title: Kcne2 deletion causes early-onset nonalcoholic fatty liver disease via iron deficiency anemia.
abstract: Nonalcoholic fatty liver disease (NAFLD) is an increasing health problem worldwide, with genetic, epigenetic, and environmental components. Here, we describe the first example of NAFLD caused by genetic disruption of a mammalian potassium channel subunit. Mice with germline deletion of the KCNE2 potassium channel β subunit exhibited NAFLD as early as postnatal day 7. Using mouse genetics, histology, liver damage assays and transcriptomics we discovered that iron deficiency arising from KCNE2-dependent achlorhydria is a major factor in early-onset NAFLD in Kcne2(─/─) mice, while two other KCNE2-dependent defects did not initiate NAFLD. The findings uncover a novel genetic basis for NAFLD and an unexpected potential factor in human KCNE2-associated cardiovascular pathologies, including atherosclerosis.
authors.affiliation: Bioelectricity Laboratory, Dept. of Pharmacology and Dept. of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: Soo Min
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Bioelectricity Laboratory, Dept. of Pharmacology and Dept. of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: Dara
authors.initials: D
authors.lastname: Nguyen
authors.affiliation: Bioelectricity Laboratory, Dept. of Pharmacology and Dept. of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Anand
authors.affiliation: Bioelectricity Laboratory, Dept. of Pharmacology and Dept. of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: Ritu
authors.initials: R
authors.lastname: Kant
authors.affiliation: Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Köhncke
authors.affiliation: Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lisewski
authors.affiliation: Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.|Clinic for Cardiology and Angiology, Charité University-Medicine Berlin, Campus Mitte, 10117 Berlin, Germany.
authors.forename: Torsten K
authors.initials: TK
authors.lastname: Roepke
authors.affiliation: Laboratory of Anesthesiology &Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Bioelectricity Laboratory, Dept. of Pharmacology and Dept. of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Abbott
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000150:complications*; D000818:Animals; D002097:C-Reactive Protein / Q000032:analysis; D059305:Diet, High-Fat; D005260:Female; D053263:Gene Regulatory Networks; D018095:Germ-Line Mutation; D006710:Homocysteine / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D059467:Transcriptome; D014280:Triglycerides / Q000097:blood
chemical_list: C489620:Kcne2 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D014280:Triglycerides; D006710:Homocysteine; D002097:C-Reactive Protein