Fig. 3

Ceramide metabolism in standard conditions and in oxidative stress. Active pathways at standard conditions are marked with black arrows, black and red shading arrows indicate pathways with diminished activity, and inactive pathways are marked with red arrows. In keratinocytes lacking NADPH, very long-chain fatty acid synthesis is impaired. C₁₆-CoA is not converted to acyl-CoA ≥ C₁₈ and accessible to other reactions, e.g., hydrolysis to palmitic acid. Natural and artificial UV radiation or ROS triggered severe depletion of NADH and/or ATP affects the maintaining of the lysosomal pH by the vacuolar (H⁺)-ATPase) and the lysosomal RedOx-chain. Raising the intralysosomal pH activates the reverse ceramide synthase activity of aCERase and the selective lysosomal synthesis and accumulation of C₁₆-ceramide [40, 41] starting from palmitic acid and sphingosine. If stearic acid is present, C₁₈-ceramide emerges likewise [40]. Alternatively, free palmitic acid in the ER can be converted to 2-hydroxy palmitic acid by fatty acid 2-hydroxylase (FA2H) [42] and recessed into ceramides in place of palmitic acid. Thereby, C₁₆ (2-hydroxy) ceramide could result, which is significantly increased in lesions of AD [37]. Emerging C₁₈-ceramide is assumed to trigger exocytosis [21]. C₁₆-ceramide and C₁₈-ceramide is increased in non-lesional and lesional atopic eczema stratum corneum [37] and hence supposed to trigger erythematous rash and pruritic papules. Instead of severe depletion of NADH and/or ATP, lysosomotropic drugs (e.g., amitriptyline and sertraline) or metabolites (e.g., nortriptyline) are likewise able to raise the lysosomal pH. With unimpeded ELOVL fatty acid elongation, there is limited palmitic acid present to synthesize C₁₆-ceramide in the lysosome. On the other hand, in the event of an impaired ELOVL fatty acid elongation, excess C₁₆-CoA is hydrolyzed to palmitic acid. Then, in the presence of lysosomotropic drugs in keratinocytes, C₁₆-ceramide synthesis and accumulation can occur, probably leading to erythema, pruritus, and finally to acute generalized exanthematous pustulosis (AGEP). That implies that the elongation of very long-chain fatty acids (ELOVL, cofactor NADPH), maintaining of the lysosomal pH/proton gradient by the vacuolar (H⁺)-ATPase (V-ATPase, energy source ATP) and the lysosomal RedOx-chain (energy source NADH) are crucial parameters to retain the ceramide rheostat in keratinocytes. In addition to lysosomotropic drugs, a breakdown of the V-ATPase, e.g., by ATP depletion or formation of a disulfide bridge due to oxidative stress between the two cysteines at positions 254 and 532 of the P-LOOP of V-ATPase, leads to a collapse of the lysosomal transmembrane proton gradient. As a consequence of the collapse, C₁₆-ceramide and the characteristic pruritic papules of PLE may occur. If excess C₁₈-CoA is present, C₁₈-ceramide can be formed via stearic acid under these conditions