# Yap1/TAZ and CD14 in the Catabolic Response to Sepsis

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2024 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10807674
- **Project number:** 1I01BX006433-01
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** LEONIDAS G. KONIARIS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807674

## Citation

> US National Institutes of Health, RePORTER application 10807674, Yap1/TAZ and CD14 in the Catabolic Response to Sepsis (1I01BX006433-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10807674. Licensed CC0.

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