Role of cholesterol sulfate in epidermal structure and function: lessons from X-linked ichthyosis

Abstract

X-linked ichthyosis is a relatively common syndromic form of ichthyosis most often due to deletions in the gene encoding the microsomal enzyme, steroid sulfatase, located on the short area of the X chromosome. Syndromic features are mild or unapparent unless contiguous genes are affected. In normal epidermis, cholesterol sulfate is generated by cholesterol sulfotransferase (SULT2B1b), but desulfated in the outer epidermis, together forming a 'cholesterol sulfate cycle' that potently regulates epidermal differentiation, barrier function and desquamation. In XLI, cholesterol sulfate levels my exceed 10% of total lipid mass (≈1% of total weight). Multiple cellular and biochemical processes contribute to the pathogenesis of the barrier abnormality and scaling phenotype in XLI. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

Keywords: Cholesterol sulfate; Corneodesmosomes; Epidermal barrier function; Epidermal lipid metabolism; Steroid sulfatase; X-linked ichthyosis.

Fig. 1

Steroid sulfatase desulfates cholesterol sulfate and other sulfated steroid hormones (modified from Elias, et al., 2010.).

Fig. 2

Epidermal Functions Impacted by Cholesterol Sulfate Cycle (modified from Elias, et al., 2004, 2010).

Fig. 3

Steroid sulfatase (SSase) activity in lamellar bodies (B) in stratum granulosum (SG) and within the extracellular spaces of the stratum corneum (SC) (A, arrows). Method for cytochemical detection of SSase activity can be found in Ref. #, Elias, et al., 2004).

Fig. 4

Potential Pathogenetic Mechanisms In X-linked Ichthyosis (modified from Elias, et al., 2004, 2010).

Fig. 5

Pathogenesis of X-Linked Ichthyosis (modified from Elias, et al., 2010).

Fig. 6

Extracellular Matrix Abnormalities in XLI. A: Ruthenium tetroxide postfixation, which revels lamellar/non-lamellar (electron-dense) phase separation; and B: Ca ++ leakage into the SC interstices (consistent with barrier abnormality) where it localizes to the external faces of corneodesmosomes (pyroantimonate precipitation method for Ca++ detection). Mag bars = 0.2 μm (A) and 0.1 μm (B). (Modified from Elias, et al., 2010.)