title: Amelioration of hypercholesterolemia by an EGFR tyrosine kinase inhibitor in mice with liver-specific knockout of Mig-6.
abstract: Mitogen-inducible gene 6 (Mig-6) is a negative feedback inhibitor of epidermal growth factor receptor (EGFR) signaling. We previously found that Mig-6 plays a critical role in the regulation of cholesterol homeostasis and in bile acid synthesis. In this study, we investigated the effects of EGFR inhibition to identify a potential new treatment target for hypercholesterolemia. We used a mouse model with conditional ablation of the Mig-6 gene in the liver (Albcre/+Mig-6f/f; Mig-6d/d) to effectively investigate the role of Mig-6 in the regulation of liver function. Mig-6d/d mice were treated with either the EGFR inhibitor gefitinib or statin for 6 weeks after administration of a high-fat or standard diet. We then compared lipid profiles and other parameters among each group of mice. After a high-fat diet, Mig-6d/d mice showed elevated serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and glucose, characteristics resembling hypercholesterolemia in diabetic patients. We observed decreases in serum levels of lipids and glucose in high-fat-diet-fed Mig-6d/d mice after 6 weeks of treatment with gefitinib or statin. Furthermore gefitinib-treated mice showed significantly greater decreases in serum levels of total, HDL and LDL cholesterol compared with statin-treated mice. Taken together, these results suggest that EGFR inhibition is effective for the treatment of hypercholesterolemia in high-fat-diet-fed Mig-6d/d mice, and our findings provide new insights into the development of possible treatment targets for hypercholesterolemia via modulation of EGFR inhibition.
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea; Department of Internal Medicine, Daejeon Veterans Hospital, Daejeon, Korea.
authors.forename: Jun Choul
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Department of Drug Development and Discovery, Graduate School of New Drug Development and Discovery, Chungnam National University, Daejeon, Korea.
authors.forename: Byung Kil
authors.initials: BK
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Sorim
authors.initials: S
authors.lastname: Choung
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Ji Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Kyong Hye
authors.initials: KH
authors.lastname: Joung
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 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 and Reproductive Biology, Michigan State University, Grand Rapids, Michigan, United States of America.
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Department of Drug Development and Discovery, Graduate School of New Drug Development and Discovery, Chungnam National University, Daejeon, Korea; Research Center for Drug Discovery Technology, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Daejeon, Korea.
authors.forename: Sang Dal
authors.initials: SD
authors.lastname: Rhee
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; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D006937:Hypercholesterolemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019426:Integrases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism
chemical_list: C475819:Errfi1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014280:Triglycerides; D002784:Cholesterol; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C045073:Cre recombinase; D019426:Integrases; D000077156:Gefitinib