Cholesterol sulfate

From LipidomicsWiki

Contents 1 Basics 1.1 Natural sources 2 Metabolism 2.1 Cholesterol Sulfotransferases

Basics

Cholesterol sulfate is quantitatively the most important known sterols sulfate in human plasma, where it is present in a concentration that overlaps that of the other abundant circulating steroid sulfate, dehydroepiandrosterone (DHEA) sulphate.

Cholesterol sulfate is a component of cell membranes where it has a stabilizing role, e.g., protecting erythrocytes from osmotic lysis and regulating sperm capacitation. It is present in platelet membranes where it supports platelet adhesion. Cholesterol sulfate can regulate the activity of serine proteases, e.g., those involved in blood clotting, fibrinolysis, and epidermal cell adhesion.

Natural sources

Cholesterol 3-sulfate

Metabolism

Sulfonation is important in the metabolism of drugs and xenobiotics (Mulder and Jakoby 1990). Sulfoglycolipids such as sphingolipids and galactoglycerolipids are abundant in myelin as well as spermatozoa, kidney, and small intestine (Makita and Taniguchi 1985), and have been implicated in a variety of physiologic functions through their interactions with extracellular matrix proteins, cellular adhesive receptors, blood coagulation systems, complement activation systems, and cation transport systems (Vos et al. 1994). Sulfonation is an important modification of cholesterol (Roberts and Lieberman 1970) and its derivatives, bile acids (Palmer and Bolt 1971), vitamin D (Nagubandi et al. 1981), and steroids (Roy and Trudinger 1970).

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Cholesterol sulfate has effects on cholesterol synthesis (Williams et al. 1985), sperm capacitation (Langlais et al. 1981), and the activity of thrombin and plasmin (Iwamori et al. 1994). Cholesterol sulfate can function as a regulatory molecule (Denning et al. 1995; Ikuta et al. 1994). One of the most investigated physiologic roles for cholesterol sulfate has been in keratinocyte differentiation and development of the epidermal barrier (Jetten et al. 1998; Kawabe et al. 1998). It is now evident that cholesterol sulfate, akin to certain other steroid sulfates such as pregnenolone sulphate (Paul and Purdy 1992), is considerably more than a simple metabolic end product "whose sole fate is removal by the excreta" (Roberts and Lieberman 1970).

Cholesterol sulfate in humans is found in urine, bile, and feces (Moser et al. 1966; Winter and Bongiovanni 1968; Eneroth and Nystrom 1968a; 1968b), in addition to its presence in the circulation; it is also a normal constituent in seminal plasma as well as spermatozoa (Langlais et al. 1982; Sion et al. 2001). Cholesterol sulfate is present in platelets (Blache et al. 1995; Merten et al. 2001) and red blood cells (Bleau et al. 1972; Bergner and Shapiro 1981; Muskiet et al. 1983; Bleau et al. 1974); it is also a normal constituent in a variety of human tissues including skin, hair, nails, aorta, adrenal, liver, and kidney (Moser et al. 1966; Drayer and Lieberman 1965).

In skin, cholesterol sulfate is located predominantly in the epidermis where it functions as an important regulatory molecule during formation of the barrier (Williams and Elias 1981; Gray and Yardley 1975, Epstein et al. 1984; Elias et al. 1984). Cholesterol sulfate is formed in the basal and spinous layers of the epidermis, reaches its highest concentration in the granular layer, and then decreases in the stratum corneum as a result of the action of steroid sulfate sulfatase (Elias et al. 1984; Lampe et al. 1983). Cholesterol thus starts to undergo sulfoconjugation in the lower reaches of the epidermis and, as keratinocytes, drop out of the cell cycle, begin the process of differentiation, and migrate into the outer layer of living epidermal cells where the amount of cholesterol sulfate reaches a maximum. It is then hydrolyzed in the dead layer of skin, the stratum corneum, creating what has been referred to as "the epidermal cholesterol sulfate cycle" (Epstein et al. 1984). In blood and gastrointestinal epithelia, cholesterol sulfate is a minor sterol constituent, and the cholesterol-cholesterol sulfate ratio approximates 500:1, whereas in the stratum corneum of the normal epidermis the ratio is 10:1 to 5:1 (Ponec and Williams 1986). However, in recessive X-linked ichthyosis, which is caused by steroid sulfatase deficiency, the ratio of cholesterol-cholesterol sulfate in the stratum corneum can be as low as 1:1 (Ponec and Williams 1986). Cholesterol sulfate is a normal constituent of hair and nails (Wrtz and Downing 1988; Serizawa et al. 1990); furthermore, similar to its elevation in the stratum corneum, the level of cholesterol sulfate in hair and nails is also significantly increased in recessive X-linked ichthyosis (Serizawa et al. 1990).

Cholesterol Sulfotransferases

Cytosolic sulfotransferases (SULTs) constitute a superfamily of enzymes that catalyze the sulfoconjugation of relatively small endogenous compounds such as hormones and neurotransmitters, as well as drugs and xenobiotics (Mulder and Jakoby 1990). The SULT superfamily is divided into five families, one of which (SULT2) is primarily engaged in the sulfoconjugation of neutral steroids and sterols. The human SULT2 family is further divided into two subfamilies, i.e., SULT2A1 and SULT2B1 (Nagata and Yamazoe 2000). Additionally, the SULT2B1 subfamily consists of two isoforms designated SULT2B1a and SULT2B1b (Her et al. 1998). SULT2A1, which is the prototypical hydroxysteroid sulfotransferase, is commonly referred to as DHEA sulfotransferase because DHEA is considered the preferred substrate, although this isozyme has a broad substrate predilection (Falany et al. 1989; Hernandez et al. 1992). In fact, the first human enzyme to be reported as exhibiting cholesterol sulfotransferase activity was SULT2A1, a conclusion that was based on biochemical and molecular studies involving liver samples (Askoy et al. 1993). It was later determined, however, that the SULT2B1b isozyme is remarkably more active in sulfonating cholesterol than SULT2A1 (Javitt et al. 2001). Interestingly, whereas the SULT2B1b isoform avidly sulfonates cholesterol, the SULT2B1a isoform preferentially sulfonates pregnenolone but not cholesterol (Fuda et al. 2002).

From a structural point of view, the outstanding feature of the SULT2B1 isoforms, as compared with the SULT2A1 isozyme as well as other cloned steroid and cognate SULTs, is their extended amino- and carboxy-terminal ends (outlined in Fig. 49 with dashed lines). All previously cloned members of the mammalian SULT superfamily, i.e., estrogen and phenol sulfotransferases as well as hydroxysteroid sulfotransferases, have sizes that range from 282 to 295 amino acids, whereas SULT2B1a and SULT2B1b consist of 350 and 365 amino acids, respectively. Overall, the SULT2A1 and SULT2B1 isozymes are 37% identical at the amino acid level. If, however, the extended amino- and carboxy-terminal ends of the SULT2B1 isoforms are excluded, identities increase to 48%. Importantly, the extended amino- and carboxy-terminal ends of the SULT2B1 isoforms aside, there remains a significant structural similarity between the SULT2A1 and SULT2B1 isozymes in their core regions, which contain residues that are highly conserved in all SULTs; residues known to be involved in interaction with the 5'-phosphoadenosine-3'-phosphosulfate cofactor.

Human SULT2B1a and SULT2B1b are derived from a single gene (SULT2B1) as a result of an alternative exon I and differential splicing (Her et al. 1998). Thus, the two SULT2B1 isoforms differ only at their N-terminal ends. Studies of the functional significance of this unique feature revealed that removal of 23 amino acids from the N-terminal end that is unique to SULT2B1b results in loss of cholesterol sulfotransferase activity; on the other hand, removal of eight amino acids from the N-terminal end that is unique to SULT2B1a has no effect on pregnenolone sulfotransferase activity (Fuda et al. 2002). In the gene for SULT2B1, exon 1B encodes for only the unique N-terminal region of SULT2B1b, whereas exon 1A encodes for the unique N-terminal end of SULT2B1a plus an additional 48 amino acids (cf. Fig. 47). Thus, if the gene for SULT2B1 employs exon 1B, cholesterol sulfotransferase is synthesized; however, if exon 1A is used, pregnenolone sulfotransferase is produced (Fuda et al. 2002).

Studies regarding the functional significance of the extended carboxy-terminal ends of the SULT2B1 isoforms revealed that the terminal 53 amino acids can be removed from both isoforms without loss in catalytic activity (Fuda et al. 2002). Nevertheless, the composition of the identical carboxy-terminal ends of the SULT2B1 isoforms is structurally interesting: this region is enriched in proline residues and contains proline, glutamic acid, serine, and threonine sequences (cf. Fig. 49) that may play a crucial role in targeting these isoforms for calpain proteolysis (Rechsteiner and Rogers 1996).

In keeping with the finding that cholesterol sulfate is widely present in human tissues, the mRNA for human SULT2B1b was also noted to be broadly expressed (Javitt et al. 2002). Quantitatively, SULT2B1b mRNA is predominantly expressed in the skin, prostate, and placenta, and to a lesser extent in the stomach, small intestine, colon, kidney, lung, and thyroid gland (unpublished observations). It's of interest that skin, lungs, kidney, and intestines were also found to be major organs engaged in cholesterol sulfate synthesis in the guinea pig (Hochberg et al. 1974).

The human SULT2B1 gene localizes to chromosome 19q13.3, 500 kb telomeric to the location of the gene for SULT2A1 (Her et al. 1998). Although a substantial number of steroid sulfotransferase genes have now been cloned in several species, there has been little information forthcoming regarding their transcriptional regulation, with the exception of the SULT2A1 gene in the rat; there are no reports as yet on the transcriptional regulation of the SULT2B1 gene. Rat SULT2A1 is selectively manifest in liver, where expression is strongly repressed by androgens (Deyman et al. 1974). In this regard, hepatocyte nuclear factor-1 and CCAAT/enhancer binding protein (C/EBP) response elements play pivotal roles (Song et al. 1998). Concerning androgen repression, a negative androgen response region in the rat SULT2A1 promoter has been mapped. Androgenic repression of the rat SULT2A1 gene requires the presence of OCT-1 and C/EBP elements that map to specific promoter locations. Furthermore, the negative androgenic regulatory effect may be exerted indirectly through transcriptional interference of OCT-1 and C/EBP rather than via a direct interaction of the androgen receptor with DNA (Song et al. 1998). In addition to its capacity as a neutral steroid sulfotransferase, rat SULT2A1 functions as bile acid sulfotransferase. Apropos to the latter function, rat SULT2A1 is inducible by primary bile acids in liver and intestinal cell lines, and this inducing effect is mediated through the bile acid-activated farnesoid X receptor (FXR), a member of the nuclear receptor super family (Song et al. 1998). The ligand-activated FXR acts as a heterodimer with the 9-cis-retinoic acid receptor (RXR) and regulates the SULT2A1 gene by binding to a cis-element cognate to the FXR-RXR- heterodimer (Song et al. 1998).

Hydrolysis of sulfonated steroids and sterols, which regenerates unconjugated substrates as free alcohols, completes the sulfurylation cycle and is carried out by a member of the sulfohydrolase or sulfatase gene family located on the X-chromosome at p22.3 (Parenti et al. 1997). Steroid sulfatase (also referred to as arylsulfatase C) is a membrane-bound microsomal enzyme that is ubiquitously expressed in mammalian tissues and hydrolyzes a variety of 3ß-hydroxysteroid sulfates, including cholesterol sulphate (Ballabio and Shapiro 1995). The importance of cholesterol sulfate hydrolysis is exemplified by the genetic disorder X-linked ichthyosis, a disease characterized by severe scaling, levels of plasma cholesterol sulfate that are strikingly elevated (Bergner and Shapiro 1981; Epstein et al. 1981; Serizawa et al. 1989), and excessive cholesterol sulfate deposition in the stratum corneum layer of the epidermis (Williams and Elias 1981); furthermore, the increase of cholesterol sulfate levels in the stratum corneum, which results from steroid sulfatase deficiency, appears to be responsible for the ichthyotic changes (Ballabio and Shapiro 1995). Little is known about how steroid sulfatase is regulated.