Inflammation Resolving Lipid Mediators: Novel Therapy for Alcohol AssociatedLiver Disease

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Alcohol-associated liver disease (ALD) is a major health problem in the US (especially in the Veteran population) and alcohol abuse/ALD has increased dramatically during the COVID pandemic. In spite of the magnitude of this problem, there is no FDA-approved therapy for any stage of ALD. In addition, the mechanisms and regulators of disease progression and severity are incompletely understood. Dietary fats play an important interactive role with alcohol consumption in ALD pathogenesis, however, the role of specific n3 polyunsaturated fatty acids (PUFAs) in ALD are not well defined. Our central hypothesis is that n3 PUFAs are beneficial in ALD, in part, via n3-PUFA-derived pro-resolving mediators, which facilitate inflammation resolution, improvement in the gut-liver axis, and subsequent attenuation of liver injury. We propose that n3 PUFA- derived resolvin D1 (RvD1) is a potential therapeutic agent in ALD acting via RvD1-FPR2-NEAT1 signaling to suppress pro-inflammatory cytokines and to promote repair of hepatocellular damage, in part, via enhancement of pro-restorative macrophages. We postulate that compromised inflammation resolution due to impaired RvD1 production/signaling is a critical nutritional factor contributing to the progression and severity of ALD/alcohol- associated hepatitis (AH) in humans. The Specific Aims of the proposal are: Aim 1: determine the role and molecular mechanism(s) underlying n3 PUFA and RvD1 beneficial effects in EtOH-induced liver injury and resolution of inflammation associated with ALD. We will determine whether beneficial effects occur through an increase in n3-PUFA-derived specialized pro-resolving mediators (SPMs), and RvD1-FPR2 and Neat1-mediated suppression of pro-inflammatory cytokine signaling and reprogramming pro-inflammatory macrophages to a pro- restorative phenotype. Wild Type (WT), Fpr2-/-, Neat1-/-, and transgenic fat-1 mice (which are able to endogenously convert n6 to n3 PUFAs) will be used in this Aim. Aim 2: examine the role n3-PUFAs and RvD1 in maintaining gut barrier integrity, and in the resolution of intestinal inflammation in experimental ALD. We will: i) test in vivo, in animal models, and in vitro, in intestinal organoid culture, whether n3 PUFAs or RvD1 improve intestinal barrier damage by attenuating intestinal immune dysregulation; ii) test in vivo whether disruption of the RvD1-FPR2 axis exacerbates, while blocking Neat1 signaling attenuates, intestinal inflammation and alterations in the gut barrier integrity; and iii) determine the contribution of the gut microbiota to the beneficial effects of n3 PUFAs and RvD1 in experimental ALD. Aim 3: translate and extend our findings in animal models to human ALD. Utilizing human samples obtained from Veteran AH patients, we will: i) examine plasma SPM levels and correlate plasma SPM levels with markers of liver injury, systemic inflammation, and intestinal permeability; ii) evaluate basal and LPS-inducible SPM production in whole blood (ex-vivo system) and blood monocytes; and iii) test whether RvD1 improves the phagocytosis/efferocytosis capacity of blood monocytes, and determine if disruption of the RvD1-FPR2 axis will enhance, while silencing of NEAT1 will decrease, pro-inflammatory cytokine expression in human monocytes. These three aims will define both untested novel mechanisms for ALD initiation/progression as well as potential novel therapy that could be rapidly initiated for Veterans with ALD.