Submitted on November 20, 2007
Revised on April 4, 2008
Accepted on April 9, 2008
Intracellular cholesterol transporter StarD4 binds free cholesterol and increases cholesterol ester formation
Daniel Rodriguez-Agudo, Shunlin Ren, Eric Wong, Dalila Marques, Kaye Redford, Gregorio Gil, Phillip Hylemon, and William M. Pandak
Internal Medicine, Virginia Commonwealth University, Richmond, VA
Corresponding Author: wmpandak{at}hsc.vcu.edu
StarD4 protein is a member of the StarD4 subfamily of START domain proteins that includes StarD5 and StarD6; proteins whose functions remain poorly defined. The objective of this study was to isolate and to 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. In contrast to StarD5, which is capable of binding both cholesterol and 25-hydroxycholesterol, StarD4, like StarD1, only bound cholesterol. As with both 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 cholesterol-ester concentration and in the rates of bile acid synthesis. The ability and specifity of StarD4 to bind cholesterol and, as a function of its level of expression, to direct endogenous cellular cholesterol, suggests that StarD4 plays an important role as a directional cholesterol transporter in the maintenance of cellular cholesterol homeostasis.
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