Structure of the human steroidogenic acute regulatory (StAR) protein gene: StAR stimulates mitochondrial cholesterol 27-hydroxylase

Sugawara, Teruo; Lin, Dong; Holt, John A.; Martin, Kumiko O.; Javitt, Norman B.; Miller, Walter L.; Strauss, Jerome F.

doi:10.1021/bi00039a004

Cited by 206 publications

(109 citation statements)

References 13 publications

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“…It is conceivable that cell types may exist in the brain that lack P450 scc and use StAR for another purpose, such as stimulating endogenous mitochondrial 26-hydroxylase activity (Sugawara et al, 1995b). Conversely, there may be cells that lack StAR and rely on StAR-independent steroidogenesis, which occurs in only one known tissue, the human placenta.…”

Section: Discussionmentioning

confidence: 99%

An Essential Component in Steroid Synthesis, the Steroidogenic Acute Regulatory Protein, Is Expressed in Discrete Regions of the Brain

Manna²,

et al. 2002

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Recent data implicate locally produced steroids, termed neurosteroids, as regulators of neuronal function. Adrenal and gonadal steroidogenesis is controlled by changes in the steroidogenic acute regulatory protein (StAR); however, little is known about the regulation of neurosteroid production. We now demonstrate unequivocally that StAR mRNA and protein are expressed within glia and neurons in discrete regions of the mouse brain, and that glial StAR expression is inducible. Consistent with a role in de novo neurosteroidogenesis, StAR colocalizes with the cholesterol side-chain cleavage enzyme P450 scc in both mouse and human brains. These data support a role for StAR in the production of neurosteroids and identify potential sites of active de novo steroid synthesis in the brain.

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Section: Discussionmentioning

confidence: 99%

An Essential Component in Steroid Synthesis, the Steroidogenic Acute Regulatory Protein, Is Expressed in Discrete Regions of the Brain

Manna²,

et al. 2002

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“…The expression of MLN64 in tissues which do not produce steroid hormones is not unexpected, since mitochondria of many tissues possess other P450 enzymes involved in cholesterol oxidation, including P450c27 (18), which produces hydroxysterols that are precursors of bile acids as well as potent controllers of cholesterol synthesis and low density lipoprotein receptor expression (19).…”

Section: Discussionmentioning

confidence: 99%

MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis

Watari¹,

Arakane²,

Moog-Lutz³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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224

154

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MLN64 is a protein that is highly expressed in certain breast carcinomas. The C terminus of MLN64 shares significant homology with the steroidogenic acute regulatory protein (StAR), which plays a key role in steroid hormone biosynthesis by enhancing the intramitochondrial translocation of cholesterol to the cholesterol side-chain cleavage enzyme. We tested the ability of MLN64 to stimulate steroidogenesis by using COS-1 cells cotransfected with plasmids expressing the human cholesterol side-chain cleavage enzyme system and wild-type and mutant MLN64 proteins. Wild-type MLN64 increased pregnenolone secretion in this system 2-fold. The steroidogenic activity of MLN64 was found to reside in the C terminus of the protein, because constructs from which the C-terminal StAR homology domain was deleted had no steroidogenic activity. In contrast, removal of N-terminal sequences increased MLN64's steroidogenesisenhancing activity. MLN64 mRNA was found in many human tissues, including the placenta and brain, which synthesize steroid hormones but do not express StAR. Western blot analysis revealed the presence of lower molecular weight immunoreactive MLN64 species that contain the C-terminal sequences in human tissues. Homologs of both MLN64 and StAR were identified in Caenorhabditis elegans, indicating that the two proteins are ancient. Mutations that inactivate StAR were correlated with amino acid residues that are identical or similar among StAR and MLN64, indicating that conserved motifs are important for steroidogenic activity. We conclude that MLN64 stimulates steroidogenesis by virtue of its homology to StAR.

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“…22). It was recently shown that StAR could enhance also sterol 27-hydroxylase activity in a COS cell system (23). Whether a StAR-mediated mechanism is of importance for the cholesterol transport in macrophages remains to be established.…”

Section: Elimination Of Cholesterol By Sterol 27-hydroxylase Mechanismmentioning

confidence: 99%

Elimination of Cholesterol in Macrophages and Endothelial Cells by the Sterol 27-Hydroxylase Mechanism

Babiker

Andersson

Lund

et al. 1997

Journal of Biological Chemistry

222

165

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Cultured macrophages and endothelial cells have been reported to secrete 27-oxygenated metabolites of cholesterol. This mechanism was compared with the classical high density lipoprotein (HDL)-dependent reverse cholesterol transport. Under standard conditions, macrophage preparations had considerably higher capacity to secrete 27-hydroxycholesterol and 3␤-hydroxy-5-cholestenoic acid than had endothelial cells and fibroblasts. Western blotting showed that lung macrophages contained the most sterol 27-hydroxylase protein of the cells tested. The relative amounts of 3␤-hydroxy-5-cholestenoic acid produced by the macrophages were also highest. Macrophages derived from monocytes of patients with sterol 27-hydroxylase deficiency did not secrete 27-oxygenated products, demonstrating that sterol 27-hydroxylase is the critical enzyme for the conversion of cholesterol into the 27-oxygenated steroids. That sterol 27-hydroxylase is responsible not only for 27-hydroxylation of cholesterol but also for the further oxidation of this steroid into 3␤-hydroxy-5-cholestenoic acid was shown with use of tritium-labeled 27-hydroxycholesterol and an inhibitor of sterol 27-hydroxylase.Secretion of 27-oxygenated products by the cultured macrophages as well as the ratio between the alcohol and the acid appeared to be dependent upon total 27-hydroxylase activity, the availability of substrate cholesterol, and the presence of an acceptor for 27-hydroxycholesterol in the medium. With albumin as extracellular acceptor, the major secreted product was 3␤-hydroxy-5-cholestenoic acid. Under such conditions, secretion of labeled 27-oxygenated products was higher than that of labeled cholesterol from lung alveolar macrophages preloaded with [4-14 C]cholesterol. With HDL as acceptor, 27-hydroxycholesterol was the major secreted product, and the total secretion of labeled 27-oxygenated products was only about 10% of that of labeled cholesterol. Thus, 27-hydroxycholesterol and cholesterol may compete for HDL-mediated efflux from the cells.The results support the contention that the sterol 27-hydroxylase-mediated elimination of cholesterol is more important in macrophages than in endothelial cells. This mechanism may be an alternative and/or a complement to the classical HDL-mediated reverse cholesterol transport in macrophages, in particular when the concentration of HDL is low.

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Structure of the human steroidogenic acute regulatory (StAR) protein gene: StAR stimulates mitochondrial cholesterol 27-hydroxylase

Cited by 206 publications

References 13 publications

An Essential Component in Steroid Synthesis, the Steroidogenic Acute Regulatory Protein, Is Expressed in Discrete Regions of the Brain

An Essential Component in Steroid Synthesis, the Steroidogenic Acute Regulatory Protein, Is Expressed in Discrete Regions of the Brain

MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis

Elimination of Cholesterol in Macrophages and Endothelial Cells by the Sterol 27-Hydroxylase Mechanism

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