Saturday, May 17, 2025
5/17/2025
Role of Soluble Epoxide Hydrolase in Alcohol-Associated Liver Disease - Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from hepatic steatosis to steatohepatitis with varying degrees of fibrosis and cirrhosis. ALD is a major cause of morbidity, mortality, and health care costs in the US and worldwide. However, there is no FDA-approved therapy for any stage of ALD. There is also an incomplete understanding of the mechanisms and mediators of disease progression and severity. Soluble epoxide hydrolase (s-EH), a master enzyme that regulates the metabolism of endogenous bioactive lipids (e.g., epoxy-fatty acids, Ep-FAs), has recently been recognized as an emerging therapeutic target in multiple diseases. The overall goal of this project is to test the therapeutic efficacy of s-EH inhibition at different stages of ALD severity, and to provide a mechanistic foundation for using s-EH inhibition as a novel therapy for alcohol-induced liver pathology. Aim 1. To test the therapeutic effectiveness of s-EH inhibition as a novel therapeutic strategy for ALD. We will: i) test whether modulation of s-EH activity by pharmacological inhibition or s-EH (Ephx2) genetic ablation can effectively attenuate or prevent EtOH-induced liver injury in experimental ALD; ii) evaluate whether s-EH inhibition leads to stabilization of blood and liver Ep-FAs; and iii) correlate changes in Ep-FA levels with markers of liver injury. Systemic and targeted liver-specific delivery of s- EH inhibitors (t-TUCB and TPPU), and WT and Ephx2 -/- mice (global and liver-specific) will be used in multiple animal models of ALD, which produce different stages of disease severity and which recapitulate different features of human ALD. This allows for a rigorous evaluation of the effects of s-EH inhibition at different stages of ALD severity. Treatment and prevention paradigms will be applied. Aim 2. To explore mechanism(s) underlying the beneficial effects of s-EH inhibition in experimental ALD. We will determine whether Ep-FA stabilization mediated by s-EH inhibition plays a critical role in attenuation of EtOH-induced liver injury. We will test whether n3 vs n6 Ep-FAs exert a greater beneficial effect by enhancing M2 macrophage polarization, increasing a pro-restorative/pro-resolving macrophage phenotype, and by Ep-FAs-PPARγ-CXCL1-mediated reduction of neutrophil infiltration. s-EH inhibitors, WT, transgenic fat-1 mice (which endogenously convert n6 PUFAs to n3 PUFAs), and hepatocyte-specific Pparγ-/- mice will be used. In vivo and in vitro studies will be performed. Aim 3. To evaluate EtOH-induced alterations in s-EH and Ep-FAs in human ALD. Utilizing de- identified human plasma and whole blood samples, we will: i) evaluate alterations in plasma Ep-FAs and establish relationships between biomarkers of liver injury and systemic inflammation in patients with alcohol- associated hepatitis (AH); ii) determine the effects of n3-PUFA dietary supplementation on plasma Ep-FAs in heavy drinking individuals; and iii) test whether s-EH inhibition and Ep-FAs (including both n3 and n6 Ep-FAs) can effectively decrease basal and LPS-stimulated pro-inflammatory cytokine production in whole blood and peripheral blood monocytes obtained from AH patients.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).