Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol
Side chain oxysterols are cholesterol derivatives thought to signal the abundance of cell cholesterol to homeostatic effector proteins. Here, we investigated how plasma membrane (PM) cholesterol might regulate 27-hydroxycholesterol (HC) biosynthesis in cultured fibroblasts. We showed that PM cholest...
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| Format: | Article |
| Language: | English |
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Elsevier
2009-09-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520307409 |
| _version_ | 1819293455284699136 |
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| author | Yvonne Lange Theodore L. Steck Jin Ye Michael H. Lanier Vasumathi Molugu Daniel Ory |
| author_facet | Yvonne Lange Theodore L. Steck Jin Ye Michael H. Lanier Vasumathi Molugu Daniel Ory |
| author_sort | Yvonne Lange |
| collection | DOAJ |
| description | Side chain oxysterols are cholesterol derivatives thought to signal the abundance of cell cholesterol to homeostatic effector proteins. Here, we investigated how plasma membrane (PM) cholesterol might regulate 27-hydroxycholesterol (HC) biosynthesis in cultured fibroblasts. We showed that PM cholesterol was a major substrate for 27-HC production. Biosynthesis commenced within minutes of loading depleted cells with cholesterol, concurrent with the rapid inactivation of hydroxy-3-methylglutaryl CoA reductase (HMGR). 27-HC production rose ∼30-fold in normal and Niemann-Pick C1 fibroblasts when PM cholesterol was increased by ∼60%. 27-HC production was also stimulated by 1-octanol, which displaces PM cholesterol from its phospholipid complexes and thereby increases its activity (escape tendency) and elevates its intracellular abundance. Conversely, lysophosphatidylserine and U18666A inhibited 27-HC biosynthesis and the inactivation of HMGR, presumably by reducing the activity of PM cholesterol and, therefore, its circulation to mitochondria. We conclude that, in this in vitro system, excess (active) PM cholesterol rapidly reaches mitochondria where, as the rate-limiting substrate, it stimulates 27-HC biosynthesis. The oxysterol product then promotes the rapid degradation of HMGR, along with other homeostatic effects. The regulation of 27-HC production by the active excess of PM cholesterol can thus provide a feedback mechanism in the homeostasis of PM cholesterol. |
| first_indexed | 2024-12-24T04:10:42Z |
| format | Article |
| id | doaj.art-0fdb03b00f6f42aeb137e530543736ca |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-24T04:10:42Z |
| publishDate | 2009-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-0fdb03b00f6f42aeb137e530543736ca2022-12-21T17:16:04ZengElsevierJournal of Lipid Research0022-22752009-09-0150918811888Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterolYvonne Lange0Theodore L. Steck1Jin Ye2Michael H. Lanier3Vasumathi Molugu4Daniel Ory5To whom correspondence should be addressed:; Department of Pathology, Rush University Medical Center, Chicago, IL 60612Department of Biochemistry and Molecular Biology, University of Chicago, 920 E. 58th Street, Chicago, IL 60637Department of Pathology, Rush University Medical Center, Chicago, IL 60612Departments of Medicine, Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110Departments of Medicine, Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110Departments of Medicine, Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110Side chain oxysterols are cholesterol derivatives thought to signal the abundance of cell cholesterol to homeostatic effector proteins. Here, we investigated how plasma membrane (PM) cholesterol might regulate 27-hydroxycholesterol (HC) biosynthesis in cultured fibroblasts. We showed that PM cholesterol was a major substrate for 27-HC production. Biosynthesis commenced within minutes of loading depleted cells with cholesterol, concurrent with the rapid inactivation of hydroxy-3-methylglutaryl CoA reductase (HMGR). 27-HC production rose ∼30-fold in normal and Niemann-Pick C1 fibroblasts when PM cholesterol was increased by ∼60%. 27-HC production was also stimulated by 1-octanol, which displaces PM cholesterol from its phospholipid complexes and thereby increases its activity (escape tendency) and elevates its intracellular abundance. Conversely, lysophosphatidylserine and U18666A inhibited 27-HC biosynthesis and the inactivation of HMGR, presumably by reducing the activity of PM cholesterol and, therefore, its circulation to mitochondria. We conclude that, in this in vitro system, excess (active) PM cholesterol rapidly reaches mitochondria where, as the rate-limiting substrate, it stimulates 27-HC biosynthesis. The oxysterol product then promotes the rapid degradation of HMGR, along with other homeostatic effects. The regulation of 27-HC production by the active excess of PM cholesterol can thus provide a feedback mechanism in the homeostasis of PM cholesterol.http://www.sciencedirect.com/science/article/pii/S0022227520307409homeostasisendoplasmic reticulumoxysterolfeedbackNiemann-Pick |
| spellingShingle | Yvonne Lange Theodore L. Steck Jin Ye Michael H. Lanier Vasumathi Molugu Daniel Ory Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol Journal of Lipid Research homeostasis endoplasmic reticulum oxysterol feedback Niemann-Pick |
| title | Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol |
| title_full | Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol |
| title_fullStr | Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol |
| title_full_unstemmed | Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol |
| title_short | Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol |
| title_sort | regulation of fibroblast mitochondrial 27 hydroxycholesterol production by active plasma membrane cholesterol |
| topic | homeostasis endoplasmic reticulum oxysterol feedback Niemann-Pick |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520307409 |
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