Yap1/TAZ and CD14 in the Catabolic Response to Sepsis

Activation of the innate immune system in response to sepsis, organ damage, or mechanical injury initiates critical catabolic processes in muscle and fat. Such catabolism provides metabolic substrates including amino acids, fatty acids, and minerals that fuel metabolically expensive but essential systemic actions needed to mitigate sepsis and allow tissue repair. These actions include supporting cellular energy needs, changes in immunity, the production of acute phase proteins, expansions of inflammatory cell populations, as well as the repair/regeneration of damaged tissues. Although enteral food intake can supplement the metabolic substrates needed to combat sepsis, the breakdown of preexisting energy and substrate stores in the body are the main source for these raw materials, particularly when faced with impaired intestinal function, anorexia, or ileus. Significant gaps in understanding the molecular mechanisms that link the response to sepsis with the associated catabolic response, and recovery remain. This lack of understanding has prevented the discovery of pharmacologic interventions to potentially improve outcomes from the catabolism-driven response to sepsis, particularly changes that occur in muscle resulting in decreased mass and weakness. Yes-associated protein (Yap1) and the transcriptional co-activator with PDZ-binding motif (TAZ) are highly related transcriptional factors regulated by the HIPPO kinase cascade (referred herein as Yap1/TAZ). Yap1/TAZ is the major regulator of metabolism in most tissues and organs. To date, crosstalk in sepsis between Yap1/TAZ and the innate immune system remain undefined. Using animal models of organ injury and sepsis, we have identified that Yap1/TAZ induces CD14, a proximal activator of innate immunity. CD14 directly induces muscle wasting in vivo. Furthermore, blocking CD14 prevents myotube wasting in vitro. Based upon these results and the current literature, we hypothesize that in response to sepsis, Yap1/TAZ directly activate CD14 expression. This critical step links a tissue and organ homeostatic signal in the liver to systemic activation of the innate immune system and catabolic response in sepsis. Furthermore, these data support that the Yap1/Taz/Cd14 signaling axis is a targetable point to potentially improve outcomes in sepsis. Proposed studies will delineate the in vivo significance of hepatic Yap1/TAZ and CD14 in systemic recovery from sepsis and its effects on the catabolic state. Both murine knockout and over- expression models will be examined. This proposal will determine the response to sepsis with a focus on systemic metabolism, liver, and muscle.