Abstract
Nuclear oxysterol receptor, Liver X receptor (LXR) is a key transcriptional regulator of liver lipid metabolism. We recently identified the oxysterol 25‐diol 3‐sulfate (25HC3S) as an important regulatory molecule in liver. We now have studied the effects of 25HC3S and its precursor, 25‐hydroxycholesterol (25HC) on the LXR/SREBP‐1 signaling pathway in microphages. Addition of 25HC3S to human macrophages markedly decreased nuclear LXR protein levels. Real time PCR and western blot results showed 25HC3S inhibited SREBP‐1 mRNA and protein mature form.25HC3S decreased the expression of SREBP‐1‐responsive genes including acetyl CoA carboxylase‐1 and fatty acid synthase, as well as HMGR and LDLR, which are key proteins involved in lipids metabolism.Subsequently, Oil‐Red O staining and TLC found 25HC3S inhibited intracellular lipids accumulation.25HC as a LXR ligand had opposite effects, increasing ABCA1, ABCG1, SREBP‐1, and FAS mRNA levels in the macrophages. In the presence of 25HC3S, 25HC and LXR agonist T0901317 failed to increase LXR targeting gene expression. We conclude that 25HC3S acts in macrophage as cholesterol satiety signal, down‐regulating cholesterol and fatty acid biosynthetic pathways via inhibition of LXR/SREBP signaling. These studies suggest that 25HC3S is a potent regulator of lipid metabolism in macrophages.
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