title: Synergistic Inhibitory Effects of Hypoxia and Iron Deficiency on Hepatic Glucose Response in Mouse Liver.
abstract: Hypoxia and iron both regulate metabolism through multiple mechanisms, including hypoxia-inducible transcription factors. The hypoxic effects on glucose disposal and glycolysis are well established, but less is known about the effects of hypoxia and iron deficiency on hepatic gluconeogenesis. We therefore assessed their effects on hepatic glucose production in mice. Weanling C57BL/6 male mice were fed an iron-deficient (4 ppm) or iron-adequate (35 ppm) diet for 14 weeks and were continued in normoxia or exposed to hypoxia (8% O2) for the last 4 weeks of that period. Hypoxic mice became hypoglycemic and displayed impaired hepatic glucose production after a pyruvate challenge, an effect accentuated by an iron-deficient diet. Stabilization of hypoxia-inducible factors under hypoxia resulted in most glucose being converted into lactate and not oxidized. Hepatic pyruvate concentrations were lower in hypoxic mice. The decreased hepatic pyruvate levels were not caused by increased utilization but rather were contributed to by decreased metabolism from gluconeogenic amino acids. Pyruvate carboxylase, which catalyzes the first step of gluconeogenesis, was also downregulated by hypoxia with iron deficiency. Hypoxia, and more so hypoxia with iron deficiency, results in hypoglycemia due to decreased levels of hepatic pyruvate and decreased pyruvate utilization for gluconeogenesis. These data highlight the role of iron levels as an important determinant of glucose metabolism in hypoxia.
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Hyeyoung
authors.initials: H
authors.lastname: Nam
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: Robert C
authors.initials: RC
authors.lastname: Cooksey
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Sandy
authors.initials: S
authors.lastname: Sink
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 Internal Medicine, University of Utah, Salt Lake City, UT Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC Department of Biochemistry, University of Utah, Salt Lake City, UT dmcclain@wakehealth.edu.
authors.forename: Donald A
authors.initials: DA
authors.lastname: McClain
mesh_terms: D000818:Animals; D005943:Gluconeogenesis; D005947:Glucose / Q000096:biosynthesis*; D007003:Hypoglycemia / Q000209:etiology; D000860:Hypoxia / Q000150:complications / Q000378:metabolism*; D007501:Iron / Q000502:physiology; D000090463:Iron Deficiencies; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D019289:Pyruvic Acid; D007501:Iron; D005947:Glucose