Sulfation of 25-hydroxycholesterol regulates lipid metabolism, inflammatory responses, and cell proliferation

Abstract

Ren S, Ning Y. Sulfation of 25-hydroxycholesterol regulates lipid metabolism, inflammatory responses, and cell proliferation. Am J Physiol Endocrinol Metab 306: E123-E130, 2014. First published December 3, 2013 doi:10.1152/ajpendo.00552.2013.-Intracellular lipid accumulation, inflammatory responses, and subsequent apoptosis are the major pathogenic events of metabolic disorders, including atherosclerosis and nonalcoholic fatty liver diseases. Recently, a novel regulatory oxysterol, 5-cholesten-3b, 25-diol 3-sulfate (25HC3S), has been identified, and hydroxysterol sulfotransferase 2B1b (SULT2B1b) has been elucidated as the key enzyme for its biosynthesis from 25-hydroxycholesterol (25HC) via oxysterol sulfation. The product 25HC3S and the substrate 25HC have been shown to coordinately regulate lipid metabolism, inflammatory responses, and cell proliferation in vitro and in vivo. 25HC3S decreases levels of the nuclear liver oxysterol receptor (LXR) and sterol regulatory element-binding proteins (SREBPs), inhibits SREBP processing, subsequently downregulates key enzymes in lipid biosynthesis, decreases intracellular lipid levels in hepatocytes and THP-1-derived macrophages, prevents apoptosis, and promotes cell proliferation in liver tissues. Furthermore, 25HC3S increases nuclear PPAR␥ and cytosolic IB␣ and decreases nuclear NF-B levels and proinflammatory cytokine expression and secretion when cells are challenged with LPS and TNF␣. In contrast to 25HC3S, 25HC, a known LXR ligand, increases nuclear LXR and decreases nuclear PPARs and cytosol IB␣ levels. In this review, we summarize our recent findings, including the discovery of the regulatory oxysterol sulfate, its biosynthetic pathway, and its functional mechanism. We also propose that oxysterol sulfation functions as a regulatory signaling pathway. oxysterol sulfate; nuclear receptor; cholesterol and triglyceride metabolism;

High levels of oxysterol sulfates in serum of patients with steroid sulfatase deficiency

“…Additionally, the effects of the continuous presence of high concentrations of certain hydroxycholesterol sulfates, which have been proved to have regulatory capacities in some cases ( 26,28 ), should be studied in detail. position 24.…”

“…Some of the most relevant monosulfated and disulfated hydroxysterols have been previously identifi ed, synthesized, and characterized (25)(26)(27)(28). Among these, 25-hydroxycholesterol-3-sulfate (25OHC3S) has been studied with more detail, and its physiological activities and regulatory capacities have been described ( 28 ).…”

“…Among these, 25-hydroxycholesterol-3-sulfate (25OHC3S) has been studied with more detail, and its physiological activities and regulatory capacities have been described ( 28 ).…”

Armand-Frappier Outstanding Student Award — The emerging role of 25-hydroxycholesterol in innate immunity

“…For example, CYP7B1 hydroxylates 25HC to form 7␣25HC, an oxysterol that also plays an important role as a guidance cue for B cells through interaction with Epstein-Barr virus induced receptor 2 (reviewed in Daugvilaite et al 2014). Recent work has also identified hydroxysterol sulfotransferase 2B1b as the enzyme that catalyzes sulfation of 25HC to 25-hydroxycholesterol-3-sulfate (25HC3S) (Ren and Ning 2014). Studies have generally found the sulfated oxysterol to have effects opposing to 25HC on both inflammation and metabolism (Ren and Ning 2014).…”

“…Recent work has also identified hydroxysterol sulfotransferase 2B1b as the enzyme that catalyzes sulfation of 25HC to 25-hydroxycholesterol-3-sulfate (25HC3S) (Ren and Ning 2014). Studies have generally found the sulfated oxysterol to have effects opposing to 25HC on both inflammation and metabolism (Ren and Ning 2014). While metabolomic profiling revealed no significant increase in sulfated oxysterol levels during IFN stimulation of macrophages (Blanc et al 2013), it remains to be seen if 25HC3S plays a role in the antiviral response in other cell types and tissues, such as the liver, where 25HC3S has been shown to be localized in the nuclei and mitochondria (Ren et al 2006).…”