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Journal of Lipid Research, Vol. 49, 1409-1419, July 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Intracellular cholesterol transporter StarD4 binds free cholesterol and increases cholesteryl ester formation^*

Daniel Rodriguez-Agudo^*, Shunlin Ren^*, Eric Wong^*, Dalila Marques^*, Kaye Redford^*, Gregorio Gil, Phillip Hylemon and William M. Pandak^1,*

^* Department of Medicine, Veterans Affairs Medical Center and Virginia Commonwealth University, Richmond, VA
Department Biochemistry and Molecular Biology, Veterans Affairs Medical Center and Virginia Commonwealth University, Richmond, VA
Department Microbiology/Immunology, Veterans Affairs Medical Center and Virginia Commonwealth University, Richmond, VA

^* This work was supported by grants from the Veterans Administration (Merit Review), the National Institutes of Health (P01 DK-38030 and R01 HL-078898), and the Jeffress Research Grant. D.R-A. is the recipient of an American Heart Association Postdoctoral Fellowship award.

Published, JLR Papers in Press, April 9, 2008.

¹ To whom correspondence should be addressed. e-mail:wmpandak{at}hsc.vcu.edu

StarD4 protein is a member of the StarD4 subfamily of steroidogenic acute regulatory-related lipid transfer (START) domain proteins that includes StarD5 and StarD6, proteins whose functions remain poorly defined. The objective of this study was to isolate and characterize StarD4's sterol binding and to determine in a hepatocyte culture model its sterol transport capabilities. Utilizing purified full-length StarD4, in vitro binding assays demonstrated a concentration-dependent binding of [¹⁴C]cholesterol by StarD4 similar to that of the cholesterol binding START domain proteins StarD1 and StarD5. Other tested sterols showed no detectable binding to StarD4, except for 7-hydroxycholesterol, for which StarD4 demonstrated weak binding on lipid protein overlay assays. Subsequently, an isolated mouse hepatocyte model was used to study the ability of StarD4 to bind/mobilize/distribute cellular cholesterol. Increased expression of StarD4 in primary mouse hepatocytes led to a marked increase in the intracellular cholesteryl ester concentration and in the rates of bile acid synthesis. The ability and specificity of StarD4 to bind cholesterol and, as a function of its level of expression, to direct endogenous cellular cholesterol suggest that StarD4 plays an important role as a directional cholesterol transporter in the maintenance of cellular cholesterol homeostasis.

Supplementary key words liver • protein • metabolism • steroidogenic acute regulatory protein • steroidogenic acute regulatory-related lipid transfer domain

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