Hydroxyeicosapentaenoic acids and epoxyeicosatetraenoic acids attenuate early occurrence of nonalcoholic fatty liver disease

Abstract

The ω-3 polyunsaturated fatty acids (PUFAs) mediate protective effects on several metabolic disorders. However, the functions of their metabolites in the early stage of nonalcoholic fatty liver disease (NAFLD) are largely unknown. EXPERIMENTAL APPROACHMice were fed a control diet, high-fat diet (HFD) or ω-3 PUFA-enriched HFD (ω3HFD) for 4 days and phenotypes were analysed. LC-MS/MS was used to determine the eicosanoid profiles. Primary hepatocytes and peritoneal macrophages were used for the mechanism study. KEY RESULTSIn short-term HFD-fed mice, the significantly increased lipid accumulation in the liver was reversed by ω-3 PUFA supplementation. Metabolomics showed that the plasma concentrations of hydroxyeicosapentaenoic acids (HEPEs) and epoxyeicosatetraenoic acids (EEQs) were reduced by a short-term HFD and markedly increased by the ω3HFD. However, HEPE/EEQ treatment had no direct protective effect on hepatocytes. ω3HFD also significantly attenuated HFD-induced adipose tissue inflammation. Furthermore, the expression of pro-inflammatory cytokines and activation of the JNK pathway induced by palmitate were suppressed by HEPEs and EEQs in macrophages. 17,18-EEQ, 5-HEPE and 9-HEPE were identified as the effective components among these metabolites, as indicated by their greater suppression of the palmitate-induced expression of inflammatory factors, chemotaxis and JNK activation compared to other metabolites in macrophages. A mixture of 17,18-EEQ, 5-HEPE and 9-HEPE significantly ameliorated the short-term HFD-induced accumulation of macrophages in adipose tissue and hepatic steatosis. CONCLUSION AND IMPLICATIONS17,18-EEQ, 5-HEPE and 9-HEPE may be potential approaches to prevent NAFLD in the early stage by inhibiting the inflammatory response in adipose tissue macrophages via JNK signalling.

Ethanol and unsaturated dietary fat induce unique patterns of hepatic ω-6 and ω-3 PUFA oxylipins in a mouse model of alcoholic liver disease

“…5-HEPE (LOX product), which was increased in the USF+EtOH group vs . USF alone, is known to reduce the inflammatory response of macrophages [ 72 ]. The marked elevation of hepatic 18-HEPE (COX product) by EtOH in both SF and USF dietary groups is of particular interest because this EPA-derived metabolite is the precursor to the resolvins of the E-series (RvE), further suggesting that inflammation and resolution of inflammation in our experimental model of ALD are tightly connected processes.…”

Fatty Acids Consumption: The Role Metabolic Aspects Involved in Obesity and Its Associated Disorders

“…The quality of dietary fatty acids may have a role in the development of NAFLD, and conversely, may be an alternative source for decreasing deleterious NAFLD effects. Therefore, the composition of liver fatty acids may be involved in hepatic damage [ 122 , 123 ]. Dietary patterns are a combination of foods that are consumed by individuals and the amount of nutrients may produce synergistic health effects.…”

“…Therefore, the activation of pro-inflammatory cytokines, as well as the activation of the JNK pathway by palmitate in macrophages, decreased with a mixture of 17,18-EEQ, 5-HEPE, and 9-HEPE, which are identified as the efficient components of these metabolites, including HEPEs and EEQs. Herein, the results have demonstrated that the mixture (17,18-EEQ, 5-HEPE, and 9-HEPE) may be an alternative therapy to prevent the early stages of NAFLD by inhibiting adipose tissue macrophage infiltration and systemic inflammation via cJun-N-terminal-kinase (JNK) signaling [ 123 ].…”

Mediterranean Diet and Multi-Ingredient-Based Interventions for the Management of Non-Alcoholic Fatty Liver Disease

“…The beneficial effects of n- 3 PUFA on oxidative stress, inflammation, and TAG accumulation in the liver make them attractive candidates for NAFLD treatment. In another recent study, a targeted metabolomics approach was applied to determine the plasma and liver eicosanoid profiles in mice fed a control diet, high-fat diet (HFD) or n- 3 PUFA supplemented HFD (ω3-HFD) for 4 days [ 139 ]. The plasma concentrations of several hydroxyeicosapentaenoic acids (HEPEs) and epoxyeicosatetraenoic acids (EEQs) were reduced by a short-term HFD and were markedly increased by the ω3-HFD, suggesting a critical role of these metabolites in the protective effects of n- 3 PUFA on NAFLD.…”

“…Thus, a mixture of these three n- 3 PUFA metabolites was injected intraperitoneally into mice fed the control diet and HFD. The mixture significantly ameliorated short-term HFD-induced lipid accumulation in the liver and adipose tissue inflammation [ 139 ].…”