期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 306, 期 2, 页码 E123-E130出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00552.2013
关键词
oxysterol sulfate; nuclear receptor; cholesterol and triglyceride metabolism; 25HC3S; LXR; SREBPs; I kappa B; NF-kappa B; PPARs
资金
- National Institutes of Health [R01 HL-078898]
- Veterans Affairs Department (VA Merit Review)
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL078898] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX001874] Funding Source: NIH RePORTER
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 gamma and cytosolic I kappa B alpha and decreases nuclear NF-kappa B levels and proinflammatory cytokine expression and secretion when cells are challenged with LPS and TNF alpha. In contrast to 25HC3S, 25HC, a known LXR ligand, increases nuclear LXR and decreases nuclear PPARs and cytosol I kappa B alpha 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.
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