Role of n3 PUFAs and inflammation-resolving lipid mediator, RvD1, in alcoholic liver disease

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Alcoholic liver disease (ALD) is a major and increasing health problem in the US (especially in Kentucky) and worldwide. 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 the disease progression and severity are not well understood. Dietary fats play an important interactive role with alcohol consumption in ALD pathogenesis, however, the role of n3 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 resolvin D1 (RvD1) is a potent therapeutic agent in severe 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 one of the critical nutritional contributing factors to the progressive ALD and severity of alcoholic hepatitis (AH) in humans. The Specific Aims of the proposal are: Aim 1. To test whether n3 PUFAs exert beneficial effects on EtOH- associated liver injury/inflammation by enhancing the effectiveness of inflammation resolution and by repair of hepatocellular damage through increase in n3-PUFA-derived specialized pro-resolving mediators promoting (SPMs), and RvD1-FPR2 and Neat1-mediated suppression of pro-inflammatory cytokine signaling and reprogramming pro-inflammatory macrophages into 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. We will also examine the therapeutic effectiveness of RvD1 utilizing a novel nanoparticle technology of targeted RvD1 delivery examine the role n3-PUFAs to the liver with plant-derived edible exosomes. Aim 2. To 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 PUFA 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; iii) test a novel therapeutic strategy of administering an engineered bacteria strain to convert n6 to n3 PUFAs in the intestine and thus to attenuate gut barrier dysfunction in mice. In Aim 3, we seek to translate and extend our findings in animal models to human ALD. Utilizing de-identified human samples we will: i) determine effects of n3-PUFA dietary supplementation on plasma SPM levels, markers of liver injury, systemic inflammation, and intestinal permeability in heavy drinking individuals; ii) examine plasma SPM levels, and SPM synthesis in whole blood and peripheral blood monocytes (PBMCs) obtained from AH patients; and iii) test whether RvD1 improves phagocytosis/efferocytosis of PBMCs obtained from AH patients.