Abstract
Oxysterols have long been believed to be ligands of nuclear receptors such as liver × receptor (LXR), and they play an important role in lipid homeostasis and in the immune system, where they are involved in both transcriptional and posttranscriptional mechanisms. However, they are increasingly associated with a wide variety of other, sometimes surprising, cell functions. Oxysterols have also been implicated in several diseases such as metabolic syndrome. Oxysterols can be sulfated, and the sulfated oxysterols act in different directions: they decrease lipid biosynthesis, suppress inflammatory responses, and promote cell survival. Our recent reports have shown that oxysterol and oxysterol sulfates are paired epigenetic regulators, agonists, and antagonists of DNA methyltransferases, indicating that their function of global regulation is through epigenetic modification. In this review, we explore our latest research of 25-hydroxycholesterol and 25-hydroxycholesterol 3-sulfate in a novel regulatory mechanism and evaluate the current evidence for these roles.
Highlights
Oxysterols are the oxidized form of cholesterol
The potent active oxysterols include 25-hydroxycholesterol (25HC), which is synthesized by cholesterol 25-hydroxylase (CH25L) in hepatocytes and macrophages [7,8]; 27-hydroxycholesterol (27HC), synthesized by cholesterol 27-hydroxylase (CYP27A1: cytochrome P450 family 27 subfamily A member 1), in many cells [9]; 24-hydroxycholesterol (24HC), synthesized by cholesterol 24-hydroxidase (CH24L) [10]; and 24, 25-epoxycholesterol, synthesized from cholesterol precursors by multiple enzymes [11]
Oxysterol sulfate can be further sulfated by sulfotransferase 2A1 (SULT2A1) to be oxysterol disulfates [20,21,22]
Summary
Oxysterols are the oxidized form of cholesterol. There are many review articles describing the origins and metabolism of oxysterols [1]. The potent active oxysterols include 25-hydroxycholesterol (25HC), which is synthesized by cholesterol 25-hydroxylase (CH25L) in hepatocytes and macrophages [7,8]; 27-hydroxycholesterol (27HC), synthesized by cholesterol 27-hydroxylase (CYP27A1: cytochrome P450 family 27 subfamily A member 1), in many cells [9]; 24-hydroxycholesterol (24HC), synthesized by cholesterol 24-hydroxidase (CH24L) (occurs mainly in brain) [10]; and 24, 25-epoxycholesterol, synthesized from cholesterol precursors by multiple enzymes [11] These oxysterols participate in many biological processes including cholesterol homeostasis, triglyceride metabolism, inflammatory responses, cell proliferation, platelet aggregation, and apoptosis [12,13,14]. The sulfated 25HC, 25HC3S converted the methylated CpG in the regions, which has been shown as a distinct yet potent regulator of cellular functions [19]
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