Kcne2 deletion causes early-onset nonalcoholic fatty liver disease via iron deficiency anemia

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.

• Publication year

  2016

• Venue

  Scientific Reports

• Publication date

  2016-03-17

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1038/srep23118PMID 26984260PMCID 4794722
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Genetics of nonalcoholic fatty liver disease.

  2016cited by this paper
• Genetic Factors in the Pathogenesis of Nonalcoholic Fatty Liver and Steatohepatitis

  2015cited by this paper
• Kcne2 deletion promotes atherosclerosis and diet-dependent sudden death.

  2015cited by this paper
• The KCNE2 K⁺ channel regulatory subunit: Ubiquitous influence, complex pathobiology.

  2015cited by this paper
• Kcne2 Deletion Creates a Multisystem Syndrome Predisposing to Sudden Cardiac Death

  2014cited by this paper
• Common Genetic Determinants of Lung Function, Subclinical Atherosclerosis and Risk of Coronary Artery Disease

  2014cited by this paper
• KCNQ1, KCNE2, and Na+-Coupled Solute Transporters Form Reciprocally Regulating Complexes That Affect Neuronal Excitability

  2014cited by this paper
• Apolipoprotein B/AI ratio is independently associated with non‐alcoholic fatty liver disease in nondiabetic subjects

  2013cited by this paper
• The genetics of NAFLD

  2013cited by this paper
• C reactive protein levels in non-alcoholic fatty liver disease.

  2012cited by this paper
• Interactions between hepatic iron and lipid metabolism with possible relevance to steatohepatitis.

  2012cited by this paper
• Non-alcoholic fatty liver disease across the spectrum of hypothyroidism.

  2012cited by this paper
• Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis.

  2012cited by this paper
• The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies.

  2012cited by this paper
• The KCNQ1‐KCNE2 K+ channel is required for adequate thyroid I− uptake

  2012cited by this paper
• Genetic dissection reveals unexpected influence of β subunits on KCNQ1 K+ channel polarized trafficking in vivo

  2011cited by this paper
• KCNE2 forms potassium channels with KCNA3 and KCNQ1 in the choroid plexus epithelium

  2011cited by this paper
• Targeted deletion of liver glucose-6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas.

  2011cited by this paper
• Genetic variation in the GCKR gene is associated with non-alcoholic fatty liver disease in Chinese people

  2011cited by this paper
• Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.

  2010cited by this paper
• Targeted Deletion of Kcne2 Causes Gastritis Cystica Profunda and Gastric Neoplasia

  2010cited by this paper
• Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis

  2009cited by this paper
• A Sequence Variation (I148M) in PNPLA3 Associated with Nonalcoholic Fatty Liver Disease Disrupts Triglyceride Hydrolysis

  2009cited by this paper
• Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease

  2009cited by this paper
• Regulation of the Kv2.1 Potassium Channel by MinK and MiRP1

  2009cited by this paper
• Targeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f

  2008cited by this paper
• KLF6 in nonalcoholic fatty liver disease: role of fibrogenesis and carcinogenesis.

  2008cited by this paper
• The genetics of nonalcoholic fatty liver disease.

  2007cited by this paper
• The KCNE2 Potassium Channel Ancillary Subunit Is Essential for Gastric Acid Secretion*

  2006cited by this paper
• Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD)

  2005cited by this paper
• The MinK-related peptides.

  2004cited by this paper
• Abnormal Lipid Metabolism in Cystathionine β-Synthase-deficient Mice, an Animal Model for Hyperhomocysteinemia*

  2004cited by this paper
• Hepatic steatosis and type 2 diabetes mellitus

  2002cited by this paper
• Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice.

  2000cited by this paper
• KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel

  2000cited by this paper
• MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.

  1999cited by this paper
• Hyperhomocyst(e)inemia. A common and easily reversible risk factor for occlusive atherosclerosis.

  1990cited by this paper
• Iron deficiency hyperlipidemia in 18-day-old rat pups: effects of milk lipids, lipoprotein lipase, and triglyceride synthesis.

  1978cited by this paper
• Edinburgh Research Explorer Disruption of the potassium channel regulatory subunit Kcne2 causes iron-deficient anemia

  year unknowncited by this paper

• KCNE gene family: From basic functions to diseases

  2025cites this paper
• The Multifunctional Role of KCNE2: From Cardiac Arrhythmia to Multisystem Disorders

  2024cites this paper
• Kv Channel Ancillary Subunits: Where Do We Go from Here?

  2022cites this paper
• NAFLD and the Gut-Liver Axis: Exploring an Undernutrition Perspective.

  2022cites this paper
• The focal adhesion protein Testin modulates KCNE2 potassium channel β subunit activity

  2021cites this paper
• Hypochlorhydria reduces mortality in heart failure caused by Kcne2 gene deletion

  2020cites this paper
• Fluorescence Fluctuation Spectroscopy enables quantification of potassium channel subunit dynamics and stoichiometry

  2020cites this paper
• The KCNE2 potassium channel β subunit is required for normal lung function and resilience to ischemia and reperfusion injury

  2019cites this paper
• AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2‐dependent sudden cardiac death

  2019cites this paper
• Kcne4 deletion sex dependently inhibits the RISK pathway response and exacerbates hepatic ischemia-reperfusion injury in mice.

  2019cites this paper
• Deletion in mice of X‐linked, Brugada syndrome–and atrial fibrillation–associated Kcne5 augments ventricular Kv currents and predisposes to ventricular arrhythmia

  2018cites this paper
• Acute loss of iron–sulfur clusters results in metabolic reprogramming and generation of lipid droplets in mammalian cells

  2018cites this paper
• Kcne2 deletion impairs insulin secretion and causes type 2 diabetes mellitus

  2017cites this paper
• Remote ischemic preconditioning differentially attenuates post-ischemic cardiac arrhythmia in streptozotocin-induced diabetic versus nondiabetic rats

  2017cites this paper
• Regulation of human cardiac potassium channels by full-length KCNE3 and KCNE4

  2016cites this paper