ. Partial replacement of cholesterol with 7-DHC also disrupted membrane lipid raft domains, although depletion of cholesterol, which also disrupts lipid rafts, did not affect UVA-induced increases in ROS and PGE 2 . Phospholipid liposomes containing 7-DHC were more rapidly oxidized by a free radical mechanism than those containing cholesterol. These results indicate that 7-DHC enhances rapid UVA-induced ROS and PGE 2 formation by enhancing free radical-mediated membrane lipid oxidation and suggests that this mechanism might underlie the UVA-photosensitivity in SLOS.

Viewpoint 3

“…Cholesterol ensures the correct structure and function of the glycolipid-and cholesterol-enriched lipid rafts, where the receptors, and the associated protein kinases, can move and cluster. The final effect will be the control of the intracellular signal transduction (28). An alteration of the PI3K pathway has recently been reported (29) and we have observed defective ERK1 ⁄ 2 and JNK activation in vitiligo fibroblasts (Picardo, unpublished data).…”

Malformation syndromes caused by disorders of cholesterol synthesis

“…Based on subsequent work by other groups, it is likely that 7DHC or 7DHC metabolites underlie the UVA sensitivity. Chignell et al ( 50 ) showed that the UVA photosensitivity in SLOS might be a result of oxidative stress induced by photolysis of cholesta-5,7,9(11)-trien-3 ␤ -ol or 9-DDHC, and Valencia et al ( 51 ) showed that 7DHC enhances UVA-induced reactive oxidative stress by enhancing free radical-mediated membrane lipid oxidation.…”

Biological activities of 7-dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome

“…One hypothesis is that 7-DHC and/or its oxidative derivatives, i.e., oxysterols, are biologically active, which may play some role in the pathology of SLOS ( 19,(21)(22)(23)(24). In one recent study, for example, it was reported that high levels of 7-DHC cause exaggerated photosensitivity to ultraviolet (UV) A for SLOS patients ( 24 ). Longwavelength UV irradiation has been shown to activate NADPH -dependent oxidase activity, leading to oxidative stress in human keratinocytes ( 24 ).…”

“…In one recent study, for example, it was reported that high levels of 7-DHC cause exaggerated photosensitivity to ultraviolet (UV) A for SLOS patients ( 24 ). Longwavelength UV irradiation has been shown to activate NADPH -dependent oxidase activity, leading to oxidative stress in human keratinocytes ( 24 ). Similarly, in the rat SLOS model, elevated 7-DHC and formation of lipid peroxides lead to retinal degeneration ( 22,25 ).…”