Effect of surgical and pharmacological obesity treatments on hepatic fat, energy flux, and mitochondria

提案摘要（摘要） 研究背景和影响：非酒精性脂肪性肝病（NAFLD）是肝脏疾病的主要原因 在全球范围内，并导致过早死亡。由于青少年NAFLD在很大程度上表现为无症状， 应该把重点放在患病风险特别高的青少年身上，包括那些极度肥胖的青少年。 和/或多囊卵巢综合征（PCOS）。唯一批准的NAFLD治疗方法是生活方式干预，但 可行性和长期维护在年轻人中极具挑战性。手术和药物性肥胖 已经探索了治疗成人NAFLD的干预措施，新出现的数据表明垂直袖 胃切除术（VSG）和胰高血糖素样肽-1受体激动剂（GLP-1 RA）改善NAFLD。中的数据 成人和临床前啮齿动物模型表明，异常的肝线粒体和肝能量通量是 关键参与NAFLD的发病机制，但这些潜在的机制是否对 治疗仍然未知。此外，这些手术和药理学治疗尚未在临床上进行研究。 青年因此，本提案的目标是使用转化研究方法来评估肝脏脂肪， 代谢和手术（VSG）和药物（GLP 1-RA）前后的线粒体功能 在由于肥胖和/或PCOS而具有NAFLD高风险的青年（和VSG小鼠）中进行干预。我们将评估 通过肝脏MRI检查肝脏脂肪，使用口服甘油同位素示踪剂，通过NMR进行血清和肝脏同位素异构体分析 量化和描述肝脏代谢的动力学，并通过高分辨率测量线粒体功能 新鲜肝组织的呼吸测定和肝内磷酸盐浓度的非侵入性31 Phos-MRS。这些 研究将为新兴的治疗选择提供极好的机制见解，并将改善 为高危青年提供短期和长期健康服务。 候选人和培训：我的长期职业目标是成为一名独立的学术科学家， 研究计划的重点是了解潜在的病理生理学的分子信号事件， 代谢性疾病，重点是NAFLD。我在临床前小鼠模型方面有丰富的经验， 要成为一名独立的翻译研究者，我需要接受临床试验研究方面的培训。这些拟议 研究将扩大我的研究能力，包括临床试验实施，稳定同位素示踪剂， 我还将扩大我的临床前和实验室科学研究技术，包括小鼠生存 手术和脂质组学。我所在机构（科罗拉多大学安舒茨医学院）提供的机会 校园）和我的导师团队（梅勒妮克里格林博士，达琳桑多瓦尔，简Reusch，克雷格马洛伊， 布赖恩伯格曼，劳拉派尔）将提供良好的培训，在综合肝脏代谢。

PROPOSAL SUMMARY (ABSTRACT) Research Background and Impact: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide and leads to early mortality. Because adolescent NAFLD largely presents as asymptomatic, research should focus on adolescents at particularly high-risk for disease, which includes those with extreme obesity and/or polycystic ovary syndrome (PCOS). The only approved treatment for NAFLD is lifestyle intervention, yet feasibility and long-term maintenance is extremely challenging in youth. Surgical and pharmacological obesity interventions have been explored for treatment of NAFLD in adults, with emerging data suggesting vertical sleeve gastrectomy (VSG) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve NAFLD. Data from both adults and pre-clinical rodent models suggest that aberrant hepatic mitochondria and hepatic energy flux are critically involved in the pathogenesis of NAFLD, but whether these underlying mechanisms are responsive to therapy remains unknown. Further, these surgical and pharmacological treatments have not been studied in youth. Therefore, the goal of this proposal is to use a translational research approach to evaluate hepatic fat, metabolism, and mitochondrial function before and after surgical (VSG) and pharmacological (GLP1-RA) interventions in youth (and mice for VSG) at high risk for NAFLD due to obesity and/or PCOS. We will assess hepatic fat via liver MRI, use oral glycerol isotope tracers and serum and hepatic isotopomer analysis via NMR to quantify and describe dynamics of hepatic metabolism, and measure mitochondria function via high resolution respirometry of fresh liver tissue and non-invasive 31Phos-MRS for intrahepatic phosphate concentrations. These studies will provide excellent mechanistic insight into emerging therapeutic options and will improve the immediate and long-term health of at-risk youth. Candidate and Training: My long-term career goal is to be an independent, academic scientist with a translational research program focused on understanding the molecular signaling events underlying the pathophysiology of metabolic disease, with a focus on NAFLD. I have extensive experience in pre-clinical mouse models but to become an independent translational investigator, I need training in clinical trial research. These proposed studies will expand my research capabilities to include clinical trial implementation, stable isotope tracers, and 31Phos MRS. I will also expand my pre-clinical and bench science research techniques to include mouse survival surgery and lipidomics. The opportunities provided by my institution (University of Colorado Anschutz Medical Campus) and by my mentorship team (Drs. Melanie Cree-Green, Darleen Sandoval, Jane Reusch, Craig Malloy, Bryan Bergman, Laura Pyle) will provide excellent training in integrative hepatic metabolism.