Abstract 10628: The Role of Hepatic Endoplasmic Reticulum Homeostasis in Liver-Heart Crosstalk in Sepsis

Abstract

The heart demands continuous supply of energy substrates, primarily in the form of lipids, to sustain its contractility and other functions. During episodes of severe stress such as sepsis, an overwhelming pathogen-induced systemic immuno-metabolic response, the heart heavily relies on lipid particles synthesized at the endoplasmic reticulum in the liver. However, it is currently unknown how this lipid-dependent crosstalk supports cardiac function during stress and how it is regulated in the liver. In this study, we employed proteomic, lipidomic, and metabolomic approaches to show that hepatic Inositol-Requiring Enzyme 1 α (IRE1α), a key regulator of ER homeostasis, interacts with and regulates the activity of Fatty Acid Synthase (FAS), a well-known enzyme that synthesizes lipids. Notably, this dynamic physical interaction was disrupted in the setting of experimental sepsis induced by lipopolysaccharide (LPS). Specific deletion of IRE1α in the liver sensitized mice to LPS-associated mortality due to cardiac dysfunction. Mechanistically, we found that loss of IRE1 did not alter hepatic or systemic cytokine response, but suppressed FAS enzymatic activity, compromising the adaptive hepatic lipid metabolic reprogramming in response to the LPS challenge. Notably, IRE1α deletion diminished the LPS-induced lysophosphatidylcholine (LPC) secretion from the liver, a critical lipid species that is positively correlated with survival in septic human patients. In turn, this impaired hepatic ER-mediated lipid reprogramming contributed to cardiac dysfunction in part through reducing cardiac oxygen consumption and promoting neutrophil infiltration in response to sepsis. Together, our study provides the first insight into how adisruption of hepatic ER-mediated lipid metabolic regulation promotes sepsis-associated cardiac immuno-metabolic imbalance. Knowledge gained from this study might speed the development of novel therapeutic targets for hepatic ER homeostasis in sepsis-associated heart dysfunction.