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Frontiers in Biology

ISSN 1674-7984

ISSN 1674-7992(Online)

CN 11-5892/Q

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Front Biol    2011, Vol. 6 Issue (3) : 190-196    https://doi.org/10.1007/s11515-011-1143-5
REVIEW
Sterol-binding proteins and endosomal cholesterol transport
Ximing DU, Hongyuan YANG()
School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, NSW, 2052, Australia
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Abstract

Endosomal compartments sort and deliver exogenous lipoprotein-derived cholesterol to the endoplasmic reticulum for regulating cellular cholesterol homeostasis. A large number of studies have focused on the removal of endosomal cholesterol, since its accumulation leads to devastating human diseases. Recent studies suggest that cytoplasmic sterol-binding proteins may be involved in endosomal cholesterol transport. In particular, endosome/lysosome-localized or-associated cholesterol-binding proteins may serve as key mediators of cholesterol removal in a non-vesicular manner. Further characterization of these cholesterol-binding proteins will shed light on the molecular mechanisms that regulate endosomal cholesterol sorting.
Keywords NPC1      NPC2      OSBP/ORP      StAR protein      endosomal cholesterol transport     
Corresponding Author(s): YANG Hongyuan,Email:h.rob.yang@unsw.edu.au   
Issue Date: 01 June 2011
 Cite this article:   
Ximing DU,Hongyuan YANG. Sterol-binding proteins and endosomal cholesterol transport[J]. Front Biol, 2011, 6(3): 190-196.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-011-1143-5
https://academic.hep.com.cn/fib/EN/Y2011/V6/I3/190
Fig.1  Endosomal transport of low-density lipoprotein (LDL)-derived cholesterol to the endoplasmic reticulum (ER). LDL particles bound to LDL-receptors are internalized and delivered to early and late endosome/lysosome. Cholesteryl ester carried by LDL is hydrolyzed by acid lipase in the late endosome/lysosome. The released free cholesterol is transported to the ER through a process mediated by NPC1, NPC2 and other unknown proteins. In the ER, LDL-derived cholesterol exert its regulatory effects by: 1) inhibiting SCAP/SREBP pathway thereby decreasing cholesterol uptake from LDL and synthesis by HMG-CoA reductase; 2) activating cholesterol esterification by ACAT thereby converting cholesterol back to cholesteryl ester stored in cytosolic lipid droplet. ACAT, acyl-coenzyme A:cholesterol acyltransferase; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; NPC, Niemann-Pick type C; SREBP, sterol-regulatory element binding protein; SCAP, SREBP cleavage activating protein.
Fig.1  Endosomal transport of low-density lipoprotein (LDL)-derived cholesterol to the endoplasmic reticulum (ER). LDL particles bound to LDL-receptors are internalized and delivered to early and late endosome/lysosome. Cholesteryl ester carried by LDL is hydrolyzed by acid lipase in the late endosome/lysosome. The released free cholesterol is transported to the ER through a process mediated by NPC1, NPC2 and other unknown proteins. In the ER, LDL-derived cholesterol exert its regulatory effects by: 1) inhibiting SCAP/SREBP pathway thereby decreasing cholesterol uptake from LDL and synthesis by HMG-CoA reductase; 2) activating cholesterol esterification by ACAT thereby converting cholesterol back to cholesteryl ester stored in cytosolic lipid droplet. ACAT, acyl-coenzyme A:cholesterol acyltransferase; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; NPC, Niemann-Pick type C; SREBP, sterol-regulatory element binding protein; SCAP, SREBP cleavage activating protein.
Fig.2  Domain structures of human OSBP, ORP5 and ORP8. PH, pleckstrin homology; FFAT, diphenylalanine in an acidic tract; ORD, OSBP-related domain; TM, transmembrane domain.
Fig.2  Domain structures of human OSBP, ORP5 and ORP8. PH, pleckstrin homology; FFAT, diphenylalanine in an acidic tract; ORD, OSBP-related domain; TM, transmembrane domain.
Fig.3  A hypothetical model for cholesterol transport at an endosome-ER junction. ORP5 or other ORPs effieicntly move cholesterol from endosome/lysosome to the ER by forming a complex with membrane lipids, NPC1, putative receptors and junction proteins. Upon completion of cholesterol transfer, the AAA ATPase VPS4/SKD1 disrupts the complex and recycles the ORPs.
Fig.3  A hypothetical model for cholesterol transport at an endosome-ER junction. ORP5 or other ORPs effieicntly move cholesterol from endosome/lysosome to the ER by forming a complex with membrane lipids, NPC1, putative receptors and junction proteins. Upon completion of cholesterol transfer, the AAA ATPase VPS4/SKD1 disrupts the complex and recycles the ORPs.
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