Applications of the Diazacholesterol Animal Model of Ichthyosis

Thematic review series: Skin Lipids. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism

“…The multisystem malformations that characterize disorders of postsqualene sterologenesis have been attributed to the following: 1) deficiency of bulk cholesterol in membrane function; 2) toxic effects of accumulated precursors; and/or 3) developmental effects of altered Hedgehog pathway signaling (114). In skin, it seems likely that cholesterol deficiency per se is the major contributor, because a cutaneous phenotype does not occur in either Smith-Lemli-Opitz syndrome (OMIM 270400), attributable to 7-dehydrocholesterol reductase deficiency, or in hairless mice treated with the 7-hydrocholesterol inhibitor AY9944 (115). In contrast, blockade of the D24 reductase, converting desmosterol to cholesterol, through the inhibitors triparanol and 20,25-diazocholesterol, is associated with ichthyosis in both rodent models and human (115,116).…”

“…In skin, it seems likely that cholesterol deficiency per se is the major contributor, because a cutaneous phenotype does not occur in either Smith-Lemli-Opitz syndrome (OMIM 270400), attributable to 7-dehydrocholesterol reductase deficiency, or in hairless mice treated with the 7-hydrocholesterol inhibitor AY9944 (115). In contrast, blockade of the D24 reductase, converting desmosterol to cholesterol, through the inhibitors triparanol and 20,25-diazocholesterol, is associated with ichthyosis in both rodent models and human (115,116). It is likely, therefore, that 7-dehydrocholesterol, but not desmosterol, can substitute for cholesterol in the formation of SC lamellar membranes.…”

Enhanced susceptibility of cholesteryl sulfate‐enriched low density lipoproteins to copper‐mediated oxidation

“…CS has also been found to display a strong ability to trigger the activation of factor XII [20] and thus to be involved in the intrinsic coagulation system. CS accumulates in X-linked ichthyosis patients deficient in aryl sulfatase [6,7], and CS is implicated in the skin scaling abnormalities of these subjects [21]. Increased plasma CS concentrations have also been found in hypercholesterolemic and cirrhotic patients, although plasma levels were less elevated than in the genetic disorder [8,9,22].…”