title: Obesity in a model of gpx4 haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathy.
abstract: OBJECTIVE
  Lipid peroxides and their reactive aldehyde derivatives (LPPs) have been linked to obesity-related pathologies, but whether they have a causal role has remained unclear. Glutathione peroxidase 4 (GPx4) is a selenoenzyme that selectively neutralizes lipid hydroperoxides, and human gpx4 gene variants have been associated with obesity and cardiovascular disease in epidemiological studies. This study tested the hypothesis that LPPs underlie cardio-metabolic derangements in obesity using a high fat, high sucrose (HFHS) diet in gpx4 haploinsufficient mice (GPx4(+/-)) and in samples of human myocardium.
  
  
  METHODS
  Wild-type (WT) and GPx4(+/-) mice were fed either a standard chow (CNTL) or HFHS diet for 24 weeks, with metabolic and cardiovascular parameters measured throughout. Biochemical and immuno-histological analysis was performed in heart and liver at termination of study, and mitochondrial function was analyzed in heart. Biochemical analysis was also performed on samples of human atrial myocardium from a cohort of 103 patients undergoing elective heart surgery.
  
  
  RESULTS
  Following HFHS diet, WT mice displayed moderate increases in 4-hydroxynonenal (HNE)-adducts and carbonyl stress, and a 1.5-fold increase in GPx4 enzyme in both liver and heart, while gpx4 haploinsufficient (GPx4(+/-)) mice had marked carbonyl stress in these organs accompanied by exacerbated glucose intolerance, dyslipidemia, and liver steatosis. Although normotensive, cardiac hypertrophy was evident with obesity, and cardiac fibrosis more pronounced in obese GPx4(+/-) mice. Mitochondrial dysfunction manifesting as decreased fat oxidation capacity and increased reactive oxygen species was also present in obese GPx4(+/-) but not WT hearts, along with up-regulation of pro-inflammatory and pro-fibrotic genes. Patients with diabetes and hyperglycemia exhibited significantly less GPx4 enzyme and greater HNE-adducts in their hearts, compared with age-matched non-diabetic patients.
  
  
  CONCLUSIONS
  These findings suggest LPPs are key factors underlying cardio-metabolic derangements that occur with obesity and that GPx4 serves a critical role as an adaptive countermeasure.
authors.affiliation: Department of Pharmacology & Toxicology, East Carolina University, Greenville, NC, United States ; Department of Public Health, East Carolina University, Greenville, NC, United States.
authors.forename: Lalage A
authors.initials: LA
authors.lastname: Katunga
authors.affiliation: Department of Pharmacology & Toxicology, East Carolina University, Greenville, NC, United States.
authors.forename: Preeti
authors.initials: P
authors.lastname: Gudimella
authors.affiliation: Department of Public Health, East Carolina University, Greenville, NC, United States ; East Carolina Heart Institute, East Carolina University, Greenville, NC, United States.
authors.forename: Jimmy T
authors.initials: JT
authors.lastname: Efird
authors.affiliation: Department of Pharmacology & Toxicology, East Carolina University, Greenville, NC, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Abernathy
authors.affiliation: Department of Pharmacology & Toxicology, East Carolina University, Greenville, NC, United States.
authors.forename: Taylor A
authors.initials: TA
authors.lastname: Mattox
authors.affiliation: Department of Pharmacology & Toxicology, East Carolina University, Greenville, NC, United States.
authors.forename: Cherese
authors.initials: C
authors.lastname: Beatty
authors.affiliation: Department of Pharmacology & Toxicology, East Carolina University, Greenville, NC, United States.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Darden
authors.affiliation: Department of Pharmacology & Toxicology, East Carolina University, Greenville, NC, United States.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Thayne
authors.affiliation: East Carolina Heart Institute, East Carolina University, Greenville, NC, United States.
authors.forename: Hazaim
authors.initials: H
authors.lastname: Alwair
authors.affiliation: East Carolina Heart Institute, East Carolina University, Greenville, NC, United States.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kypson
authors.affiliation: Department of Physiology, East Carolina University, Greenville, NC, United States.
authors.forename: Jitka A
authors.initials: JA
authors.lastname: Virag
authors.affiliation: Department of Pharmacology & Toxicology, East Carolina University, Greenville, NC, United States ; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States.
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Anderson
keywords: 4-HNE, 4-hydroxynonenal; BMI, body mass index; CNTL, control; Coll1a1, collagen, type I, alpha; Coll4a1, collagen, type IV, alpha 1; EF, ejection fraction; FS, fractional shortening; GPx4, glutathione peroxidase 4; Glutathione peroxidase 4; HDL, high-density lipoprotein; HFHS, high fat, high sucrose; Human heart; IL-1β, interleukin-1 beta; IL-6, interleukin-6; Inflammation; LPPs, lipid peroxidation end products; Lipid peroxidation; Mitochondria; Nrf2, nuclear factor (erythroid-derived 2)-like 2; Obesity; PUFA, polyunsaturated fatty acids; RAGE, receptor for advanced glycation end products; RNS, reactive nitrogen species; ROS, reactive oxygen species; TG, triglycerides; TGF-β1, transforming growth factor beta 1; TGF-β2, transforming growth factor beta 2; TNF-α, tumor necrosis factor-α; WT, wild type; iNOS, inducible nitric oxide synthase; β-MHC, β myosin heavy chain