Cholesterol Sulfate (sodium salt) (Synonyms: SCS, Sodium Cholesteryl Sulfate)

Cholesterol sulfate was first isolated from human plasma in 1965 and found to be present in a concentration of 300 µg/100 ml ^[1]. The apparent validity of this initial value was soon confirmed by reports of plasma cholesterol sulfate levels involving a limited number of subjects that ranged from 174 to 328 µg/100 ml ^[2,3].

Cholesterol sulfate has the ability to trigger the intrinsic blood coagulation system by activating Factor XII, an action that is not shared by other steroid sulfates or by unconjugated cholesterol. Cholesterol sulfate activates prekallikrein in the presence of Factor XII ^[4]. Cholesterol sulfate activates multiple epidermal protein kinase C isozymes, especially the ε, Η, and ζ isoforms ^[5].In vitro, cholesterol sulfate is a novel activator of the Η isoform of protein kinase C, and in so doing is more potent than phosphatidylserine plus phorbol ester [6]. Thrombin and plasmin, serine proteases that play essential roles in blood clotting and fibrinolysis, respectively, are potently inhibited by cholesterol sulfate ^[7].

Cholesterol Sulfate (sodium salt) (100 µM 2 h) pretreatment resulted in substantially attenuated anti-CD3-induced CD3ζ phosphorylation, Cholesterol Sulfate specifically interacts with the TCR to inhibit transmembrane signaling without interfering with downstream components of the signaling pathway ^[8]. A strong reduction in the (T cell antigen receptor) TCR nanoclusters extracted from Cholesterol Sulfate-treated 5C.C7 T cells ^[8]. Increasing the amount of Cholesterol Sulfate (20 µl 25 mM) in the thymus of mice by intrathymic injection led to a decrease in the number of total thymocytes ^[8].

References:
[1]. Drayer NM, Lieberman S. Isolation of cholesterol sulfate from human blood and gallstones. Biochemical and biophysical research communications. 1965 Jan 4;18(1):126-30.
[2]. Gurpide E, Roberts KD, Welch MT, Bandy L, Lieberman S. Studies on the metabolism of blood-borne cholesterol sulfate. Biochemistry. 1966 Oct 1;5(10):3352-62.
[3]. Winter JS, Bongiovanni AM. Identification of cholesterol sulfate in urine and plasma of normal and hypercholesterolemic subjects. The Journal of Clinical Endocrinology & Metabolism. 1968 Jun 1;28(6):927-30.
[4]. Shimada T, Kato H, Iwanaga S, Iwamori M, Nagai Y. Activation of factor XII and prekallikrein with cholesterol sulfate. Thrombosis research. 1985 Apr 1;38(1):21-31.
[5]. Denning MF, Kazanietz MG, Blumberg PM, Yuspa SH. Cholesterol sulfate activates multiple protein kinase C isoenzymes and induces granular cell differentiation in cultured murine keratinocytes. Cell Growth and Differentiation-Publication American Association for Cancer Research. 1995 Dec 1;6(12):1619-26.
[6]. Ikuta T, Chida K, Tajima O, Matsuura Y, Iwamori M, Ueda Y, Mizuno K, Ohno S, Kuroki T. Cholesterol sulfate, a novel activator for the eta isoform of protein kinase C. Cell Growth & Differentiation: the Molecular Biology Journal of the American Association for Cancer Research. 1994 Sep 1;5(9):943-7.
[7]. Iwamori M, Iwamori Y, Ito N. Regulation of the activities of thrombin and plasmin by cholesterol sulfate as a physiological inhibitor in human plasma. The Journal of Biochemistry. 1999 Mar 1;125(3):594-601.
[8]. Wang F, Beck-García K, Zorzin C, et al. Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol[J]. Nature immunology, 2016, 17(7): 844-850.