Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways
Two parallel pathways produce cholesterol: the Bloch and Kandutsch-Russell pathways. Here we used stable isotope labeling and isotopomer analysis to trace sterol flux through the two pathways in mice. Surprisingly, no tissue used the canonical K–R pathway. Rather, a hybrid pathway was identified tha...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2015-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/07999 |
| _version_ | 1828375107842605056 |
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| author | Matthew A Mitsche Jeffrey G McDonald Helen H Hobbs Jonathan C Cohen |
| author_facet | Matthew A Mitsche Jeffrey G McDonald Helen H Hobbs Jonathan C Cohen |
| author_sort | Matthew A Mitsche |
| collection | DOAJ |
| description | Two parallel pathways produce cholesterol: the Bloch and Kandutsch-Russell pathways. Here we used stable isotope labeling and isotopomer analysis to trace sterol flux through the two pathways in mice. Surprisingly, no tissue used the canonical K–R pathway. Rather, a hybrid pathway was identified that we call the modified K–R (MK–R) pathway. Proportional flux through the Bloch pathway varied from 8% in preputial gland to 97% in testes, and the tissue-specificity observed in vivo was retained in cultured cells. The distribution of sterol isotopomers in plasma mirrored that of liver. Sterol depletion in cultured cells increased flux through the Bloch pathway, whereas overexpression of 24-dehydrocholesterol reductase (DHCR24) enhanced usage of the MK–R pathway. Thus, relative use of the Bloch and MK–R pathways is highly variable, tissue-specific, flux dependent, and epigenetically fixed. Maintenance of two interdigitated pathways permits production of diverse bioactive sterols that can be regulated independently of cholesterol. |
| first_indexed | 2024-04-14T07:43:04Z |
| format | Article |
| id | doaj.art-30a88456db3540b8ae30dc03b2354799 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:43:04Z |
| publishDate | 2015-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-30a88456db3540b8ae30dc03b23547992022-12-22T02:05:26ZengeLife Sciences Publications LtdeLife2050-084X2015-06-01410.7554/eLife.07999Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathwaysMatthew A Mitsche0Jeffrey G McDonald1Helen H Hobbs2Jonathan C Cohen3Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United StatesCenter for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, United StatesTwo parallel pathways produce cholesterol: the Bloch and Kandutsch-Russell pathways. Here we used stable isotope labeling and isotopomer analysis to trace sterol flux through the two pathways in mice. Surprisingly, no tissue used the canonical K–R pathway. Rather, a hybrid pathway was identified that we call the modified K–R (MK–R) pathway. Proportional flux through the Bloch pathway varied from 8% in preputial gland to 97% in testes, and the tissue-specificity observed in vivo was retained in cultured cells. The distribution of sterol isotopomers in plasma mirrored that of liver. Sterol depletion in cultured cells increased flux through the Bloch pathway, whereas overexpression of 24-dehydrocholesterol reductase (DHCR24) enhanced usage of the MK–R pathway. Thus, relative use of the Bloch and MK–R pathways is highly variable, tissue-specific, flux dependent, and epigenetically fixed. Maintenance of two interdigitated pathways permits production of diverse bioactive sterols that can be regulated independently of cholesterol.https://elifesciences.org/articles/07999mass spectrometryisotopomerdeuteriumstable isotopecholesterol metabolism |
| spellingShingle | Matthew A Mitsche Jeffrey G McDonald Helen H Hobbs Jonathan C Cohen Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways eLife mass spectrometry isotopomer deuterium stable isotope cholesterol metabolism |
| title | Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways |
| title_full | Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways |
| title_fullStr | Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways |
| title_full_unstemmed | Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways |
| title_short | Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways |
| title_sort | flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell type specific pathways |
| topic | mass spectrometry isotopomer deuterium stable isotope cholesterol metabolism |
| url | https://elifesciences.org/articles/07999 |
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