Therapeutic Potential of Cholesteryl O-acyl α-glucoside Found in Helicobacter pylori

Abstract

Steryl glycosides are derivatives of sterols where the 3β-hydroxy group is glycosylated. Some of them are further converted to steryl O-acyl glycosides. Steryl glycosides and their derivatives are widely distributed in plants, algae, and fungi, but are relatively rarely distributed in bacteria and animals. Accumulating evidence suggests that glycosylation of sterols not only modifies physicochemical properties of cell membranes but also alters immunogenicity of the cells. Helicobacter pylori, that colonizes the stomach and causes gastric diseases, is auxotrophic for cholesterol, so that it extracts this lipid from plasma membranes of epithelial cells of the host stomach. Since incorporation of cholesterol promotes immune responses of the host, Helicobacter pylori converts cholesterol to cholesteryl glucoside (ChG) and then to cholesteryl 6'-O-acyl glucoside (ChAcG) to evade the immune surveillance. We have found that ChAcG thus produced is specifically recognized by invariant Vα14-Jα18 TCR(+) (Vα14) NKT cells in a CD1-dependent manner. We have also found that activation of Vα14 NKT cells by administration of ChAcG retains homeostasis of immunity upon exposure to allergens and reduces the incidence of allergy. In this article, overview of immunological functions of steryl glycosides with an emphasis on the immunoregulatory functions of ChAcG, is demonstrated.

Structure, metabolism and biological functions of steryl glycosides in mammals

“…We demonstrated that glycolipid extracts from H. pylori-induced immune responses from murine and human iNKT cells in a CD1d-dependent manner, and that ChAcαG is responsible for the antigenic activity using synthesized ChAcαG [62,138]. To our knowledge, this is the first report on the recognition of cholesterol derivatives by TCR.…”

“…Conversion of cholesterol to its glycoside affects the interaction between H. pylori and the host in a manner different from the manners described above (section 'Glycosylation of cholesterol facilitates H. pylori to evade immune surveillance of the host') that are beneficial for the pathogens to survive in the host. We recently demonstrated that ChAcαG produced by H. pylori is presented by the non-classical MHC class Ib molecules CD1d following phagocytosis and processing of the microbes by APCs, and recognized by invariant TCR-bearing NKT cells [62,138]. Murine invariant Vα14-Jα18 TCR + and their human counterpart invariant Vα24-Jα18 TCR + NKT (iNKT) cells are a subset of T lymphocytes [139] that are selected by non-classical MHC class I molecule CD1d in the thymus.…”

Steryl Glycosides in Fungal Pathogenesis: An Understudied Immunomodulatory Adjuvant

“…Again, we point the reader to other reviews for more in-depth bacterial SG literature [15,82,83]. Bacteria lack the enzymes necessary for SG production [7], so the major bacteria involved in SG production literature are Helicobacter pylori, a human gastrointestinal pathogen, and Borrelia burgdorferi, the causative agent of Lyme disease, both glycosylate host cholesterol into SGs [83]. Odder, compared to the majority of the prokaryotes, H. pylori uses the SGs to evade the host immune system.…”

The enzymatic biosynthesis of acylated steroidal glycosides and their cytotoxic activity

“…Among 10 reactive 3β-and 17β-hydroxylsteroids, dehydroepiandrosterone (4) had a maximum conversion approaching 100%, followed by diosgenin (5) with 82% conversion and the other compounds having conversion below 80% ( Fig. 1A).…”

“…Steroidal glycosides (SGs) are characterized by a steroidal skeleton glycosidically linked to sugar moieties, which can be further acylated with aliphatic and aromatic acids thus forming complex acylated steroidal glycosides (ASGs) 1 . The resulting steroidal glycoside esters (SGEs) exhibit a wide variety of biological activities, like cholesterol-lowering effect 2 , anti-diabetic properties 3 , anti-complementary activity 4 , immunoregulatory functions 5,6 and anti-cancer actions [7][8][9] , which made ASGs promising compounds with pharmaceutical potential. Numerous methods, including direct extraction 9 , chemical synthesis 10,11 and biosynthesis 12 , have been developed to synthesize these acylated steroidal glycosides.…”