Epidermal sphingolipids: Metabolism, function, and roles in skin disorders

Abstract

Mammalian epidermis produces and delivers large quantities of glucosylceramide and sphingomyelin precursors to stratum corneum extracellular domains, where they are hydrolyzed to corresponding ceramide species. This cycle of lipid precursor formation and subsequent hydrolysis represents a mechanism that protects the epidermis against potentially harmful effects of ceramide accumulation within nucleated cell layers. Prominent skin disorders, such as psoriasis and atopic dermatitis, have diminished epidermal ceramide levels, reflecting altered sphingolipid metabolism, that may contribute to disease severity/ progression. Enzymatic processes in the hydrolysis of glucosylceramide and sphingomyelin, and the roles of sphingolipids in skin diseases, are the focus of this review. Keywords: ABCA12; Barrier; Ceramide; Dermis; Epidermis; Gaucher; Glucocerebrosidase; Glucosylceramides; Ichthyosis; Niemann-Pick; Prosaposin; Saposins; Sphingolipid; Sphingomyelin; Sphingomyelinase; Stratum corneum Sphingolipids in the structure and function of mammalian epidermisMammalian skin is composed of two distinct layers divided by a basement membrane zone: (1) the underlying dermis containing primarily fibroblasts embedded in an acellular collagen/elastin matrix that accounts for the majority of skin thickness; and (2) the overlying epidermis, responsible for formation and maintenance of the skin barrier to both desiccation and penetration of xenobiotics. The function of this barrier resides primarily in the extracellular lipid domains between the outermost, enucleated cells, called corneocytes, of the stratum corneum (SC). Mammalian SC contains extensive quantities of lipids, localized to these extracellular domains (interstices), comprised of nearly equimolar quantities of ceramides (Cer), cholesterol, and free fatty acids, a ratio that is imperative for normal organization into the lamellar membrane structures primarily responsible for epidermal barrier homeostasis [1,2]. Cer species comprise approximately half of the total intercellular lipid content by weight, and are critical for these lamellar membrane structures [3,4]. The specific roles for Cer in epidermal function have been revealed in studies with both normal and diseased human skin, as well as animal models and model membranes in vitro [5,6]. For example, the Cer content is altered in patients with both atopic dermatitis [7][8][9] and psoriasis [10,11] (discussed further below). Likewise, cholesterol as well as both essential and non-essential free fatty acids play separate, critical roles in epidermal barrier homeostasis.Given that human SC contains at least nine major Cer fractions (see Fig. 1), many of which are unique to the epidermis, including omega(x)-hydroxylated and x-acylated forms, as well as x-hydroxy-Cer species that are covalently attached via the x-hydroxyl of the N-acyl fatty acid to cornified envelope proteins of the enucleate stratum corneum cells (i.e., corneocytes), the metabolism of these unique sphingolipids is of significant interest. It is ...

Sphingosine-1-phosphate Phosphatase 1 Regulates Keratinocyte Differentiation and Epidermal Homeostasis

“…As keratinocytes differentiate within the epidermis, they synthesize and package complex sphingolipids, such as sphingomyelin and ␤-glucosylceramide, along with other lipids, into lamellar bodies that are secreted by cells of the outer layers in the stratum granulosum (28). These complex sphingolipids in the lamellar bodies are then processed in the extracellular space into ceramides.…”

“…Sphingolipids are recognized for their importance in skin biology as both structural and signaling molecules (27)(28)(29)(30). Recently, S1P has been shown to have signaling properties that regulate keratinocyte cell function (31)(32)(33)(34)(35)(36).…”

Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

“…Most ceramides of the stratum corneum derive from glucosylceramide and sphingomyelin and are liberated from these precursors by extracellular hydrolysis. The transient "conversion" of free ceramides into other sphingolipids enables keratinocytes to produce large amounts of ceramides without increasing intracellular free ceramide concentration, which otherwise could affect various signaling pathways (11). In contrast to the established role of ceramide -hydroxylation (see above), much less is known about the function of other hydroxyl modifications found in skin sphingolipids, like 2-hydroxylation of the acyl residues and 4-hydroxylation of the sphingoid base.…”

“…Mammalian epidermis contains large amounts of ceramide, glucosylceramide, and sphingomyelin synthesized by differentiating keratinocytes (11). Most ceramides of the stratum corneum derive from glucosylceramide and sphingomyelin and are liberated from these precursors by extracellular hydrolysis.…”

Basic structural and functional characteristics of the epidermal barrier in wild mammals living in different habitats and climates

“…Elias et al 1977;Meyer 1986;Goldsmith 1991;Meyer et al 2009). The glycolipids in question are ceramides (glycosphingolipids), whereby in the barrier region, glucosylceramides are most important (Holleran et al 1993(Holleran et al , 2006Hamanaka et al 2005;Jennemann et al 2007;Mizutani et al 2009). In the latter case, the formation of lamellar bodies, in particular, prevents uncontrolled water loss through the skin as a basic critical feature of the evolution of terrestrial vertebrates to survive within the new biotopes on land.…”