Identification of a novel sulfonated oxysterol, 5-cholesten-3beta,25-diol 3-sulfonate, in hepatocyte nuclei and mitochondria |
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Authors: | Ren Shunlin Hylemon Phillip Zhang Zong-Ping Rodriguez-Agudo Daniel Marques Dalila Li Xiaobo Zhou Huiping Gil Gregorio Pandak William M |
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Affiliation: | Department of Medicine, Medical College of Virginia at Virginia Commonwealth University, Richmond, 23298, USA. |
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Abstract: | This study reports the discovery of a novel sulfonated oxysterol found at high levels in the mitochondria and nuclei of primary rat hepatocytes after overexpression of the gene encoding steroidogenic acute regulatory protein (StarD1). Forty-eight hours after infection of primary rat hepatocytes with recombinant adenovirus encoding StarD1, rates of bile acid synthesis increased by 4-fold. Concurrently, [(14)C]cholesterol metabolites (oxysterols) were increased dramatically in both the mitochondria and nuclei of StarD1-overexpressing cells, but not in culture medium. A water-soluble [(14)C]oxysterol product was isolated and purified by chemical extraction and reverse-phase HPLC. Enzymatic digestion, HPLC, and tandem mass spectrometry analysis identified the water-soluble oxysterol as 5-cholesten-3beta,25-diol 3-sulfonate. Further experiments detected this cholesterol metabolite in the nuclei of normal human liver tissues. Based upon these observations, we hypothesized a new pathway by which cholesterol is metabolized in the mitochondrion. |
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Keywords: | nucleus steroidogenic acute regulatory protein cholesterol transporter bile acids cholesterol metabolism nuclear oxysterol ligands |
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