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

PGAM5在肝脏脂质代谢调控及癌变中的作用 (PI：Andrea约翰斯顿，兽医学博士，哲学博士）。 这个项目的主要目标是确定线粒体代谢的变化是否 机制上影响从非酒精性脂肪肝（NAFLD）到 肝细胞癌（HCC）。NAFLD正在成为HCC的主要原因。HCC生存率 结果很差。定义NAFLD的生物能量病理生理学及其进展 HCC将发现新的生物标志物和治疗靶点。线粒体膜蛋白 磷酸甘油酸酯β 5（PGAM5）调节一系列线粒体稳态途径。 最近的研究表明，PGAM5的消耗可以防止高脂饮食（HFD）诱导的 肥胖和HCC的进展。这项拟议中的研究将检验这一假设， 线粒体代谢途径是造成这些效应的原因。肝脏特异性基因敲除 将产生小鼠以确定PGAM5的肝细胞特异性损失是否将抑制 HFD模型中的脂肪变性。人HCC细胞系的单细胞RNA测序将确定 PGAM5耗竭改变与肝脏脂质代谢相关的基因表达。HCC 球状体将用于表征PGAM5的缺失如何调节线粒体呼吸 和糖酵解。提出了两个具体目标：目标1将确定 PGAM5敲除抑制肝细胞脂肪变性。目标2将确定PGAM5缺失是否 改变HCC中的线粒体代谢，导致活性氧产生增加。

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.