Obesity in a model of haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathy

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dc.contributor.authorKatunga, Lalage Adalaide
dc.contributor.authorGudimella, Preeti
dc.contributor.authorEfird, Jimmy T.
dc.contributor.authorAbernathy, Scott
dc.contributor.authorMattox, Taylor A.
dc.contributor.authorBeatty, Cherese
dc.contributor.authorDarden, Timothy M.
dc.contributor.authorThayne, Kathleen A.
dc.contributor.authorAlwair, Hazaim
dc.contributor.authorKypson, Alan P.
dc.contributor.authorVirag, Jitka A. I.
dc.contributor.authorAnderson, Ethan
dc.date.accessioned2016-06-27T18:22:53Z
dc.date.available2016-06-27T18:22:53Z
dc.date.issued2015-04
dc.description.abstractLipid 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. CONCLUSION: 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.en_US
dc.identifier.citationMolecular Metabolism; 4:6 p. 493-506en_US
dc.identifier.doi10.1016/j.molmet.2015.04.001
dc.identifier.issn2212-8778
dc.identifier.pmidpmc4443294en_US
dc.identifier.urihttp://hdl.handle.net/10342/5762
dc.relation.urihttp://www.ncbi.nlm.nih.gov/pubmed/26042203en_US
dc.subject4-HNEen_US
dc.subject4-hydroxynonenalen_US
dc.subjectBMIen_US
dc.subjectbody mass indexen_US
dc.subjectCNTLen_US
dc.subjectColl1a1en_US
dc.subjectHFHS,en_US
dc.subjectreactive nitrogen speciesen_US
dc.subjecttransforming growth factor beta 2en_US
dc.subjectTGF-β2en_US
dc.subjectβ-MHCen_US
dc.titleObesity in a model of haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathyen_US
dc.typeArticleen_US
ecu.journal.issue6en_US
ecu.journal.nameMolecular Metabolismen_US
ecu.journal.pages493-506en_US
ecu.journal.volume4en_US

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