title: Dietary iron controls circadian hepatic glucose metabolism through heme synthesis.
abstract: The circadian rhythm of the liver maintains glucose homeostasis, and disruption of this rhythm is associated with type 2 diabetes. Feeding is one factor that sets the circadian clock in peripheral tissues, but relatively little is known about the role of specific dietary components in that regard. We assessed the effects of dietary iron on circadian gluconeogenesis. Dietary iron affects circadian glucose metabolism through heme-mediated regulation of the interaction of nuclear receptor subfamily 1 group d member 1 (Rev-Erbα) with its cosuppressor nuclear receptor corepressor 1 (NCOR). Loss of regulated heme synthesis was achieved by aminolevulinic acid (ALA) treatment of mice or cultured cells to bypass the rate-limiting enzyme in hepatic heme synthesis, ALA synthase 1 (ALAS1). ALA treatment abolishes differences in hepatic glucose production and in the expression of gluconeogenic enzymes seen with variation of dietary iron. The differences among diets are also lost with inhibition of heme synthesis with isonicotinylhydrazine. Dietary iron modulates levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional activator of ALAS1, to affect hepatic heme. Treatment of mice with the antioxidant N-acetylcysteine diminishes PGC-1α variation observed among the iron diets, suggesting that iron is acting through reactive oxygen species signaling.
authors.affiliation: Department of Biochemistry, University of Utah, Salt Lake City, UT.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Simcox
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Thomas Creighton
authors.initials: TC
authors.lastname: Mitchell
authors.affiliation: Department of Biochemistry, University of Utah, Salt Lake City, UT.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Just
authors.affiliation: Veterans Administration Research Service, VA Salt Lake City Health Care System, Salt Lake City, UT.
authors.forename: Robert
authors.initials: R
authors.lastname: Cooksey
authors.affiliation: Department of Biochemistry, University of Utah, Salt Lake City, UT.
authors.forename: James
authors.initials: J
authors.lastname: Cox
authors.affiliation: Department of Biochemistry, University of Utah, Salt Lake City, UT.
authors.forename: Richard
authors.initials: R
authors.lastname: Ajioka
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Deborah
authors.initials: D
authors.lastname: Jones
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Soh-Hyun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, University of Utah, Salt Lake City, UT.
authors.forename: Daniel
authors.initials: D
authors.lastname: King
authors.affiliation: Department of Biochemistry, University of Utah, Salt Lake City, UT.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Biochemistry, University of Utah, Salt Lake City, UT Department of Internal Medicine, University of Utah, Salt Lake City, UT Veterans Administration Research Service, VA Salt Lake City Health Care System, Salt Lake City, UT donald.mcclain@hsc.utah.edu.
authors.forename: Donald A
authors.initials: DA
authors.lastname: McClain
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D006418:Heme / Q000096:biosynthesis*; D056945:Hep G2 Cells; D006801:Humans; D019266:Iron, Dietary / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000975:Antioxidants; D019266:Iron, Dietary; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D006418:Heme; D000622:Aminolevulinic Acid; D005947:Glucose; D000111:Acetylcysteine