title: Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways.
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.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Mitsche
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: McDonald
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Hobbs
authors.affiliation: Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cohen
mesh_terms: D000825:Animal Structures / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D007553:Isotope Labeling; D064688:Metabolic Flux Analysis; D051379:Mice; D010949:Plasma / Q000737:chemistry
chemical_list: D002784:Cholesterol
keywords: biochemistry; cholesterol metabolism; deuterium; isotopomer; mass spectrometry; mouse; stable isotope