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

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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.