title: Role of the E3 ubiquitin ligase gene related to anergy in lymphocytes in glucose and lipid metabolism in the liver.
abstract: Gene related to anergy in lymphocytes (GRAIL) is an E3 ubiquitin ligase that regulates energy in T-lymphocytes. Whereas, the relevance of GRAIL to T lymphocyte function is well established, the role of this protein in other cell types remains unknown. Given that GRAIL is abundant in the liver, we investigated the potential function of GRAIL in nutrient metabolism by generating mice in which the expression of GRAIL is reduced specifically in the liver. Adenovirus-mediated transfer of a short hairpin RNA specific for GRAIL mRNA markedly reduced the amounts of GRAIL mRNA and protein in the liver. Blood glucose levels of the mice with hepatic GRAIL deficiency did not differ from those of control animals in the fasted or fed states. However, these mice manifested glucose intolerance in association with a normal increase in plasma insulin levels during glucose challenge. The mice also manifested an increase in the serum concentration of free fatty acids, whereas the serum levels of cholesterol and triglyceride were unchanged. The hepatic abundance of mRNAs for glucose-6-phosphatase, catalytic (a key enzyme in hepatic glucose production) and for sterol regulatory element-binding transcription factor 1 (an important transcriptional regulator of lipogenesis) was increased in the mice with hepatic GRAIL deficiency, possibly contributing to the metabolic abnormalities of these animals. Our results thus demonstrate that GRAIL in the liver is essential for maintenance of normal glucose and lipid metabolism in living animals.
authors.affiliation: Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Sachie
authors.initials: S
authors.lastname: Nakamichi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Senga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Aki
authors.initials: A
authors.lastname: Emi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuki
authors.forename: Eijiro
authors.initials: E
authors.lastname: Watanabe
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hiramatsu
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
mesh_terms: D000818:Animals; D017635:Clonal Anergy / Q000276:immunology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology*; D008214:Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases; D005947:Glucose