Macrophage Mitochondrial Pyruvate Carrier in Nonalcoholic Steatohepatitis

项目摘要 非酒精性脂肪性肝炎(NASH)是一种进行性肝脏疾病，是与肝脏相关的主要原因 发病率和死亡率。患有NASH极大地增加了患终末期肝病的风险，如 肝硬变和肝细胞癌。尽管医疗保健负担沉重，但目前还没有获得许可的药物疗法 纳什。NASH表现为肝细胞损伤、炎症和不同程度的纤维化，但明显 推动这一进程的机制尚不清楚。然而，有证据表明，渗入的巨噬细胞 在纳什进程中发挥着关键作用。巨噬细胞是一种先天免疫细胞，可以极化为炎症- 可加重肝脏损伤的表型，或可促进肝脏修复的表型。还没有 在NASH进展中驱动巨噬细胞极性的机制尚不清楚。迫切需要 了解在NASH进程中决定巨噬细胞极化的过程，以确定TERA-R 减轻纳什负担的理想目标。 我们的长期目标是了解决定巨噬细胞极化的代谢调节机制- 致力于开发治疗NASH及其相关并发症的方法。重要的是，巨噬细胞极化 导致线粒体代谢的代谢重排。这不仅是两极分化的结果- 过程中，但特定的三元酸(TCA)循环衍生的中间产物的积累深刻 影响巨噬细胞炎症和抗炎基因的表达。一名参赛的核心球员- 干代谢是线粒体丙酮酸载体(MPC)，它运输丙酮酸，它是丙酮酸的主要产物 糖酵解，进入线粒体基质，在那里它可以进入TCA循环。先前的证据表明，MPC-Hi- BIG改变代谢细胞如心肌细胞和肝细胞内的TCA代谢物，但对 巨噬细胞是未知的。此外，我们的实验室还表明，目前临床上使用的新型MPC抑制剂 试验有效地减少了小鼠的NASH。重要的是，巨噬细胞中MPC抑制的作用尚不明确。 鉴于中间代谢在巨噬细胞激活中的重要性，以及 线粒体代谢中的MPC，本应用的主要目的是[1]通过 哪种MPC有助于巨噬细胞的激活和极化，以及[2]决定如何具体删除 巨噬细胞中的MPC影响NASH进展。我们的中心假设是，单核细胞中的MPC抑制。 细胞来源的巨噬细胞将减少炎症反应，减缓NASH的发展。完全- 这些研究将有助于理解线粒体代谢在巨噬细胞功能中的作用 和NASH进展，并强调巨噬细胞在NASH中的临床应用。

Project Summary Nonalcoholic steatohepatitis (NASH) is a progressive liver disease that is a leading cause of liver-related morbidity and mortality. Having NASH greatly increases the risk of developing end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Despite the healthcare burden, there are no licensed drug therapies for NASH. NASH presents as hepatocyte damage, inflammation, and varying degrees of fibrosis, but the distinct mechanisms that drive this progression are unclear. However, evidence shows that infiltrating macrophages play a pivotal role in NASH progression. Macrophages are innate immune cells that can polarize into inflamma- tory phenotypes that exacerbate hepatic injury, or into resolving phenotypes that can mediate liver repair. Yet the mechanisms driving macrophage polarity in NASH progression are undefined. There is a critical need to understand the processes that dictate macrophage polarization in NASH progression in order to identify thera- peutic targets that decrease the burden of NASH. Our long-term goal is to understand the metabolic regulatory mechanisms dictating macrophage polariza- tion to develop treatments for NASH and its associated comorbidities. Importantly, macrophage polarization results in the metabolic rewiring of mitochondrial metabolism. This is not only a consequence of the polariza- tion process, but the accumulation of specific tricarboxylic acid (TCA) cycle-derived intermediates profoundly influences inflammatory and anti-inflammatory gene expression in macrophages. A central player in mitochon- drial metabolism is the mitochondrial pyruvate carrier (MPC), which transports pyruvate, a primary product of glycolysis, into the mitochondrial matrix where it can enter the TCA cycle. Previous evidence shows MPC inhi- bition alters intracellular TCA metabolites in metabolic cells like myocytes and hepatocytes, but the effect on macrophages is unknown. Furthermore, our lab has shown that novel MPC inhibitors currently used in clinical trials effectively reduce NASH in mice. Importantly, the effect of MPC inhibition in macrophages is undefined. Given the significance of intermediary metabolism in macrophage activation, and the significant role of the MPC in mitochondrial metabolism, the primary objective of this application is to [1] identify the mechanisms by which MPC contributes to macrophage activation and polarization, and [2] determine how specific deletion of MPC in macrophages influences NASH progression. Our central hypothesis is that MPC inhibition in mono- cyte-derived macrophages will reduce the inflammatory response and mitigate NASH development. Comple- tion of these studies will contribute to the understanding of mitochondrial metabolism in macrophage function and NASH progression, and highlight the clinical utility of macrophages in NASH.