Phosphoglycerate mutase 5 (PGAM5) in the regulation of hepatic lipid metabolism and carcinogenesis

综述：前列腺素AM5在调节肝脂代谢和癌变中的作用 (PI：Andrea Johnston，DVM，博士) 这个项目的主要目标是确定线粒体新陈代谢的变化 从机制上影响非酒精性脂肪性肝病(NAFLD)向 肝细胞癌(HCC)。非酒精性脂肪肝正在成为肝细胞癌的主要病因。肝癌存活率 结果很糟糕。NAFLD的生物能量病理生理学的定义及其进展 肝细胞癌将确定新的生物标志物和治疗靶点。线粒体膜蛋白 磷酸甘油酸变位酶5(PGAM5)调节一系列线粒体内稳态通路。 最近的研究表明，消耗PGAM5可以防止高脂饮食(HFD)引起的 肥胖与肝细胞癌的进展。这项拟议的研究将检验这一假设，即 线粒体代谢途径是造成这些影响的原因。一种肝脏特异性基因敲除 将产生小鼠，以确定肝细胞特异性丢失的PGAM5是否会抑制 高脂血症模型中的脂肪变性。人类肝癌细胞系的单细胞RNA测序将决定 PGAM5缺失改变了与肝脂代谢相关的基因表达。肝细胞癌 球体将被用来表征PGAM5的缺失如何调节线粒体的呼吸 脂肪变性模型中的糖酵解。提出了两个具体目标：目标1将决定是否 PGAM5基因敲除可抑制肝细胞脂肪变性。AIM 2将决定是否删除PGAM5 改变肝细胞癌的线粒体新陈代谢，导致活性氧的产生增加。

Summary: PGAM5 in the regulation of hepatic lipid metabolism and carcinogenesis (PI: Andrea Johnston, DVM, PhD). The broad objective of this project is to determine whether changes in mitochondrial metabolism mechanistically influence the transition from non-alcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC). NAFLD is emerging as a leading cause of HCC. HCC survival outcomes are poor. Defining the bioenergetic pathophysiology of NAFLD and its progression to HCC will identify new biomarkers and therapeutic targets. The mitochondrial membrane protein phosphoglycerate mutase 5 (PGAM5) regulates an array of mitochondrial homeostatic pathways. Recent research shows that depletion of PGAM5 prevents both high fat diet (HFD) induced obesity and the progression of HCC. The proposed research will test the hypothesis that distinct mitochondrial metabolic pathways are responsible for these effects. A liver specific knockout mouse will be generated to determine whether hepatocyte specific loss of PGAM5 will inhibit steatosis in a HFD model. Single cell RNA sequencing of a human HCC cell line will determine if PGAM5 depletion alters gene expression associated with hepatic lipid metabolism. HCC spheroids will be used to characterize how loss of PGAM5 modulates mitochondrial respiration and glycolysis in a steatosis model. Two specific aims are proposed: Aim 1 will determine whether PGAM5 knockout inhibits hepatocellular steatosis. Aim 2 will determine whether PGAM5 deletion alters mitochondrial metabolism in HCC leading to increased reactive oxygen species production.