title: The FBXL5-IRP2 axis is integral to control of iron metabolism in vivo.
abstract: Iron-dependent degradation of iron-regulatory protein 2 (IRP2) is a key event for maintenance of an appropriate intracellular concentration of iron. Although FBXL5 (F box and leucine-rich repeat protein 5) is thought to mediate this degradation, the role of FBXL5 in the control of iron homeostasis in vivo has been poorly understood. We have now found that mice deficient in FBXL5 died in utero, associated with excessive iron accumulation. This embryonic mortality was prevented by additional ablation of IRP2, suggesting that impaired IRP2 degradation is primarily responsible for the death of Fbxl5(-)(/-) mice. We also found that liver-specific deletion of Fbxl5 resulted in deregulation of both hepatic and systemic iron homeostasis, leading to the development of steatohepatitis. The liver-specific mutant mice died with acute liver failure when fed a high-iron diet. Thus, our results uncover a major role for FBXL5 in ensuring an appropriate supply of iron to cells.
authors: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
authors: Toshiro
authors: T
authors: Moroishi
authors: Masaaki
authors: M
authors: Nishiyama
authors: Yukiko
authors: Y
authors: Takeda
authors: Kazuhiro
authors: K
authors: Iwai
authors: Keiichi I
authors: KI
authors: Nakayama
mesh_terms: D000818:Animals; D044783:F-Box Proteins / Q000235:genetics*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D005526:Food, Formulated / Q000009:adverse effects; D017353:Gene Deletion; D006651:Histocytochemistry; D017403:In Situ Hybridization; D019190:Iron Overload / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D035942:Iron Regulatory Protein 2 / Q000172:deficiency* / Q000235:genetics; D019266:Iron, Dietary / Q000378:metabolism*; D000090263:Leucine-Rich Repeat Proteins; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D015996:Survival Rate
chemical_list: D044783:F-Box Proteins; C569388:FBXL5 protein, mouse; D019266:Iron, Dietary; D000090263:Leucine-Rich Repeat Proteins; D011506:Proteins; D035942:Iron Regulatory Protein 2