title: Hepatic NPC1L1 overexpression ameliorates glucose metabolism in diabetic mice via suppression of gluconeogenesis.
abstract: 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.
  
  
  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.
authors: Department of Clinical Laboratory Medicine, Graduate School of Medicine, University of Tokyo, Japan. Electronic address: kurano-tky@umin.ac.jp.
authors: Makoto
authors: M
authors: Kurano
authors: Department of Internal Medicine IV, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan. Electronic address: masumihara-tky@umin.ac.jp.
authors: Masumi
authors: M
authors: Hara
authors: Department of Nephrology, Hypertension, Diabetology, Endocrinology, and Metabolism, Fukushima Medical University, Fukushima, Japan. Electronic address: hiroakis-tky@umin.ac.jp.
authors: Hiroaki
authors: H
authors: Satoh
authors: Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Fukushima, Japan. Electronic address: kazut@fmu.ac.jp.
authors: Kazuhisa
authors: K
authors: Tsukamoto
mesh_terms: D000818:Animals; D015153:Blotting, Western; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D012333:RNA, Messenger; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose
keywords: FoxO1; Gluconeogenesis; NPC1L1