Cholesterol sulfate in human physiology: what's it all about?

Strott, Charles A.; Higashi, Yuko

doi:10.1194/jlr.r300005-jlr200

Cited by 205 publications

(191 citation statements)

References 125 publications

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“…In this study, we identified CS as a key molecule for the regulation of encystation. In mammals, the roles of CS in cellular functions are relatively well characterized (e.g., regulation of lipid metabolism, protection of erythrocytes from osmotic lysis, supporting platelet adhesion, and acting as a nuclear receptor ligand) (11,27). However, there have been few reports concerning CS, or even its production, in unicellular eukaryotes (28).…”

Section: Discussionmentioning

confidence: 99%

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Entamoeba mitosomes play an important role in encystation by association with cholesteryl sulfate synthesis

Mi-ichi

Miyamoto

Takao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

114

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Hydrogenosomes and mitosomes are mitochondrion-related organelles (MROs) that have highly reduced and divergent functions in anaerobic/microaerophilic eukaryotes. Entamoeba histolytica, a microaerophilic, parasitic amoebozoan species, which causes intestinal and extraintestinal amoebiasis in humans, possesses mitosomes, the existence and biological functions of which have been a longstanding enigma in the evolution of mitochondria. We previously demonstrated that sulfate activation, which is not generally compartmentalized to mitochondria, is a major function of E. histolytica mitosomes. However, because the final metabolites of sulfate activation remain unknown, the overall scheme of this metabolism and the role of mitosomes in Entamoeba have not been elucidated. In this study we purified and identified cholesteryl sulfate (CS) as a final metabolite of sulfate activation. We then identified the gene encoding the cholesteryl sulfotransferase responsible for synthesizing CS. Addition of CS to culture media increased the number of cysts, the dormant form that differentiates from proliferative trophozoites. Conversely, chlorate, a selective inhibitor of the first enzyme in the sulfate-activation pathway, inhibited cyst formation in a dose-dependent manner. These results indicate that CS plays an important role in differentiation, an essential process for the transmission of Entamoeba between hosts. Furthermore, we show that Mastigamoeba balamuthi, an anaerobic, free-living amoebozoan species, which is a close relative of E. histolytica, also has the sulfate-activation pathway in MROs but does not possess the capacity for CS production. Hence, we propose that a unique function of MROs in Entamoeba contributes to its adaptation to its parasitic life cycle. mitochondrion-related organelles | protist | sulfolipids | differentiation M itochondrion-related organelles (MROs) are derived from canonical mitochondria and are found in a wide range of anaerobic/microaerophilic eukaryotes (1, 2). During the course of evolution MROs have undergone secondary loss of mitochondrial functions; this loss has occurred independently multiple times, resulting in the broad phylogenetic distribution of organisms possessing MROs (2). Furthermore, MROs occasionally acquire novel functions from other organisms by lateral gene transfer (LGT) (1, 3). Hence, MROs are not simply remnants of mitochondria but rather are organelles that display a variety of unique features (1-5).Unique features have been demonstrated in different types of MRO (2-4). Some anaerobic lineages of eukaryotes possess MROs (hydrogenosomes or hydrogen-producing mitochondria) that have remodeled their mitochondria drastically to couple ATP generation with hydrogen production (2-4). Mitosomes, another type of MRO maintained in some organisms that inhabit anaerobic/microaerophilic environments, do not produce ATP or hydrogen and have lost typical mitochondrial functions, such as the tricarboxylic acid (TCA) cycle, electron transport, oxidative phosphorylation, and β-oxidation...

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Section: Discussionmentioning

confidence: 99%

“…CS, a constituent of cellular membranes, originally was isolated from human plasma, and its synthesis is mediated by an SULT that uses cholesterol and PAPS as substrates (10,11). To date, several genes for cholesteryl SULTs have been identified in mammals (10,12).…”

Section: Resultsmentioning

confidence: 99%

Entamoeba mitosomes play an important role in encystation by association with cholesteryl sulfate synthesis

Mi-ichi

Miyamoto

Takao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

114

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“…Cholesterol sulfate is present in various tissues and body fluids, and it accumulates during squamous cell differentiation in the epithelial cells of barrier tissues, such as the respiratory tract and esophageal mucosa (11,12,42). Cholesterol sulfate is also found in considerable quantities in the skin, predominantly in the epidermis (10), where it acts as an important regulator during the formation of the epidermal barrier (42).…”

Section: Discussionmentioning

confidence: 99%

“…Cholesterol sulfate is also found in considerable quantities in the skin, predominantly in the epidermis (10), where it acts as an important regulator during the formation of the epidermal barrier (42).…”

Section: Discussionmentioning

confidence: 99%

Receptor Mincle promotes skin allergies and is capable of recognizing cholesterol sulfate

Kostarnoy

Gancheva

Lepenies

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Sterile (noninfected) inflammation underlies the pathogenesis of many widespread diseases, such as allergies and autoimmune diseases. The evolutionarily conserved innate immune system is considered to play a key role in tissue injury recognition and the subsequent development of sterile inflammation; however, the underlying molecular mechanisms are not yet completely understood. Here, we show that cholesterol sulfate, a molecule present in relatively high concentrations in the epithelial layer of barrier tissues, is selectively recognized by Mincle (Clec4e), a C-type lectin receptor of the innate immune system that is strongly up-regulated in response to skin damage. Mincle activation by cholesterol sulfate causes the secretion of a range of proinflammatory mediators, and s.c. injection of cholesterol sulfate results in a Mincle-mediated induction of a severe local inflammatory response. In addition, our study reveals a role of Mincle as a driving component in the pathogenesis of allergic skin inflammation. In a well-established model of allergic contact dermatitis, the absence of Mincle leads to a significant suppression of the magnitude of the skin inflammatory response as assessed by changes in ear thickness, myeloid cell infiltration, and cytokine and chemokine secretion. Taken together, our results provide a deeper understanding of the fundamental mechanisms underlying sterile inflammation.innate immunity | sterile inflammation | allergy | Mincle | cholesterol sulfate

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“…However, CS in its own right can act as a regulatory molecule 41,42 . Of the selected metabolites, CS was our only candidate that fitted into networks generated in Ingenuity pathway analysis ® (IPA).…”

Section: Identification Of Candidate Biological Moleculesmentioning

confidence: 99%

Tunable Supramolecular Hydrogels for Selection of Lineage-Guiding Metabolites in Stem Cell Cultures

Alakpa

Jayawarna

Lampel

et al. 2016

Chem

188

189

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Abstract. Stem cells are known to differentiate in response toHowever, identification of these stem cell inducing molecules is non-trivial and rational approaches to discover drugs for achieving reproducible, targeted stem cell control remain elusive. Here, we demonstrate the design of supramolecular hydrogels that allow targeting of a range of stem cell phenotypes, providing a useful platform for discovery of differentiation inducing metabolites. These gels are simple in composition, containing a fibre forming aromatic peptide amphiphile, which is coassembled with a surfactant-like amphiphile that provides hydrophilic surface functionality to the fibres. The stiffness of the gels can be precisely tuned over the entire range that is typically associated with stem cell differentiation (0.1-40 kPa). 3We demonstrate that the gels can be used to direct stem cell differentiation without the need for induction media and they are therefore ideally suited to study stem cell behaviour -including as drug discovery platforms. To achieve this, we study the cell's usage of biological small molecules, metabolites, during differentiation and select bioactive metabolites that can target bone and cartilage formation specifically. This new use of designed supramolecular biomaterials can be envisaged to remove serendipity from discovery of metabolites associated with biological processes as drug candidates. Introduction.

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Cholesterol sulfate in human physiology: what's it all about?

Cited by 205 publications

References 125 publications

Entamoeba mitosomes play an important role in encystation by association with cholesteryl sulfate synthesis

Entamoeba mitosomes play an important role in encystation by association with cholesteryl sulfate synthesis

Receptor Mincle promotes skin allergies and is capable of recognizing cholesterol sulfate

Tunable Supramolecular Hydrogels for Selection of Lineage-Guiding Metabolites in Stem Cell Cultures

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