title: Role of Mig-6 in hepatic glucose metabolism.
abstract: BACKGROUND
  Mitogen-inducible gene 6 (Mig-6) has an important role in the regulation of cholesterol homeostasis and bile acid synthesis. However, the physiological functions of Mig-6 in the liver remain poorly understood.
  
  
  METHODS
  To investigate Mig-6 functioning in the liver, we used conditionally ablated Mig-6 using the Albumin-Cre mouse model (Alb(cre/+) Mig-6(f/f) ; Mig-6(d/d) ). Male mice were killed after a 24-h fast and refed after 24 h fasting. Fasting glucose and insulin levels were measured and western blot analyses were performed to determine epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK) 1/2, AKT, mammalian target of rapamycin (mTOR), c-Jun N-terminal kinase (JNK), and Insulin receptor substrate-1 (IRS-1) in liver tissue samples. In addition, human hepatocellular carcinoma HepG2 cells were transfected with Mig-6 short interference (si) RNA before western blot analysis.
  
  
  RESULTS
  Serum fasting glucose levels were significantly higher in Mig-6(d/d) versus Mig-6(f/f) mice. On an insulin tolerance test, insulin sensitivity was decreased in Mig-6(d/d) versus Mig-6(f/f) mice. Furthermore, hepatic expression of the glucokinase (Gck), glucose-6-phosphatase (G6pc), and phosphoenolpyruvate carboxykinase 1 (Pck1) genes was decreased significantly in Mig-6(d/d) mice. Phosphorylation of EGFR, ERK1/2, AKT, mTOR, JNK, and IRS-1 was increased in Mig-6(d/d) compared with Mig-6(f/f) mice.
  
  
  CONCLUSIONS
  Liver-specific ablation of Mig-6 caused hyperglycemia by hepatic insulin resistance. Increased EGFR signaling following Mig-6 ablation activated JNK and eventually induced insulin resistance by increasing phosphorylation of IRS-1 at serine 307. This is the first report of Mig-6 involvement in hepatic insulin resistance and a new mechanism that explains hepatic insulin resistance.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, Michigan, USA.
authors.forename: Jung-Yoon
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, Michigan, USA.
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Sieun
authors.initials: S
authors.lastname: Kong
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Ju Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Food Science and Technology, Korea National University of Transportation, Chungju, Korea.
authors.forename: Wonseok
authors.initials: W
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Koon Soon
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, Michigan, USA.
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Bon Jeong
authors.initials: BJ
authors.lastname: Ku
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005947:Glucose / Q000378:metabolism*; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D019426:Integrases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C475819:Errfi1 protein, mouse; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt; C045073:Cre recombinase; D019426:Integrases; D005947:Glucose
keywords: Mig-6; glucose metabolism; insulin; liver; 肝脏; 胰岛素; 葡萄糖代谢