resolvin-d1 and Hepatitis

High-fat diet (HFD)-fed mice show obesity with development of liver steatosis and a proinflammatory state without establishing an inflammatory reaction. The aim of this work was to assess the hypothesis that eicosapentaenoic acid (EPA) plus hydroxytyrosol (HT) supplementation prevents the inflammatory reaction through enhancement in the hepatic resolvin content in HFD-fed mice. Male C57BL/6J mice were fed an HFD or a control diet and supplemented with EPA (50 mg/kg/day) and HT (5 mg/kg/day) or their respective vehicles for 12 weeks. Measurements include liver levels of EPA, DHA and palmitate (gas chromatography), liver resolvins and triglyceride (TG) and serum aspartate transaminase (AST) (specific kits) and hepatic and serum inflammatory markers (quantitative polymerase chain reaction and enzyme-linked immunosorbent assay). Compared to CD, HFD induced body weight gain, liver steatosis and TG accumulation, with up-regulation of proinflammatory markers in the absence of histological inflammation or serum AST changes; these results were accompanied by higher hepatic levels of resolvins RvE1, RvE2, RvD1 and RvD2, with decreases in EPA and DHA contents. EPA+HT supplementation in HFD feeding synergistically reduced the steatosis score over individual treatments and increased the hepatic levels of EPA, DHA and resolvins, with attenuation of proinflammatory markers. Lack of progression of HFD-induced proinflammatory state into overt inflammation is associated with resolvin up-regulation, which is further increased by EPA+HT supplementation eliciting steatosis attenuation. These findings point to the importance of combined protocols in hepatoprotection due to the involvement of cross-talk mechanisms, which increase effectiveness and diminish dosages, avoiding undesirable effects.

Topics: Animals; Diet, High-Fat; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids; Hepatitis; Liver; Male; Mice, Inbred C57BL; NF-kappa B; Phenylethyl Alcohol

Resolvins, an endogenous lipid mediator derived from eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) of fish oil, has been reported to have anti-inflammatory and antitumor effect in various pathogenic processes. However, there are no studies about the effects of resolvin D1 and E1 on concanavalin A-induced hepatitis. Hence, the present study is to illustrate whether resolvin D1 and E1 inhibit concanavalin A-induced liver injury, liver cancer and underlying mechanisms by which they may recover. C57BL/6 mice were pretreated with resolvin D1 and E1 for 4 h, and then injected with concanavalin A for 12 h. Subsequently, blood and liver tissue were collected at 0, 2, 4, 8 and 12 h for different analysis. Analysis of inflammatory cytokines indicated that the inhibition of necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-1β and IL-6 could be performed by resolvin D1 and E1. Moreover, Toll-like receptor (TLR) 4 expression, NF-κB and AP-1 activity also have been confirmed to have key roles in the development of liver injury. They were significantly suppressed in the treatment group, compared to model. In addition, resolvin D1 and E1 markedly downregulated CD4+ and CD8+ cell infiltration in the liver. A long-term concanavalin A treatment for 32 weeks was performed to analyze the changes of hepatitis to liver cancer and the antitumor effect of resolving D1 and E1. These results indicated that resolvin D1 and E1 prevent concanavalin A-induced liver injury and the changes of hepatitis to liver cancer in mice through inhibition of inflammatory cytokine secretion and NF-κB/AP-1 activity. Thus, they could be novel target to be considered in the process of finding sufficient drug to protect against various forms of hepatitis and liver cancer.

Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Concanavalin A; Cytokines; Docosahexaenoic Acids; Eicosapentaenoic Acid; Gene Expression Regulation, Neoplastic; Hepatitis; Liver Neoplasms, Experimental; Male; Mice