StAR-related Lipid Transfer (START) Proteins: Mediators of Intracellular Lipid Metabolism

StAR-related lipid transfer (START) 1The abbreviations used are: START, StAR-related lipid transfer; StAR, steroidogenic acute regulatory protein; PCTP, phosphatidylcholine transfer protein; PC, phosphatidylcholine; StarD1, START domain containing 1; GPBP, Goodpasture antigen-binding protein; THEA, thioesterase adiposeassociated; CACH, cytosolic acetyl-CoA hydrolase; DLC-1, deleted in liver cancer 1; PH, Pleckstrin homology; RhoGAP, Rho GTPase-activating protein; SAM, sterile α motif; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; ER, endoplasmic reticulum; NPC, Niemann-Pick C; SRE, sterol regulatory element; SREBP, SRE-binding protein; EST, expressed sequence tag cDNA clone; GP, Goodpasture. domains are ∼210-amino acid lipid binding domains implicated in intracellular lipid transport, lipid metabolism, and cell signaling events. The prototype is the steroidogenic acute regulatory protein (StAR), which transfers cholesterol to mitochondria in steroid hormone-producing cells (1Stocco D.M. Annu. Rev. Physiol. 2001; 63: 193-213Crossref PubMed Scopus (700) Google Scholar). START domains are found in an extensive protein family, including START domain only and multidomain proteins, but lipid ligands have only been identified in a few cases (2Ponting C.P. Aravind L. Trends Biochem. Sci. 1999; 24: 130-132Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). The human and mouse genomes each have 15 genes encoding START domains (Table I), and phylogenetic analysis divides the family into six subfamilies (Fig. 1, A and B) (3Soccio R.E. Adams R.M. Romanowski M.J. Sehayek E. Burley S.K. Breslow J.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6943-6948Crossref PubMed Scopus (155) Google Scholar).Table INomenclature and chromosomal locations of 15 mammalian START genesStarD nameOther namesMouseHumanStarD1StAR8, 24.5 Mb8, 37.4 MbStAR pseudogene13, 59.8 MbStarD2PCTP11, 90.7 Mb17, 53.6 MbStarD3MLN64, es64, CAB111, 99.1 Mb17, 37.3 MbStarD4CRSP18, 33.4 Mb5, 110.5 MbStarD5None7, 73.3 Mb15, 77.6 MbStarD6None18, 70.8 Mb18, 52.0 MbStarD6 pseudogene10, 56.8 MbStarD7GTT12, 128.3 Mb2, 94.7 MbStarD8KIAA0189-RhoGAPX, 81.9 MbX, 64.1 MbStarD9KIAA13002, 121.1 Mb15, 38.4 MbStarD10PCTP-like, SDCCAG28, CGI-527, 91.1 Mb11, 74.8 MbStarD11GPBP, COL4A3BP13, 93.9 Mb5, 73.5 MbStarD12DLC-1, Arhgap7, p122-RhoGAP8, 35.5 Mb8, 12.7 MbStarD13GT650, 4902678-RhoGAP5, 150.3 Mb13, 31.7 Mb(StarD14)CACH13, 88.9 Mb5, 80.8 Mb(StarD15)THEA, BFIT, KIAA07074, 104.5 Mb1, 54.8 Mb Open table in a new tab X-ray crystal structures have been solved for the MLN64 START domain (4Tsujishita Y. Hurley J.H. Nat. Struct. Biol. 2000; 7: 408-414Crossref PubMed Scopus (450) Google Scholar), StarD4 (5Romanowski M.J. Soccio R.E. Breslow J.L. Burley S.K. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6949-6954Crossref PubMed Scopus (142) Google Scholar), and phosphatidylcholine transfer protein (PCTP) (6Roderick S.L. Chan W.W. Agate D.S. Olsen L.R. Vetting M.W. Rajashankar K.R. Cohen D.E. Nat. Struct. Biol. 2002; 9: 507-511PubMed Google Scholar). All three share the same helix-grip fold (7Iyer L.M. Koonin E.V. Aravind L. Proteins. 2001; 43: 134-144Crossref PubMed Scopus (192) Google Scholar), with α-helices at the N and C termini separated by nine β-strands and two shorter α-helices. The curved β-sheet forms a deep pocket with the C-terminal α-helix acting as a lid, resulting in an internal hydrophobic cavity (Fig. 2). The START structure differs from other hydrophobic cavity lipid-binding proteins, such as sterol carrier protein 2 (SCP-2) (8Choinowski T. Hauser H. Piontek K. Biochemistry. 2000; 39: 1897-1902Crossref PubMed Scopus (63) Google Scholar), phosphatidylinositol transfer protein (PITP) (9Yoder M.D. Thomas L.M. Tremblay J.M. Oliver R.L. Yarbrough L.R. Helmkamp Jr., G.M. J. Biol. Chem. 2001; 276: 9246-9252Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar), and the fatty acid-binding proteins (FABPs) (10Bernlohr D.A. Simpson M.A. Hertzel A.V. Banaszak L.J. Annu. Rev. Nutr. 1997; 17: 277-303Crossref PubMed Scopus (196) Google Scholar). The PCTP structure was reported with a phosphatidylcholine (PC) molecule in the cavity (6Roderick S.L. Chan W.W. Agate D.S. Olsen L.R. Vetting M.W. Rajashankar K.R. Cohen D.E. Nat. Struct. Biol. 2002; 9: 507-511PubMed Google Scholar), whereas the MLN64 and StarD4 structures contain cavities large enough (∼850 Å3) to accommodate a cholesterol ligand (∼740 Å3) (5Romanowski M.J. Soccio R.E. Breslow J.L. Burley S.K. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6949-6954Crossref PubMed Scopus (142) Google Scholar). In each structure, lipid entry or egress would require a major conformational change, most likely opening or unfolding of the C-terminal α-helix lid. In fact, this helix of PCTP has been implicated in membrane binding and PC extraction (11Feng L. Chan W.W. Roderick S.L. Cohen D.E. Biochemistry. 2000; 39: 15399-15409Crossref PubMed Scopus (46) Google Scholar). Furthermore, StAR can form partially unfolded states (12Christensen K. Bose H.S. Harris F.M. Miller W.L. Bell J.D. J. Biol. Chem. 2001; 276: 17044-17051Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar) and loses helical content upon binding a cholesterol analogue (13Petrescu A.D. Gallegos A.M. Okamura Y. Strauss III, J.F. Schroeder F. J. Biol. Chem. 2001; 276: 36970-36982Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). Recent modeling of StAR using structure-based thermodynamics showed that an open lid conformational state can exist at equilibrium and that cholesterol binding and lid closure would significantly stabilize the complex (14Mathieu A.P. Fleury A. Ducharme L. Lavigne P. LeHoux J.G. J. Mol. Endocrinol. 2002; 29: 327-345Crossref PubMed Scopus (70) Google Scholar). StAR—The rate-limiting step in steroidogenesis is StAR-mediated delivery of cholesterol to the P450 side chain cleavage enzyme (P450scc/Cyp11A1), which resides on the matrix side of the inner mitochondrial membrane (IMM) and converts cholesterol to pregnenolone (Fig. 3, pathway 2) (1Stocco D.M. Annu. Rev. Physiol. 2001; 63: 193-213Crossref PubMed Scopus (700) Google Scholar, 15Miller W.L. Strauss III, J.F. J. Steroid Biochem. Mol. Biol. 1999; 69: 131-141Crossref PubMed Scopus (148) Google Scholar). After stimulation by pituitary trophic hormones, acute steroidogenesis results from phosphorylation of pre-existing StAR and rapid synthesis of new StAR (15Miller W.L. Strauss III, J.F. J. Steroid Biochem. Mol. Biol. 1999; 69: 131-141Crossref PubMed Scopus (148) Google Scholar). When StAR is mutated in humans with congenital lipoid adrenal hyperplasia (16Bose H.S. Sugawara T. Strauss III, J.F. Miller W.L. N. Engl. J. Med. 1996; 335: 1870-1878Crossref PubMed Scopus (534) Google Scholar) or knock-out mice (17Caron K.M. Soo S.C. Parker K.L. Endocr. Res. 1998; 24: 827-834Crossref PubMed Scopus (18) Google Scholar), there are marked defects in steroidogenesis by adrenal cortex and gonads. Early studies did not detect StAR mRNA in the other steroidogenic organs, placenta and brain (18Sugawara T. Holt J.A. Driscoll D. Strauss III, J.F. Lin D. Miller W.L. Patterson D. Clancy K.P. Hart I.M. Clark B.J. Stocco D.M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4778-4782Crossref PubMed Scopus (349) Google Scholar), but StAR expression was recently shown in both tissues (19Koh P.O. Kim Y.S. Cheon E.W. Kang S.S. Cho G.J. Choi W.S. Mol. Cell. 2002; 14: 355-360Google Scholar, 20King S.R. Manna P.R. Ishii T. Syapin P.J. Ginsberg S.D. Wilson K. Walsh L.P. Parker K.L. Stocco D.M. Smith R.G. Lamb D.J. J. Neurosci. 2002; 22: 10613-10620Crossref PubMed Google Scholar). However, StAR null fetuses produce normal levels of placental progesterone (16Bose H.S. Sugawara T. Strauss III, J.F. Miller W.L. N. Engl. J. Med. 1996; 335: 1870-1878Crossref PubMed Scopus (534) Google Scholar), suggesting alternate steroidogenic mechanisms. In order for P450scc to act, cholesterol must get to the outer mitochondrial membrane (OMM), across the intermembranous space, and to the IMM. StAR is synthesized as a 37-kDa protein, but the N-terminal presequence directs mitochondrial import before being cleaved in the matrix, leaving a 30-kDa protein. Despite its final matrix localization, StAR most likely acts at the OMM (21Bose H. Lingappa V.R. Miller W.L. Nature. 2002; 417: 87-91Crossref PubMed Scopus (294) Google Scholar). In transfection assays and studies with isolated mitochondria, StAR lacking the presequence (N-62 StAR) has equivalent activity to full-length StAR (22Arakane F. Sugawara T. Nishino H. Liu Z. Holt J.A. Pain D. Stocco D.M. Miller W.L. Strauss III, J.F. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 13731-13736Crossref PubMed Scopus (254) Google Scholar, 23Arakane F. Kallen C.B. Watari H. Stayrook S.E. Lewis M. Strauss III, J.F. Endocr. Res. 1998; 24: 463-468Crossref PubMed Scopus (32) Google Scholar). In studies using StAR fusions to mitochondrial proteins, StAR at the OMM facing the cytosol is fully active, whereas StAR in the intermembranous space or matrix is inactive (21Bose H. Lingappa V.R. Miller W.L. Nature. 2002; 417: 87-91Crossref PubMed Scopus (294) Google Scholar). StAR could simply drop off cholesterol or alter the OMM to facilitate cholesterol desorption to the IMM (15Miller W.L. Strauss III, J.F. J. Steroid Biochem. Mol. Biol. 1999; 69: 131-141Crossref PubMed Scopus (148) Google Scholar). An alternate view is that StAR must be imported to act, because data supporting an OMM site of action rely on non-physiological isolated mitochondria or transfection of non-steroidogenic cells (24Jefcoate C. J. Clin. Invest. 2002; 110: 881-890Crossref PubMed Scopus (141) Google Scholar). If StAR acts at the OMM, then what is the purpose of mitochondrial import? StAR can act as a cholesterol transfer protein in vitro, as N-62 StAR selectively transfers sterols from donor liposomes to acceptor mitochondria (25Kallen C.B. Billheimer J.T. Summers S.A. Stayrook S.E. Lewis M. Strauss III, J.F. J. Biol. Chem. 1998; 273: 26285-26288Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). However, N-62 StAR lacks target specificity, as other acceptors include trypsin-treated mitochondria, endoplasmic reticulum (ER), and phospholipid vesicles (25Kallen C.B. Billheimer J.T. Summers S.A. Stayrook S.E. Lewis M. Strauss III, J.F. J. Biol. Chem. 1998; 273: 26285-26288Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 26Tuckey R.C. Headlam M.J. Bose H.S. Miller W.L. J. Biol. Chem. 2002; 277: 47123-47128Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). Therefore, the presequence may direct cholesterol transfer to mitochondria in preference to other organelles (15Miller W.L. Strauss III, J.F. J. Steroid Biochem. Mol. Biol. 1999; 69: 131-141Crossref PubMed Scopus (148) Google Scholar). In addition, import may rapidly inactivate StAR (21Bose H. Lingappa V.R. Miller W.L. Nature. 2002; 417: 87-91Crossref PubMed Scopus (294) Google Scholar), as StAR undergoes proteolytic degradation in mitochondria (27Granot Z. Silverman E. Friedlander R. Melamed-Book N. Eimerl S. Timberg R. Hales K.H. Hales D.B. Stocco D.M. Orly J. Endocr. Res. 2002; 28: 375-386Crossref PubMed Scopus (33) Google Scholar). MLN64 —MLN64 was cloned as a gene amplified in breast, gastric, and esophageal cancers (28Tomasetto C. Regnier C. Moog-Lutz C. Mattei M.G. Chenard M.P. Lidereau R. Basset P. Rio M.C. Genomics. 1995; 28: 367-376Crossref PubMed Scopus (228) Google Scholar, 29Akiyama N. Sasaki H. Ishizuka T. Kishi T. Sakamoto H. Onda M. Hirai H. Yazaki Y. Sugimura T. Terada M. Cancer Res. 1997; 57: 3548-3553PubMed Google Scholar). Although MLN64 could play a causative role in tumorigenesis (30Moog-Lutz C. Tomasetto C. Regnier C.H. Wendling C. Lutz Y. Muller D. Chenard M.P. Basset P. Rio M.C. Int. J. Cancer. 1997; 71: 183-191Crossref PubMed Scopus (117) Google Scholar, 31Watari H. Arakane F. Moog-Lutz C. Kallen C.B. Tomasetto C. Gerton G.L. Rio M.C. Baker M.E. Strauss III, J.F. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8462-8467Crossref PubMed Scopus (205) Google Scholar), amplification likely reflects close genomic proximity (within 36 kb) to the oncogene c-erb-B2 (her-2/neu) (28Tomasetto C. Regnier C. Moog-Lutz C. Mattei M.G. Chenard M.P. Lidereau R. Basset P. Rio M.C. Genomics. 1995; 28: 367-376Crossref PubMed Scopus (228) Google Scholar), which is invariantly co-amplified (31Watari H. Arakane F. Moog-Lutz C. Kallen C.B. Tomasetto C. Gerton G.L. Rio M.C. Baker M.E. Strauss III, J.F. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8462-8467Crossref PubMed Scopus (205) Google Scholar). The N terminus of MLN64 includes four transmembrane helices, whereas the C-terminal START domain is 37% identical to StAR (30Moog-Lutz C. Tomasetto C. Regnier C.H. Wendling C. Lutz Y. Muller D. Chenard M.P. Basset P. Rio M.C. Int. J. Cancer. 1997; 71: 183-191Crossref PubMed Scopus (117) Google Scholar). Like StAR, the isolated MLN64 START domain binds (4Tsujishita Y. Hurley J.H. Nat. Struct. Biol. 2000; 7: 408-414Crossref PubMed Scopus (450) Google Scholar) and transfers (32Zhang M. Liu P. Dwyer N.K. Christenson L.K. Fujimoto T. Martinez F. Comly M. Hanover J.A. Blanchette-Mackie E.J. Strauss III, J.F. J. Biol. Chem. 2002; 277: 33300-33310Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar) cholesterol in vitro and stimulates steroidogenesis when co-transfected with P450scc (31Watari H. Arakane F. Moog-Lutz C. Kallen C.B. Tomasetto C. Gerton G.L. Rio M.C. Baker M.E. Strauss III, J.F. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8462-8467Crossref PubMed Scopus (205) Google Scholar, 33Bose H.S. Whittal R.M. Huang M.C. Baldwin M.A. Miller W.L. Biochemistry. 2000; 39: 11722-11731Crossref PubMed Scopus (82) Google Scholar). MLN64 expression is detected in all tissues (31Watari H. Arakane F. Moog-Lutz C. Kallen C.B. Tomasetto C. Gerton G.L. Rio M.C. Baker M.E. Strauss III, J.F. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8462-8467Crossref PubMed Scopus (205) Google Scholar), and it is a candidate for StAR-independent steroidogenesis in placenta. However, the transmembrane domain of MLN64 localizes it to late endosomes with the START domain facing the cytosol (32Zhang M. Liu P. Dwyer N.K. Christenson L.K. Fujimoto T. Martinez F. Comly M. Hanover J.A. Blanchette-Mackie E.J. Strauss III, J.F. J. Biol. Chem. 2002; 277: 33300-33310Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 34Alpy F. Stoeckel M.E. Dierich A. Escola J.M. Wendling C. Chenard M.P. Vanier M.T. Gruenberg J. Tomasetto C. Rio M.C. J. Biol. Chem. 2001; 276: 4261-4269Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). Given this localization, full-length MLN64 is relatively inactive in steroidogenesis assays, but proteolysis could release the START domain allowing delivery of cholesterol to mitochondria (31Watari H. Arakane F. Moog-Lutz C. Kallen C.B. Tomasetto C. Gerton G.L. Rio M.C. Baker M.E. Strauss III, J.F. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8462-8467Crossref PubMed Scopus (205) Google Scholar). Supporting this notion, antibodies against the MLN64 START domain detect full-length protein and prominent smaller bands in placenta and transfected cells (31Watari H. Arakane F. Moog-Lutz C. Kallen C.B. Tomasetto C. Gerton G.L. Rio M.C. Baker M.E. Strauss III, J.F. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8462-8467Crossref PubMed Scopus (205) Google Scholar). MLN64 also functions in cholesterol mobilization from endosomes via the Niemann-Pick C (NPC) pathway. In NPC disease low density lipoprotein-derived cholesterol accumulates in the late endosome/lysosome compartment, and two causative genes have been identified (35Strauss J.F. Liu P. Christenson L.K. Watari H. Steroids. 2002; 67: 947-951Crossref PubMed Scopus (36) Google Scholar). NPC2 is a soluble endosomal cholesterol-binding protein, whereas NPC1 is an endosomal transmembrane efflux pump that co-localizes with MLN64 (32Zhang M. Liu P. Dwyer N.K. Christenson L.K. Fujimoto T. Martinez F. Comly M. Hanover J.A. Blanchette-Mackie E.J. Strauss III, J.F. J. Biol. Chem. 2002; 277: 33300-33310Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 34Alpy F. Stoeckel M.E. Dierich A. Escola J.M. Wendling C. Chenard M.P. Vanier M.T. Gruenberg J. Tomasetto C. Rio M.C. J. Biol. Chem. 2001; 276: 4261-4269Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). Endosomal cholesterol could thus move sequentially from luminal NPC2 through NPC1 to MLN64 and finally to a cytosolic acceptor (Fig. 3, pathway 1) (35Strauss J.F. Liu P. Christenson L.K. Watari H. Steroids. 2002; 67: 947-951Crossref PubMed Scopus (36) Google Scholar). MLN64 mutations have not been reported in NPC disease, but overexpression of the MLN64 transmembrane domain with no START domain results in an NPC phenocopy with cholesterol accumulation in enlarged endosomes (32Zhang M. Liu P. Dwyer N.K. Christenson L.K. Fujimoto T. Martinez F. Comly M. Hanover J.A. Blanchette-Mackie E.J. Strauss III, J.F. J. Biol. Chem. 2002; 277: 33300-33310Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). A similar phenotype was observed upon overexpression of MENTHO (MLN64 N-terminal domain homologue), an endosomal membrane protein 70% identical to the MLN64 transmembrane domain but without a START domain (36Alpy F. Wendling C. Rio M.-C. Tomasetto C. J. Biol. Chem. 2002; 277: 50780-50787Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). StarD4 and StarD5 share 30% amino acid identity and are expressed in most tissues with highest levels in liver and kidney (3Soccio R.E. Adams R.M. Romanowski M.J. Sehayek E. Burley S.K. Breslow J.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6943-6948Crossref PubMed Scopus (155) Google Scholar). In the co-transfection assay for StAR-like activity, both StarD4 and StarD5 can stimulate steroidogenesis by mitochondrial P450scc. 2R. Soccio, R. Adams, and J. Breslow, unpublished data. Because they are widely expressed, other roles in non-vesicular intracellular cholesterol transport have been proposed (3Soccio R.E. Adams R.M. Romanowski M.J. Sehayek E. Burley S.K. Breslow J.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6943-6948Crossref PubMed Scopus (155) Google Scholar, 37Maxfield F.R. Wustner D. J. Clin. Invest. 2002; 110: 891-898Crossref PubMed Scopus (281) Google Scholar). Like StAR (38Sugawara T. Lin D. Holt J.A. Martin K.O. Javitt N.B. Miller W.L. Strauss III, J.F. Biochemistry. 1995; 34: 12506-12512Crossref PubMed Scopus (197) Google Scholar, 39Pandak W.M. Ren S. Marques D. Hall E. Redford K. Mallonee D. Bohdan P. Heuman D. Gil G. Hylemon P. J. Biol. Chem. 2002; 277: 48158-48164Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar), StarD4 and StarD5 may also deliver cholesterol to mitochondrial Cyp27, which generates 27-hydroxycholesterol (Fig. 3, pathway 3). In liver, this is the initial step in alternative bile acid synthesis, a process that may be rate-limited by cholesterol delivery to mitochondria (39Pandak W.M. Ren S. Marques D. Hall E. Redford K. Mallonee D. Bohdan P. Heuman D. Gil G. Hylemon P. J. Biol. Chem. 2002; 277: 48158-48164Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). In peripheral cells, 27-hydroxycholesterol may function as an agonist for the liver X receptor (LXR) nuclear receptors (40Fu X. Menke J.G. Chen Y. Zhou G. MacNaul K.L. Wright S.D. Sparrow C.P. Lund E.G. J. Biol. Chem. 2001; 276: 38378-38387Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar), which activate reverse cholesterol transport (41Tall A.R. Costet P. Wang N. J. Clin. Invest. 2002; 110: 899-904Crossref PubMed Scopus (188) Google Scholar), and as a more soluble oxysterol that can leave cells directly. StarD4 —StarD4 was identified using microarrays, as hepatic StarD4 mRNA is decreased 2–3-fold on a high cholesterol diet (3Soccio R.E. Adams R.M. Romanowski M.J. Sehayek E. Burley S.K. Breslow J.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6943-6948Crossref PubMed Scopus (155) Google Scholar). StarD4 mRNA levels are also sterol-regulated in cultured cells (3Soccio R.E. Adams R.M. Romanowski M.J. Sehayek E. Burley S.K. Breslow J.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6943-6948Crossref PubMed Scopus (155) Google Scholar), consistent with transcriptional regulation by sterol regulatory element (SRE)-binding proteins (SREBPs) (42Horton J.D. Goldstein J.L. Brown M.S. J. Clin. Invest. 2002; 109: 1125-1131Crossref PubMed Scopus (3838) Google Scholar). Reporter transfection assays have identified a functional SRE in the StarD4 promoter. 2R. Soccio, R. Adams, and J. Breslow, unpublished data. Because StarD4 is coordinately regulated with SREBP2 target genes involved in cholesterol synthesis, 2R. Soccio, R. Adams, and J. Breslow, unpublished data. it may transport a cholesterol precursor sterol to facilitate this process (3Soccio R.E. Adams R.M. Romanowski M.J. Sehayek E. Burley S.K. Breslow J.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6943-6948Crossref PubMed Scopus (155) Google Scholar). StarD5—StarD5 is not regulated by sterols, but ER stress by various agents activates StarD5 expression over 6-fold in cultured cells. 2R. Soccio, R. Adams, and J. Breslow, unpublished data. Cells respond to perturbations in ER function by the unfolded protein response, which activates transcription of ER stress response genes (43Harding H.P. Calfon M. Urano F. Novoa I. D. Annu. Rev. Biol. 2002; PubMed Scopus Google Scholar). The ER is a membrane being the site of cholesterol synthesis F.R. Wustner D. J. Clin. Invest. 2002; 110: 891-898Crossref PubMed Scopus (281) Google Scholar), sterol transport by StarD5 may ER expression is to the (3Soccio R.E. Adams R.M. Romanowski M.J. Sehayek E. Burley S.K. Breslow J.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6943-6948Crossref PubMed Scopus (155) Google Scholar), in cells at all but not in and cells. Soccio, J. Breslow, and P. unpublished data. could be for as sterols play roles in cells from M. J. Mol. Med. 1998; PubMed Scopus Google Scholar) to J. Clin. Invest. 2002; 110: PubMed Scopus Google Scholar), and high of in may facilitate Lin D.S. M. J. Res. 1998; 39: Full Text Full Text PDF PubMed Google Scholar). the other PCTP, and Goodpasture antigen-binding protein not share a or the START In the PCTP structure, in the hydrophobic cavity PC (6Roderick S.L. Chan W.W. Agate D.S. Olsen L.R. Vetting M.W. Rajashankar K.R. Cohen D.E. Nat. Struct. Biol. 2002; 9: 507-511PubMed Google Scholar), and of are identical or similar in including of the that may also PC, whereas and at and of the suggesting is an lipid-binding protein, as it transfer of PC but not other or sterols Annu. Rev. Biochem. PubMed Scopus Google Scholar). PCTP is a cytosolic protein, but it to mitochondria upon in cell and this a phosphorylation site at A.P. J. A. Res. 2002; PubMed Scopus Google Scholar). PCTP is widely expressed with highest levels in liver D.E. R.M. 1999; PubMed Scopus Google Scholar), and a function has been proposed in the of PC into bile (Fig. 3, pathway However, PCTP knock-out mice reported with normal PC but in this low liver PCTP protein levels with A. A. R. J.F. J. J.H. A. T. M.A. D. P. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). PCTP may also play a role in lipid efflux via binding which forms high density by efflux of and cholesterol to (41Tall A.R. Costet P. Wang N. J. Clin. Invest. 2002; 110: 899-904Crossref PubMed Scopus (188) Google Scholar). of PCTP results in a of this suggesting that PCTP the membrane with that have been by (Fig. 3, pathway J.M. S.E. Cohen D.E. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). are no on but over expressed sequence tag cDNA from tissues and mRNA is by in liver, and M. M. H. Y. H. K. J. N. H. M. K. A. K. Y. Biol. 2000; PubMed Scopus Google Scholar), and there are from In is expressed in but not cells M. M. H. Y. H. K. J. N. H. M. K. A. K. Y. Biol. 2000; PubMed Scopus Google Scholar), similar to widely expressed has an N-terminal Pleckstrin two and a C-terminal START domain A. F. S. J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). binds and Goodpasture the C terminus of human which is the target of in A. F. S. J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). domains or and the and domains are for binding A. F. S. J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). lacks a but activity is in a protein the C terminus A. F. S. J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the site is not but the START domain is more likely regulatory mRNA is and the most form lacks the domain A. F. P. S. E. F. J. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). that the full-length protein but not in and which are in and in from with A. F. P. S. E. F. J. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is implicated in human via with but other roles are likely as is in without the on and in and acetyl-CoA and thioesterase each have two thioesterase domains and a C-terminal START contain which to fatty are regulated by receptors and roles in lipid M.C. S.E. Res. 2002; PubMed Scopus Google Scholar). has high activity for acetyl-CoA low activity for chain but no activity for and chain N. K. K. Y. F. J. Biochem. 2001; PubMed Scopus Google Scholar). activity is detected only in liver and kidney cytosol T. F. Y. Sakamoto Y. J. Biochem. PubMed Scopus Google Scholar), and hepatic activity is regulated in both and a diet activity, suggesting that acetyl-CoA levels for fatty acid and synthesis T. F. Y. Sakamoto Y.