Shih Pei-An Betty
Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive #0863, La Jolla, CA 92093-0863, USA.
Prostaglandins Other Lipid Mediat. 2017 Sep;132:69-76. doi: 10.1016/j.prostaglandins.2017.02.002. Epub 2017 Feb 21.
Anorexia Nervosa (AN) is a serious mental illness characterized by emaciation, an intense fear of gaining weight despite being underweight, and distorted body image. Few treatments reverse the core symptoms in AN such as profound aversion to food and food avoidance. Consequently, AN has a chronic and relapsing course and the highest mortality rate of any psychiatric illness. A more complete understanding of the disease pathogenesis is needed in order to develop better treatments and improve AN outcome. The pathogenesis and psychopathophysiology of AN can be better elucidated by combining longitudinal phenotyping with multiple "omics" techniques, including genomics, proteomics, lipidomics, and metabolomics.
This paper summarizes the key findings of a series of interrelated studies including new experimental data and previously published data, and describes our current initiatives and future directions.
Exon sequencing data was analyzed in 1205 AN and 1948 controls. Targeted metabolomics, lipidomics, and proteomics data were collected in two independent convenience samples consisting of 75 subjects with eating disorders and 61 sex- and age-matched healthy controls. Study participants were female and the mean age was 22.9 (4.9 [SD]) years. Epoxide hydrolase 2 (EPHX2) genetic variations were significantly associated with AN risk, and epoxide hydrolase (sEH) activity was elevated in AN compared to controls. The polyunsaturated fatty acids (PUFAs) and eicosanoids data revealed that cytochrome P450 pathway was implicated in AN, and AN displayed a dysregulated postprandial metabolism of PUFAs and sEH-dependent eicosanoids.
Collectively, our data suggest that dietary factors may contribute to the burden of EPHX2-associated AN susceptibility and affect disease outcome. We are implementing new investigations using a longitudinal study design in order to validate and develop an EPHX2 multi-omics biomarker system. We will test whether sEH-associated postprandial metabolism increases AN risk and affects treatment outcome through an ω-6 rich breakfast challenge. Participants will include 100 ill AN patients, 100 recovered AN patients, and 100 age- and race-matched healthy women. These data will allow us to investigate 1) how genetic and dietary factors independently and synergistically contribute to AN risk and progression, and 2) if clinical severity and treatment response in AN are affected by sEH activity and eicosanoid dysregulation. Results of our study will 1) identify clinically relevant biomarkers, 2) unravel mechanistic functions of sEH, and 3) delineate contributory roles of dietary PUFAs and cytochrome P450 pathway eicosanoids for the purpose of developing novel AN treatments and improving disease prognosis.
神经性厌食症（AN）是一种严重的精神疾病，其特征为消瘦、尽管体重过轻却极度害怕体重增加以及身体形象扭曲。很少有治疗方法能逆转神经性厌食症的核心症状，如对食物的极度厌恶和回避。因此，神经性厌食症病程呈慢性且易复发，是所有精神疾病中死亡率最高的。为了开发更好的治疗方法并改善神经性厌食症的治疗效果，需要对该疾病的发病机制有更全面的了解。通过将纵向表型分析与多种“组学”技术（包括基因组学、蛋白质组学、脂质组学和代谢组学）相结合，可以更好地阐明神经性厌食症的发病机制和精神心理病理生理学。
本文总结了一系列相互关联研究的关键发现，包括新的实验数据和先前发表的数据，并描述了我们当前的研究计划和未来方向。
对1205名神经性厌食症患者和1948名对照进行了外显子测序数据分析。在两个独立的便利样本中收集了靶向代谢组学、脂质组学和蛋白质组学数据，这两个样本分别由75名饮食失调患者和61名年龄及性别匹配的健康对照组成。研究参与者均为女性，平均年龄为22.9（4.9[标准差]）岁。环氧水解酶2（EPHX2）基因变异与神经性厌食症风险显著相关，与对照组相比，神经性厌食症患者的环氧水解酶（sEH）活性升高。多不饱和脂肪酸（PUFAs）和类花生酸数据显示，细胞色素P450途径与神经性厌食症有关，神经性厌食症患者的餐后PUFAs和sEH依赖性类花生酸代谢失调。
总体而言，我们的数据表明饮食因素可能导致与EPHX2相关的神经性厌食症易感性负担，并影响疾病结局。我们正在采用纵向研究设计开展新的调查，以验证和开发EPHX2多组学生物标志物系统。我们将通过富含ω-6的早餐挑战来测试与sEH相关的餐后代谢是否会增加神经性厌食症风险并影响治疗效果。参与者将包括100名神经性厌食症患病患者、100名康复的神经性厌食症患者以及100名年龄和种族匹配的健康女性。这些数据将使我们能够研究：1）遗传和饮食因素如何独立以及协同作用导致神经性厌食症风险和病情进展；2）神经性厌食症的临床严重程度和治疗反应是否受sEH活性和类花生酸失调的影响。我们研究的结果将：1）识别临床相关生物标志物；2）揭示sEH的机制功能；3）阐明饮食PUFAs和细胞色素P450途径类花生酸的作用，以便开发新的神经性厌食症治疗方法并改善疾病预后。
