Hepatic NPC1L1 Overexpression Ameliorates Glucose Metabolism in Diabetic Mice Via Suppression of Gluconeogenesis Makoto Kurano a , Masumi Hara b , Hiroaki Satoh c , Kazuhisa Tsukamoto d, ⁎ a Department of Clinical Laboratory Medicine, Graduate School of Medicine, University of Tokyo, Japan b Department of Internal Medicine IV, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan c Department of Nephrology, Hypertension, Diabetology, Endocrinology, and Metabolism, Fukushima Medical University, Fukushima, Japan d Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Fukushima, Japan ARTICLE INFO ABSTRACT Article history: Received 7 July 2014 Accepted 21 January 2015 Objective. Inhibition of intestinal NPC1L1 by ezetimibe has been demonstrated to improve glucose metabolism in rodent models; however, the role of hepatic NPC1L1 in glucose metabolism has not been elucidated. In this study, we analyzed the effects of hepatic NPC1L1 on glucose metabolism. Material and Methods. We overexpressed NPC1L1 in the livers of lean wild type mice, diet- induced obesity mice and db/db mice with adenoviral gene transfer. Results. We found that in all three mouse models, hepatic NPC1L1 overexpression lowered fasting blood glucose levels as well as blood glucose levels on ad libitum; in db/db mice, hepatic NPC1L1 overexpression improved blood glucose levels to almost the same as those found in lean wild type mice. A pyruvate tolerance test revealed that gluconeogenesis was suppressed by hepatic NPC1L1 overexpression. Further analyses revealed that hepatic NPC1L1 overexpression decreased the expression of FoxO1, resulting in the reduced expression of G6Pase and PEPCK, key enzymes in gluconeogenesis. Conclusions. These results indicate that hepatic NPC1L1 might have distinct properties of suppressing gluconeogenesis via inhibition of FoxO1 pathways. © 2015 Elsevier Inc. All rights reserved. Keywords: NPC1L1 Gluconeogenesis FoxO1 1. Introduction Diabetes and dyslipidemia are both worldwide spreading diseases threatening human health. Several studies have shown that some agents for dyslipidemia modulate glucose metabolism. Among them, ezetimibe, an inhibitor of Niemann-Pick C1 like 1 protein (NPC1L1), has been reported to improve insulin resistance and fatty liver in rodents [1]; deletion of NPC1L1 gene in rodent has also been shown to ameliorate insulin resistance [2]. In contrast to the remark- able improvement of glucose metabolism in these rodent models by ezetimibe, only a few reports have demonstrated METABOLISM CLINICAL AND EXPERIMENTAL 64 (2015) 588 – 596 Abbreviations: Ad-L1, adenovirus coding NPC1L1; Ad-Null, blank adenovirus; DIO, diet-induced obesity; FoxO1, forkhead box O 1; G6Pase, glucose 6-phosphatase; L1-mice, mice infected with Ad-L1; NPC1L1, Niemann-Pick C1 like 1 protein; Null-mice, mice infected with Ad-Null; PEPCK, phosphoenolpyruvate carboxykinase. ⁎ Corresponding author at: Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, 21–2 Maeda, Tanisawa, Kawahigashi, Aizu-wakamatsu City, Fukushima, 969–3492, Japan. Tel.: +81 242 75 2100; fax: +81 242 75 2568. E-mail addresses: kurano-tky@umin.ac.jp (M. Kurano), masumihara-tky@umin.ac.jp (M. Hara), hiroakis-tky@umin.ac.jp (H. Satoh), kazut@fmu.ac.jp (K. Tsukamoto). http://dx.doi.org/10.1016/j.metabol.2015.01.011 0026-0495/© 2015 Elsevier Inc. All rights reserved. Available online at www.sciencedirect.com Metabolism www.metabolismjournal.com