Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways

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Abstract

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.

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Matthew A Mitsche

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
No competing interests declared.
Jeffrey G McDonald

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
No competing interests declared.
Helen H Hobbs

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
Helen H Hobbs, Reviewing editor, eLife.
Jonathan C Cohen

Human Nutrition Center, University of Texas Southwestern Medical Center, Dallas, United States

For correspondence
jonathan.cohen@utsouthwestern.edu

Competing interests
No competing interests declared.

Ethics

Animal experimentation: This study protocol was approved approved by the institutional animal care and use committee (IACUC) of the University of Texas Southwestern Medical Center (APN 2008-0321). All studies were performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.