Lipocalin 2, a key molecular switch in regulating liver metabolism and immunity

以前认为脂质运载蛋白家族的成员是转运蛋白，在难溶性或化学敏感性化合物（包括维生素、类固醇和代谢产物）的储存和转运中仅具有一般作用。然而，这种观点在过去几年中发生了巨大变化。特别是，脂质运载蛋白在介导保护性免疫调节和抗菌作用中的作用以及它们参与防御氧化应激的作用已经被强调。已经鉴定了几种受体和相互作用的伴侣，并发现了其他功能。Lipocalin 2（LCN 2），以前称为中性粒细胞明胶酶相关蛋白（NGAL），是一种抗菌蛋白，它与铁载体结合以防止细菌吸收铁，这对于控制大肠杆菌的全身感染至关重要。我们和其他人已经表明，LCN 2在肝脏炎症期间介导其作为“帮助我”信号的作用。从受损的肝细胞中释放出来，它提供了将炎性细胞招募到受损组织所必需的信号。其保护作用在许多实验性肝损伤模型中得到证实。我们最近发现LCN 2影响肝脏中的过氧化物酶体和线粒体生物学，以维持甘油三酯和氧化应激平衡。它还通过调节脂滴外壳蛋白Perilipin 5（PLIN 5）的表达来控制细胞内脂滴的形成。然而，大多数这些发现的机制背景只是知之甚少。该提案的目标是全面分析LCN 2在肝脏疾病中的功能。特别是，LCN 2用于在代谢和免疫调节功能之间切换的机制，以及其在肝病环境中与铁稳态的联系将得到解决。此外，游离LCN 2和外泌体包裹的LCN 2的自分泌和旁分泌作用活性应在炎症性肝病的情况下进行研究。

Formerly it was thought that members of the lipocalin protein family are transport proteins having only general roles in the storage and transport of poorly soluble or chemically sensitive compounds including vitamins, steroids, and metabolic products. However, this view has changed drastically during the last years. In particular, the role of lipocalins in mediating protective immunoregulation and antibacterial effects as well as their involvement in defending against oxidative stress has been highlighted. Several receptors and interacting partners have been identified and additional functions have been discovered. Prototypically, the Lipocalin 2 (LCN2), formerly known as Neutrophil gelatinase-associated protein (NGAL), acts as an antimicrobial protein, which binds to siderophores to prevent bacterial uptake of iron, which is critical for the control of systemic infection with Escherichia coli. We and others have shown that LCN2 mediates its effects as a “help me” signal during hepatic inflammation. Released from injured hepatocytes, it provides signals necessary to recruit inflammatory cells to the damaged tissue. Its protective effects were confirmed in many experimental liver injury models. We have recently shown that LCN2 influences peroxisomal and mitochondrial biology in the liver to maintain triglyceride and oxidative stress balance. It further controls the formation of intracellular lipid droplets by regulating expression of the lipid droplet coat protein Perilipin 5 (PLIN5). However, the mechanistic background of most of these findings is only poorly understood. The goal of this proposal is a comprehensive analysis of LCN2 functions in liver disease. In particular, the mechanisms used by LCN2 to switch between metabolic and immunomodulatory functions as well as its connection to iron homeostasis in the setting of hepatic disease will be addressed. Moreover, autocrine and paracrine acting activities of free LCN2 and exosome-encapsulated LCN2 should be investigated in the setting of inflammatory hepatic diseases.