Epidermal sphingomyelins are precursors for selected stratum corneum ceramides

Abstract

Epidermal ceramides (Cer) comprise a heterogeneous family of seven species, including two unique -hydroxylated Cer, that are key components of the stratum corneum (SC) intercellular lamellar membranes responsible for the epidermal permeability barrier. Although both glucosylceramide (GlcCer) and the phospho-sphingolipid sphingomyelin (SM) are potential precursors of SC Cer, based on reported chemical structures of epidermal GlcCer and SC Cer, it is assumed that all major subfractions of SC Cer are generated from lamellar body-derived GlcCer. Yet, we and others have shown that SM-derived Cer are required for normal barrier homeostasis. Moreover, two pools of SM, one from plasma membrane, the other from lamellar body-derived contents, are potentially available for Cer production. To clarify the role of SM as a potential precursor of bulk or specific SC Cer, we compared Cer moieties in epidermal SM, Cer generated from epidermal SM by sphingomyelinase treatment, Cer within SC, and Cer that persist in Gaucher SC, where GlcCer cannot generate Cer due to an absence of ␤ -glucocerebrosidase. Using gas chromatographymass spectrometry, fast atom bombardment-mass spectrometry, and nuclear magnetic resonance for Cer characterization, epidermal SM comprise three major subfractions with distinctive amide-linked ( N -acyl) fatty acid (FA) compositions: that is, either long-chain FA (SM-1; C 22-26 ), short-chain FA (SM-2; primarily C 16 ), and short-chain ␣ -hydroxy FA (SM-3; C 16-18 ). In contrast, only trace quantities of -hydroxy FA were present. For each SM subfraction, the sphingoid base was either sphingosine or sphinganine, but phytosphingosine was not detected. Comparison of these SM with corresponding sphingomyelinase-generated epidermal Cer and SC Cer revealed that the Cer moieties of SM-1 and SM-3 are equivalent to Cer 2 (NS) and Cer 5 (AS), respectively. Moreover, both Cer 2 and Cer 5 occurred in Gaucher SC, whereas other Cer subfractions did not occur. These results indicate that two epidermal SM, that is, SM-1 and SM-3, are important precursors of two corresponding Cer in mammalian SC, that is, Cer 2 and Cer 5, but other Cer species, including the -hydroxy Cer species, do not derive from SM.

Epidermal Barrier Dysfunction in Atopic Dermatitis

“…This results in a considerable deficiency in the acid, lipid, and enzyme constituents of the SC, leading to a defective barrier function (Mecheleidt et al, 2002). An increase in sphingomyelin deacylase activity is also associated with AD and results in a decreased production of ceramide (Hara et al, 2000).…”

“…Conversely, cathepsin LZ and cathepsin D have an acidic pH optimum (Horikoshi et al, 1999;Bernard et al, 2003). The lipid-generating enzymes, b-glucocerebrosidase and sphingomyelinase, also exhibit low acid pH optimum (Holleran et al, 1993;Jensen et al, 1999;Schmuth et al, 2000;Uchida et al, 2000). Taken together, the pH gradient across the epidermis is very important in regulating desquamation and the generation of the lamellar matrix.…”

Glycosphingolipids in Filamentous Fungi: Biological Roles and Potential Applications in Cosmetics and Health Foods

“…Low levels of GluCer and ceramide in atherosclerosis-prone mice led to skin inflammation and hair discoloration and loss (Bedja et al, 2018). Prior studies demonstrated that all molecular species of stratum corneum ceramides are derived from GlcCer (Uchida et al, 2000;Hamanaka et al, 2002). In addition, GlcCer also prevents dehydration of the stratum corneum and repaired the barrier function of skin.…”

Pathogenic and Compensatory Mechanisms in Epidermis of Sphingomyelin Synthase 2-Deficient Mice

“…During activation of sphingomyelinase in response to stimuli; for example, cytokines and oxidative stressors [1,2], SM is hydrolyzed to ceramide (Cer), which in turn serves as a lipid regulator of cellular functions [3,4]. In epidermis, Cer produced from SM and glucosylceramides (GlcCers) at the transition from the stratum granulosum (SG) to the stratum corneum (SC) are constituents of the epidermal permeability barrier, which is required for mammalian survival in a terrestrial environment [5][6][7]. SM synthase (SMS)1 and SMS2, which are distributed in the trans-Golgi and plasma membranes, respectively, synthesize SM [3].…”