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...

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Bibliographic Details
Published in:eLife 2015-06, Vol.4, p.e07999-e07999
Main Authors: Mitsche, Matthew A, McDonald, Jeffrey G, Hobbs, Helen H, Cohen, Jonathan C
Format: Article
Language:English
Subjects:
Animal Structures - chemistry
Animal Structures - metabolism
Animals
Biochemistry
Biosynthesis
Cells, Cultured
Cholesterol
Cholesterol - biosynthesis
cholesterol metabolism
Chromatography
deuterium
Enzymes
Isotope Labeling
isotopomer
Liver
mass spectrometry
Metabolic Flux Analysis
Mice
Plasma - chemistry
Preputial gland
Reductase
stable isotope
Sterols
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.07999