Obesity in a model of gpx4 haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathy

Abstract

ObjectiveLipid 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.MethodsWild-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.ResultsFollowing 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.ConclusionThese 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.

Oxidative stress and lipotoxicity

“…Strikingly, decreased GPx4 mRNA expression was observed in human heart tissue from subjects with diabetes compared with nondiabetic controls. This expression pattern was accompanied by an increase in 4-HNE adducts in the diabetic samples, further highlighting the importance of this enzyme in mediating the effect of lipid peroxidation (34,79).…”

“…Recent work by Katunga et al (34) highlighted the importance of GPx4 in the context of obesity. While whole body knockout of this enzyme is embryonic lethal, Gpx4 haploinsufficient mice maintained on a high-fat high-sucrose diet exhibit increased carbonyl stress, exemplified by increased 4HNE adduct in the liver and heart accompanied by elevated ROS and mitochondrial dysfunction in the heart (34). Strikingly, decreased GPx4 mRNA expression was observed in human heart tissue from subjects with diabetes compared with nondiabetic controls.…”

“…2). Furthermore, oxidation of CL is known to be accompanied by decreased activity of complexes I and IV, leading to impaired mitochondrial respiration (32)(33)(34). Accordingly, decreases in membrane CL content as well as oxidation of CL are strongly correlated with a variety of disease models in which mitochondrial dysfunction plays a major role, including atherosclerosis, obesity, and cardiac injury during ischemia/reperfusion (35,36).…”

“…Supporting this hypothesis is the observation techniques improve, identification of specific proteins that become modified has facilitated the discovery that protein carbonylation plays an active role in a wide array of cellular mechanisms, including the oxidative stress response, autophagy, ER stress response, proliferation, mitochondrial function, and apoptosis. In obesity, for example, total protein carbonylation is significantly increased in visceral adipose tissue (16,56) and in the heart (34). Although the specific role of protein carbonylation remains complex, a number of studies suggest that protein carbonylation is a mechanistic connection between obesity and the development of metabolic dysfunction, particularly in the adipose tissue (48).…”

Cellular senescence: Implications for metabolic disease

“…Increased metabolic loading is associated with mitochondrial respiration uncoupling, attenuated electron transport chain function, and increased production of reactive oxidative species (ROS). Indeed, increased markers of ROS damage have been identified in adipose tissue (Talior et al, 2003; Furukawa et al, 2004), cardiovascular tissue (Lee et al, 2012; Katunga et al, 2015), and liver (Pessayre, 2007; Matsuzawa-Nagata et al, 2008) of obese humans and mice. In addition, DNA damage robustly activates senescence, and increased frequency of genomic damage makers have been identified in obese individuals with type 2 diabetes (Al-Aubaidy and Jelinek, 2011).…”