Docosahexaenoic acid (DHA) blunts liver injury by conversion to protective lipid mediators: protectin D1 and 17S‐hydroxy‐DHA

Abstract

Docosahexaenoic acid (DHA) is a omega-3 essential fatty acid that reduces the incidence and severity of a number of diseases. Recently, a novel series of DHA-derived lipid mediators with potent protective actions has been identified. In this study we demonstrate that dietary amplification of these DHA-derived products protects the liver from necroinflammatory injury. In vitro, supplementation of hepatocytes with DHA significantly reduced hydrogen peroxide-induced DNA damage, evaluated by the "comet assay," and oxidative stress, determined by measurement of malondialdehyde levels. In vivo, dietary supplementation of mice with DHA ameliorated carbon tetrachloride-induced necroinflammatory damage. In addition, hepatic cyclooxygenase-2 expression and PGE2 levels were significantly reduced in mice fed DHA-enriched diets. In these animals, increased hepatic formation of DHA-derived lipid mediators (i.e., 17S-hydroxy-DHA (17S-HDHA) and protectin D1) was detected by HPLC-gas chromatography/mass spectrometry analysis. Consistent with these findings, synthetic 17-HDHA abrogated genotoxic and oxidative damage in hepatocytes and decreased TNF-alpha release and 5-lipoxygenase expression in macrophages. In a transactivation assay, 17-HDHA acted in a concentration-dependent manner as a PPARgamma agonist. Taken together, these findings identify a potential role for DHA-derived products, specifically 17S-HDHA and protectin D1, in mediating the protective effects of dietary DHA in necroinflammatory liver injury.

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

“…Metabolic syndrome is linked to inflammatory changes in both WAT and liver [1]. In this study, in accordance with the previous findings [17,18,21], dietary LC n-3 PUFA supplementation resulted in the inhibition of formation of various LC n-6 PUFA-derived pro-inflammatory eicosanoids in both tissues as well as in the induction of the antiinflammatory molecules. In WAT, in contrast to the liver, the levels of EPA, DHA, AA and their active metabolites, including the anti-inflammatory molecules PD1 and prostaglandin 15d-PGJ 2, were increased in a synergistic manner by the combination treatment (Fig.…”

“…They can act as ligands for surface receptors or can interact with signalling proteins including the transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and nuclear factor κ light-chain enhancer of activated B cells (NF-κB) [19]. Notably, resolvins and protectins mediate the antiinflammatory and protective actions of LC n-3 PUFA in obesity-induced insulin resistance and hepatic steatosis [17,21]. As LC n-3 PUFA and LC n-6 PUFA compete for common enzymatic pathways, a relatively small increase in the LC n-3 PUFA intake usually slows down synthesis of pro-inflammatory metabolites derived from arachidonic acid (AA; 20:4 n-6) [17,18].…”

Effects of Docosahexaenoic Acid in an Experimental Rat Model of Nonalcoholic Steatohepatitis

“…Indeed, these n-3 PUFA-derived lipid mediators showed potent protective actions in an experimental brain ischemic reperfusion model and in obesity-induced insulin resistance and steatosis [22][23][24][25][26] . Of particular interest is resolvin E1, a representative member of these novel lipid autacoids.…”

Role of bioactive lipid mediators in obese adipose tissue inflammation and endocrine dysfunction

“…Indeed, hepatocytes from transgenic fat-1 mice, which have increased levels of resolvins, and wild-type hepatocytes incubated with nanomolar concentrations of RvD1, show a reduction in neutral lipid accumulation (steatosis) as well as inflammation (Lopez-Vicario et al, 2015b, 2014. In addition, PD1 and 17S-HDHA are able to attenuate DNA damage and oxidative stress in hepatocytes and reduce TNFa release in macrophages (Gonzalez-Periz et al, 2006), whereas LXA 4 and AT-LXA 4 efficiently block IL-8 secretion by hepatocytes (Planaguma et al, 2002). Moreover, in precision-cut liver slices, an ex vivo model that overrides the influence of extrahepatic circulating factors, Rius and collaborators have demonstrated that RvD1 reduces hypoxia-induced mRNA and protein expression for inflammatory genes including COX-2, IL1b, IL-6 and CCR7 .…”