Cholesterol sulfate alleviates ulcerative colitis by promoting cholesterol biosynthesis in colonic epithelial cells

Abstract

Cholesterol sulfate, produced by hydroxysteroid sulfotransferase 2B1 (SULT2B1), is highly abundant in the intestine. Herein, we study the functional role and underlying intestinal epithelial repair mechanisms of cholesterol sulfate in ulcerative colitis. The levels of cholesterol and cholesterol sulfate, as well as the expression of Sult2b1 and genes involved in cholesterol biosynthesis, are significantly higher in inflamed tissues from patients with ulcerative colitis than in intestinal mucosa from healthy controls. Cholesterol sulfate in the gut and circulation is mainly catalyzed by intestinal epithelial SULT2B1. Specific deletion of the Sult2b1 gene in the intestinal epithelial cells aggravates dextran sulfate sodium-induced colitis; however, dietary supplementation with cholesterol sulfate ameliorates this effect in acute and chronic ulcerative colitis in mice. Cholesterol sulfate promotes cholesterol biosynthesis by binding to Niemann-Pick type C2 protein and activating sterol regulatory element binding protein 2 in colonic epithelial cells, thereby alleviates ulcerative colitis. In conclusion, cholesterol sulfate contributes to the healing of the mucosal barrier and exhibits therapeutic efficacy against ulcerative colitis in mice.

Spatial Transcriptomic and Metabolomic Landscapes of Oral Submucous Fibrosis‐Derived Oral Squamous Cell Carcinoma and its Tumor Microenvironment

“…[ 79 , 80 ] We found that the classical metabolite of squamous cell carcinoma, cholesterol sulfate ( m/z 465.3044), exhibited a specific accumulation and distribution in the malignant epithelial region of OSF‐derived OSCC, which may be associated with tumor cell differentiation and the inhibition of immune cell infiltration and activation. [ 81 , 82 , 83 ] Phospholipids are important components of the cellular membrane system, and phospholipid metabolism in tumor cells has attracted attention as a potential target for cancer therapy. [ 84 ] Our results revealed that phosphatidyl ethanolamine (PE (28:1), m/z 634.4442) had a relatively higher abundance in the Adjacent Epithelium and ISC regions, while phosphatidyl choline (PC (38:7), m/z 804.5539) and phosphatidyl serine (PS (38:4), m/z 810.5292) were remarkably enriched in the Stroma and OSF regions (Figure S8 , Supporting Information).…”

Revisiting the effect of cholesteryl sulfate on clotting and fibrinolysis: Inhibition of human thrombin and other human blood proteases

“…4 ). Given the results of this study, we strongly recommend further in vitro (for example, thrombo-elastography) and in vivo (for example, animal models of venous and arterial thrombosis) investigation of CS to better understand its (patho-)physiological roles in coagulation and hemostasis which may intersect with the other reported biological effects of CS [ [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] ].…”

Cholesterol sulfate limits neutrophil recruitment and gut inflammation during mucosal injury

“…A recent study has reported that IEC-specific Sult2b1 deletion mice (Sult2b1 f/f Villin-Cre mice) develop severe DSS-induced colitis, compared with the control Sult2b1 f/f mice (24). Although they suggested that CS alleviates gut inflammation by promoting cholesterol biosynthesis in IECs (24), the effect of CS on intestinal immune cells remains unexplored. DOCK2 is a Rac activator predominantly expressed in hematopoietic cells.…”

“…In humans and mice, cholesterol sulfation is mediated primarily by the sulfotransferases SULT2B1b and, to a lesser extent, SULT2B1a, which are produced from the same gene, SULT2B1, through alternative splicing (22,23). Currently, CS has been implicated in many biological processes including sperm capacitation, platelet adhesion, blood clotting, cholesterol or leukotriene biosynthesis, and T-cell receptor signaling (21, 24,25). In addition, we have revealed that CS is an endogenous inhibitor of DOCK2 (26).…”