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Journal of Lipid Research, Vol. 47, 1081-1090, May 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Identification of a novel sulfonated oxysterol, 5-cholesten-3ß,25-diol 3-sulfonate, in hepatocyte nuclei and mitochondria

Shunlin Ren^1,*,, Phillip Hylemon, Zong-Ping Zhang^**, Daniel Rodriguez-Agudo^*,, Dalila Marques^*,, Xiaobo Li, Huiping Zhou, Gregorio Gil and William M. Pandak^*,

^* Department of Medicine, Medical College of Virginia at Virginia Commonwealth University, Richmond, VA 23298
Veterans Affairs Medical Center, Richmond, VA 23249
Department of Microbiology and Immunology, Medical College of Virginia at Virginia Commonwealth University, Richmond, VA 23298
^** Department of Pharmaceutics, Medical College of Virginia at Virginia Commonwealth University, Richmond, VA 23298
Department of Biochemistry, Medical College of Virginia at Virginia Commonwealth University, Richmond, VA 23298

Published, JLR Papers in Press, February 27, 2006.

¹ To whom correspondence should be addressed. e-mail: shunlin.ren{at}va.gov

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, [¹⁴C]cholesterol metabolites (oxysterols) were increased dramatically in both the mitochondria and nuclei of StarD1-overexpressing cells, but not in culture medium. A water-soluble [¹⁴C]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-3ß,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.

Supplementary key words nucleus • steroidogenic acute regulatory protein • cholesterol transporter • bile acids • cholesterol metabolism • nuclear oxysterol ligands

Abbreviations: CYP27A1, cholesterol 27-hydroxylase; CYP7A1, cholesterol 7-hydroxylase; HST2, hydroxycholesterol sulfonate transferase 2; LXR, liver sterol receptor; StarD1, steroidogenic acute regulatory protein

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