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This Article Accepted manuscript (PDF) All Versions of this Article: JME-08-0145v1 42/2/161    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nakamichi, S. Articles by Kasuga, M. Search for Related Content PubMed PubMed Citation Articles by Nakamichi, S. Articles by Kasuga, M.

S Nakamichi, Department of Internal Medicine, Division of Diabetes, Metabolism and Endocrinbology, Kobe University Graduate School of Medicine, Kobe, Japan
Y Senga, Kobe, Japan
H Inoue, Frontier Science Organization, Kanazawa University, Kanazawa, Japan
A Emi, Department of Internal Medicine, Division of Diabetes, Metabolism, Kobe University Graduate School of Medicine,, Kobe, Japan
Y Matsuki, Pharmacology Research Laboratories, Dainippon Sumitomo Pharmaceuticals, Osaka, Japan
E Watanabe, Osaka, Japan
R Hiramatsu, Osaka, Japan
W Ogawa, Department of Internal Medicine, Division of Diabetes, Metabolism, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
M Kasuga, Research Institute, International Medical Center of Japan, Tokyo, Japan

Correspondence: Wataru Ogawa, Email: ogawa{at}med.kobe-u.ac.jp

Abstract

GRAIL (gene related to anergy in lymphocytes) is an E3 ubiquitin ligase that regulates anergy 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 (a key enzyme in hepatic glucose production) and for sterol regulatory element-binding protein 1c (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.