目的:脂质过氧化物及其活性醛衍生物(LPP)与肥胖相关的病理有关,但是它们是否有因果作用尚不清楚。谷胱甘肽过氧化物酶4(GPx4)是一种硒酶,可以选择性地中和脂质氢过氧化物,在流行病学研究中,人类gpx4基因变异与肥胖和心血管疾病有关。这项研究检验了以下假设:LPPs是肥胖患者使用高脂肪的心脏代谢紊乱的基础,gpx4单倍体不足小鼠(GPx4(/-))和人心肌样品中的高蔗糖(HFHS)饮食。
方法:给野生型(WT)和GPx4(+/-)小鼠喂食标准食物(CNTL)或HFHS饮食24周,在整个过程中测量代谢和心血管参数。在研究结束时对心脏和肝脏进行生化和免疫组织学分析,并分析了心脏的线粒体功能。还对来自接受选择性心脏手术的103名患者的人心房心肌样本进行了生化分析。
结果:遵循HFHS饮食,WT小鼠表现出4-羟基壬烯醛(HNE)-加合物和羰基应激的适度增加,肝脏和心脏中的GPx4酶增加1.5倍,而gpx4单倍体不足(GPx4(+/-))小鼠在这些器官中有明显的羰基应激伴随着葡萄糖不耐受加剧,血脂异常,和肝脏脂肪变性.虽然血压正常,心脏肥大在肥胖时很明显,和心肌纤维化在肥胖GPx4(+/-)小鼠中更为明显。线粒体功能障碍表现为脂肪氧化能力降低和活性氧增加也存在于肥胖的GPx4(+/-),但不是WT心脏,以及促炎和促纤维化基因的上调。糖尿病和高血糖患者的心脏表现出明显较少的GPx4酶和较高的HNE加合物,与年龄匹配的非糖尿病患者相比。
结论:这些研究结果表明,LPPs是肥胖患者心脏代谢紊乱的关键因素,GPx4作为一种适应性对策发挥着关键作用。
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.