Recessive x-Linked Ichthyosis: Role of Cholesterol-Sulfate Accumulation in the Barrier Abnormality

Abstract

Cholesterol sulfate is a multifunctional sterol metabolite, produced in large amounts in squamous keratinizing epithelia. Because patients with recessive x-linked ichthyosis display not only a 10-fold increase in cholesterol sulfate, but also a 50% reduction in cholesterol, we assessed here whether cholesterol sulfate accumulation and/or cholesterol deficiency produce abnormal barrier function in recessive x-linked ichthyosis. Patients with recessive x-linked ichthyosis display both an abnormal barrier under basal conditions, and a delay in barrier recovery after acute perturbation, which correlate with minor abnormalities in membrane structure and extensive lamellar-phase separation. Moreover, both the functional and the structural abnormalities were corrected by topical cholesterol. Yet, topical cholesterol sulfate produced both a barrier abnormality in intact skin and extracellular abnormalities in isolated stratum corneum, effects largely reversed by coapplications of cholesterol. Together, these results suggest that cholesterol sulfate accumulation rather than cholesterol deficiency is responsible for the barrier abnormality. Despite the apparent importance of cholesterol sulfate-to-cholesterol processing for normal barrier homeostasis, neither steroid sulfatase activity nor mRNA levels are upregulated following acute perturbations. These results demonstrate both a potential role for cholesterol sulfate-to-cholesterol processing in normal permeability barrier homeostasis, and that basal levels of steroid sulfatase are sufficient to accommodate acute insults to the permeability barrier.

Bricks and mortar of the epidermal barrier

“…X-linked ichthyosis is due to cholesterol sulfate accumulation owing to a deficiency of the arylsulfatase C/cholesterol sulfatase gene (Shapiro et al ., 1978;Kubilus et al ., 1979;Baden et al, 1980). How abnormally high levels of cholesterol sulfate cause barrier dysfunction has not yet been clearly elucidated (Zettersten et al, 1998), although the T G M 1 gene may be involved (Kawabe et al, 1998). Some ichthyoses are the direct result of genetic defects of lipid metabolism, as exemplified by Refsum's disease (phytanic acid accumul-ation owing to phytanoyl-CoA hydroxylase deficiency) (Steinberg et al, 1978;Jansen et al ., 1997), and Sjogren-L a r s s o n 's syndrome (pathological lipid metabolism owing to fatty aldehyde dehydrogenase deficiency (De Laurenzi et al, 1996;De Laurenzi et al, 1997).…”

Cholesterol 3-Sulfate Interferes with Cornified Envelope Assembly by Diverting Transglutaminase 1 Activity from the Formation of Cross-links and Esters to the Hydrolysis of Glutamine

“…It was proposed that since CSO 4 has trypsin and chymotrypsin inhibitory properties in vitro, it might thereby affect breakdown of desmosomes, thus causing retention hyperkeratoses and abnormal scaling (18). The strong charge of its sulfate moiety conferring mild detergent properties to CSO 4 was shown to interfere with spontaneous sheet-formation of epidermal lipids in vivo and thus theorized to affect epidermal barrier function by deranging skin lipid layers, repressing cholesterol synthesis, and replacing cholesterol in the lipid sheets (16). More recently, it was demonstrated that CSO 4 can induce TGase 1 expression in cultured keratinocytes (19), but the connection between excess TGase expression and disease etiology remains unclear.…”

“…In a conceptually related argument, CSO 4 was shown to interfere with spontaneous sheet formation of epidermal lipids in vivo, perhaps due to the strong charge of its sulfate moiety conferring detergent properties to CSO 4 . Thus it was theorized that CSO 4 affects epidermal barrier function both by deranging skin lipid layers and by replacing cholesterol in the lipid sheets (16). In another study, it was proposed that since CSO 4 has trypsin and chymotrypsin inhibitory properties in vitro, it might thereby affect breakdown of desmosomes, thus causing retention hyperkeratosis and abnormal scaling (18).…”

Influence of cholesterol on the structure of stratum corneum lipid model membrane

“…Although the CS accumulation seems to be the primary mechanism contributing to the barrier abnormalities in RXLI, the reduced CHOL levels also play an important role, especially in the altered membrane dynamics. Topically administrated CHOL reverses the pathologic effects of excess CS on SC membrane structure, barrier function, and desquamation [4]. Additionally, ichthyotic symptoms can be induced by cholesterol-lowering drugs [5].…”