10-Oxo-trans-11-octadecenoic acid generated from linoleic acid by a gut lactic acid bacterium Lactobacillus plantarum is cytoprotective against oxidative stress.

Oxidative stress is a well-known cause of multiple diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway plays a central role in cellular antioxidative responses. In this study, we investigated the effects of novel fatty acid metabolite derivatives of linoleic acid generated by the gut lactic acid bacteria Lactobacillus plantarum on the Nrf2-ARE pathway. 10-Oxo-trans-11-octadecenoic acid (KetoC) protected HepG2 cells from cytotoxicity induced by hydrogen peroxide. KetoC also significantly increased cellular Nrf2 protein levels, ARE-dependent transcription, and the gene expression of antioxidative enzymes such as heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GCLM), and NAD(P)H: quinone oxidoreductase 1 (NQO1) in HepG2 cells. Additionally, a single oral dose administration of KetoC also increased antioxidative gene expression and protein levels of Nrf2 and HO-1 in mouse organs. Since other fatty acid metabolites and linoleic acid did not affect cellular antioxidative responses, the cytoprotective effect of KetoC may be because of its α,ß-unsaturated carbonyl moiety. Collectively, our data suggested that KetoC activated the Nrf2-ARE pathway to enhance cellular antioxidative responses in vitro and in vivo, which further suggests that KetoC may prevent multiple diseases induced by oxidative stress.

Dietary Effects of Oxidized Eicosapentaenoic Acid (EPA) and Intact EPA on Hepatic Steatosis Induced by a High-sucrose Diet and Liver-X-receptor α Agonist in Mice.

Numerous studies have shown that dietary omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA), improve lipid metabolism. The beneficial effects of PUFA-derived oxidation products have been increasingly reported. However, EPA is easily oxidized in food products and in the human body, generating various derivatives of oxidized EPA (oxEPA), such that these oxidation products may partially contribute to EPA's effect. We previously reported that oxEPA was more potent than intact EPA in reducing liver-X-receptor α (LXRα)-induced cellular triacylglycerol (TG) accumulation. However, the in vivo hypolipidemic effects of oxEPA remain unclear. In the present study, we evaluated the effect of oral administration of EPA and oxEPA on hepatic steatosis in mice induced by a high-sucrose diet and a synthetic LXRα agonist, TO-901317. Both EPA and oxEPA reduced TG accumulation in the liver and plasma biomarkers of liver injury. Furthermore, they suppressed the expression of lipogenic genes, but not ß-oxidation genes, in a similar pattern as the biomarkers. Our results suggest that oxEPA and intact EPA suppress de novo lipogenesis to ameliorate hepatic steatosis.

Gut Microbial Fatty Acid Metabolites Reduce Triacylglycerol Levels in Hepatocytes.

Hydroxy and oxo fatty acids were recently found to be produced as intermediates during gut microbial fatty acid metabolism. Lactobacillus plantarum produces these fatty acids from unsaturated fatty acids such as linoleic acid. In this study, we investigated the effects of these gut microbial fatty acid metabolites on the lipogenesis in liver cells. We screened their effect on sterol regulatory element binding protein-1c (SREBP-1c) expression in HepG2 cells treated with a synthetic liver X receptor α (LXRα) agonist (T0901317). The results showed that 10-hydroxy-12(Z)-octadecenoic acid (18:1) (HYA), 10-hydroxy-6(Z),12(Z)-octadecadienoic acid (18:2) (γHYA), 10-oxo-12(Z)-18:1 (KetoA), and 10-oxo-6(Z),12(Z)-18:2 (γKetoA) significantly decreased SREBP-1c mRNA expression induced by T0901317. These fatty acids also downregulated the mRNA expression of lipogenic genes by suppressing LXRα activity and inhibiting SREBP-1 maturation. Oral administration of KetoA, which effectively reduced triacylglycerol accumulation and acetyl-CoA carboxylase 2 (ACC2) expression in HepG2 cells, for 2 weeks significantly decreased Srebp-1c, Scd-1, and Acc2 expression in the liver of mice fed a high-sucrose diet. Our findings suggest that the hypolipidemic effect of the fatty acid metabolites produced by L. plantarum can be exploited in the treatment of cardiovascular diseases or dyslipidemia.

Oxidized eicosapentaenoic acids more potently reduce LXRα-induced cellular triacylglycerol via suppression of SREBP-1c, PGC-1ß and GPA than its intact form.

Dietary polyunsaturated fatty acids (PUFA), especially eicosapentaenoic acid (EPA), improve lipid metabolism and contribute to the prevention of vascular diseases such as atherosclerosis. However, EPA in the diet is easily oxidized at room temperature and several types of oxidized EPA (OEPA) derivatives are generated. To compare the efficiencies of OEPAs on lipid metabolism with EPA, human hepatocellular liver carcinoma cell line (HepG2) was treated with EPA or OEPAs and their effects on lipid metabolism related genes were studied. OEPAs more potently suppressed the expression of sterol-responsive element-binding protein (SREBP)-1c, a major transcription factor that activates the expression of lipogenic genes, and its downstream target genes than did EPA under conditions of lipid synthesis enhanced by T0901317, a synthetic liver X receptor (LXR) agonist. Furthermore, PGC-1ß, a coactivator of both LXRα and SREBP-1, was markedly down-regulated by OEPAs compared with EPA. The treatment of OEPAs also significantly down-regulated the expression of glycerol-3-phosphate acyltransferase (GPA), the initiating enzyme in triacylglycerol (TG) synthesis, more than EPA. Therefore, the advantageous effects of OEPAs on cardiovascular diseases might be due to their SREBP-1c, PGC-1ß and GPA mediated ameliorating effects.