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Background The transcription factor nuclear factor-E2-related factor-2 (Nrf2) inhibits lipid accumulation and oxidative stress in the liver by interfering with lipogenic pathways and inducing antioxidative stress genes. Methods The involvement of Nrf2 in defense against the development of steatohepatitis was studied in an experimental model induced by an atherogenic plus high-fat (Ath + HF) diet. Wild-type (WT) and Nrf2 -null mice were fed the diet. Their specimens were analyzed for pathology as well as for the expression levels of genes involved in fatty acid metabolism and those involved via the Nrf2 transcriptional pathway. Results In Nrf2 -null mice fed the diet, steatohepatitis developed rapidly, leading to precirrhosis. The Ath + HF diet increased hepatic triglyceride levels and changed fatty acid composition in both mouse groups. However, oleic acid (C18:1 n-9) predominated in the livers of Nrf2 -null mice. Correlating well with the pathology, the mRNA levels of the factors involved in fatty acid metabolism ( Lxr , Srebp - 1a , 1c , Acc - 1 , Fas , Scd - 1 , and Fatty acid transporting peptides 1 , 3 , 4 ), the inflammatory cytokine genes ( Tnf - α and IL - 1β ), and the fibrogenesis-related genes ( Tgf - β1 and α - Sma ) were significantly increased in the livers of Nrf2 -null mice fed the diet, compared with the levels of these factors in matched WT mice. Oxidative stress was significantly increased in the livers of Nrf2 -null mice fed the diet. This change was closely associated with the decreased levels of antioxidative stress genes. Conclusions Nrf2 deletion leads to the rapid onset and progression of steatohepatitis induced by an Ath + HF diet, through both up-regulation of co-regulators of fatty acid metabolism and down-regulation of oxidative metabolism regulators in the liver.

Marine-derived tocopherol (MDT), which is typically found in marine organisms that inhabit cold water, is a monounsaturated tocol having vitamin E (VE) activity. To evaluate the functionality of this minor VE homolog, we have studied the influence of MDT on adipocyte differentiation and the production of inflammatory factors in mouse cell line 3T3-L1 adipocytes and mouse monocyte/macrophage cell line RAW264.7 cells. Treatment of 3T3-L1 adipocytes with 10 and 20 μM MDT during differentiation enhanced lipid accumulation and concurrently upregulated peroxisome proliferator activated receptor gamma and CCAAT/enhancer-binding protein expression. Compared to the control adipocytes, MDT treatment also increased the secretion and gene expression of adiponectin, while it decreased the secretion and gene expression of interleukin 6 (IL-6) and monocyte chemoattractant protein-1. Treatment with MDT resulted in higher adipogenesis activity and higher regulation of inflammatory factors than did treatment with α- and γ-tocopherol, the predominant homologous series of VE. MDT-treated RAW264.7 cells showed significantly decreased lipopolysaccharide-induced IL-6 and tumor necrosis factor alpha secretion compared to the control RAW264.7 cells. These results suggest that MDT could have a potential role for preventing obesity-related inflammation progressing to metabolic disorders.

After the incidents, the Ministry of Health and Welfare, currently the Ministry of Health, Labor and Welfare, in Japan set standards for instant noodles in the Food Sanitation Law to protect against food poisoning and to control the quality of instant noodles. Therefore, the formation of hydroperoxide, the primary oxidized product of fat and oil, must be suppressed to protect against the oxidation of fat and oil and the formation of secondary oxidized products from both food quality and food safety perspectives.

Postprandial hypertriglyceridemia is a potential target for cardiovascular disease prevention in patients with diabetic dyslipidemia. Metformin has been reported to reduce plasma triglyceride concentrations in the postprandial states. However, little is known about the mechanisms underlying the triglyceride-lowering effect of metformin. Here, we examined the effects of metformin on lipid metabolism after olive oil-loading in 129S mice fed a high fat diet for three weeks. Metformin administration (250 mg/kg) for one week decreased postprandial plasma triglycerides. Pre-administration (250 mg/kg) of metformin resulted in a stronger triglyceride-lowering effect (approximately 45% lower area under the curve) than post-administration. A single administration (250 mg/kg) of metformin lowered plasma postprandial triglycerides comparably to administration for one week, suggesting an acute effect of metformin on postprandial hypertriglyceridemia. To explore whole body lipid metabolism after fat-loading, stomach size, fat absorption in the intestine, and fat oxidation (13C/12C ratio in expired CO2 after administration of glyceryl-1-13C tripalmitate) were measured with and without metformin (250 mg/kg) pre-treatment. In metformin-treated mice, larger stomach size, lower fat oxidation, and no change in lipid absorption were observed. In conclusion, metformin administration before fat loading reduced postprandial hypertriglyceridemia, most likely by delaying gastric emptying.

Oxidative stress (OS) contributes to nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. We investigated whether antioxidative self-assembling nanoparticles (SMAPoTN) could reduce the development of NASH and hepatocellular carcinoma (HCC) in p62/Sqstm1 and Nrf2 double knockout (DKO) mice and studied protective mechanisms. We measured disease development in male DKO mice fed a normal chow (NASH model) or a 60% high-fat diet (HFD; HCC model) with or without SMAPoTN administration for 26 weeks. SMAPoTN inhibited liver fibrosis in both groups and prevented HCC development (0% vs. 33%, p < 0.05) in the HFD group. SMAPoTN reduced OS, inflammatory cytokine signaling, and liver fibrosis. RNA-sequencing revealed that SMAPoTN decreased endoplasmic reticulum stress signaling genes in both groups, HCC driver genes, and cancer pathway genes, especially PI3K-AKT in the HFD groups. In the SMAPoTN treatment HFD group, serum lipopolysaccharide levels and liver lipopolysaccharide-binding protein expression were significantly lower compared with those in the nontreatment group. SMAPoTN improved the α-diversity of gut microbiota, and changed the microbiota composition. Oral SMAPoTN administration attenuated NASH development and suppressed hepatocarcinogenesis in DKO mice by improving endoplasmic reticulum stress in the liver and intestinal microbiota. SMAPoTN may be a new therapeutic option for NASH subjects and those with a high HCC risk.

The liver oils of six shallow-water shark species, silky (Carcharhinus falciformis), thresher (Alopias superciliosus), oceanic whitetip (Carcharhinus longimanus), blue (Prionace glauca), hammerhead (Sphyrna lewini) and salmon (Lamna ditropis) were analyzed with particular attention to the regioisomeric composition of triacylglycerols (TAG). The TAG compositions were analyzed by using an HPLC-evaporative light scattering detector and each molecular species identified by HPLC-atmospheric pressure chemical ionization/mass spectrometry. Major lipid components of all sharks’ oils were TAG (~80 %) made up of omega-3 polyunsaturated fatty acids at 26–40 % and 20–25 % docosahexaenoic acid (DHA). Forty different molecular species were detected in the TAG fractions. TAG consisting of one palmitic acid, one DHA and one oleic acid (12.5–19.9 %) and TAG consisting of two palmitic acids and one DHA (8.4–15.4 %) were the predominant form while 30–50 % TAG molecular species were bound to one or more DHA. Distribution of fatty acids in the primary (sn-1 and sn-3) and secondary (sn-2) position of the glycerol backbones was examined by regiospecific analysis by using pancreatic lipase and it was found that DHA was preferentially positioned at sn-2. These findings greatly extend the utilization of shark liver oils in food productions and may have a significant impact on the future development of the fish oil industry.

The biologic availability of two kinds of tocomonoenols, marine-derived tocopherol (MDT) and α-tocomonoenol, was investigated in ICR mice. Vitamin E-deficient ICR mice were fed MDT and α-tocomonoenol together with α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, and storage in liver, spleen, lung, and brain was quantified using reverse-phase high-performance liquid chromatography. The vitamin E relative biologic availability (VE-RBA) in liver was 100 for α-tocopherol, 26 ± 3 for β-tocopherol, 4 ± 2 for γ-tocopherol, not detected for δ-tocopherol, 49 ± 6 for MDT, and 30 ± 7 for α-tocomonoenol. The VE-RBA in brain was 100 for α-tocopherol, 5 ± 2 for β-tocopherol, not detected for γ-tocopherol and δ-tocopherol, 8 ± 1 for MDT, and 4 ± 1 for α-tocomonoenol. Tocopherols and tocomonoenols did not accumulate in the spleen or lung. MDT and α-tocomonoenol had high VE-RBA values. The VE-RBA value for MDT was much higher than that for β-tocopherol.

Most tumours have an aberrantly activated lipid metabolism 1 , 2 that enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive to approaches that target fatty acid metabolism and, in particular, fatty acid desaturation 3 . This suggests that many cancer cells contain an unexplored plasticity in their fatty acid metabolism. Here we show that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, mouse hepatocellular carcinomas, and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known fatty acid desaturation pathway that is dependent on stearoyl-CoA desaturase. Thus, only by targeting both desaturation pathways is the in vitro and in vivo proliferation of cancer cells that synthesize sapienate impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers. In several human and mouse cancer cell lines and carcinomas, a sapienate biosynthesis pathway underpins metabolic plasticity by allowing these cells to bypass stearoyl-CoA desaturase-dependent fatty acid desaturation.

Palm oil and lard are edible fats which are rich in palmitic (P) and oleic acids (O). In this study, triacylglycerol (TAG) positional isomers (symmetric and asymmetric isomers) and enantiomers (asymmetric isomers) in palm oil and lard were quantified simultaneously by using liquid chromatography/mass spectrometry. The CHIRALPAK IF-3 column used in our previous study recognized the difference of TAG isomers consisting of P and O in palm oil and lard, separated sn-OPP/sn-PPO/sn-POP and sn-OPO/sn-OOP/sn-POO into each isomer peak, and enabled the quantification of these TAG isomers with good recovery (95–120%). Although sn-POP and sn-OPO were the major TAGs in palm oil and lard, a comparison of the abundance ratios of TAG enantiomers such as sn-PPO/sn-OPP and sn-OOP/sn-POO revealed that there were slightly more TAG enantiomers with O at the sn-1 position and P at the sn-3 position in palm oil and P at the sn-1 position and O at the sn-3 position in lard. These results were consistent with previous reports for the positional distribution of fatty acids of palm oil and lard. This is the first study that has enabled all TAG isomers consisting of P and O in natural oils and fats to be individually quantified by mass spectrometry.