Hepatic Polyunsaturated Fatty Acids Research Articles

Coordinated alteration of hepatic gene expression in fatty acid and triglyceride synthesis in LCAT-null mice is associated with altered PUFA metabolism

Complete lecithin:cholesterol acyltransferase (LCAT) deficiency is associated with fasting hypertriglyceridemia (HTG). We recently reported that, in ldlr(-/-)xlcat(-/-) mice, fasting HTG is associated with hepatic triglyceride overproduction in association with an upregulation of the hepatic srebp1 gene and altered expression of its target genes in lipogenesis and gluconeogenesis. We further investigated the role of hepatic polyunsaturated fatty acid (PUFA) metabolism in the modulation of the lipid phenotypes. In the ldlr(-/-)xlcat(-/-) mice, using the ldlr(-/-)xlcat(+/+) littermate as controls, the hepatic level of cholesterol esters (CE) were reduced by 61.0% whereas the 20:4-CE and 22:6-CE contents were each reduced by >80%. In contrast, the hepatic levels of 20:4- and 22:6-containing phospholipid (PL) species were either unchanged or mildly elevated. Similar alterations of the hepatic PUFA in CE and in PL were also observed in the lcat(-/-) mice compared with their wild-type controls. In ldlr(-/-)xlcat(-/-) mice, hepatic mRNA level was markedly reduced for Delta-6 desaturase (fads2) (70.2%) and acyl-CoA:cholesterol acyltransferase-2 (soat2) (57.0%). A similar pattern of gene expression change was also observed in the lcat(-/-) single-knockout mice. In contrast, the acyl-CoA:diacylglycerol acyltransferase-2 (dgat2) mRNA level was 1.7-fold upregulated in the double-knockout mice. In summary, we observed coordinated alterations in hepatic expression of the gene for fads2, soat2, and dgat2, resulting in a reduction in total hepatic PUFA pool and differentially in the PUFA-CE pool, in association with an increase in dgat2 gene expression for promoting triglyceride synthesis and secretion. Some of the phenotypes are not readily explained by known mechanisms and may represent novel regulatory pathways.

Effect of dietary fat level and sesamin on the polyunsaturated fatty acid metabolism in rats.

In this study, we examined the effects of sesamin and vegetable oil on the concentrations of polyunsaturated fatty acid (PUFA) and lipids (triacylglycerol, free cholesterol, and phospholipid), and beta-oxidation enzyme activities in the rat liver. Rats were fed a diet containing 5% (low-fat diet) or 20% (high-fat diet) salad oil (rapeseed oil: soybean oil, 7:3) with or without sesamin (0.5% w/w) for 4 wk. As a result, the concentrations of linoleic acid (LA, n-6), alpha-linolenic acid (ALA, n-3), and total PUFA in the liver increased significantly as the result of the high-fat diet. In the high-fat diet groups, sesamin administration decreased the concentrations of LA, ALA, and total PUFA to almost the same level as the low-fat diet group, while it increased the concentrations of dihomo-gamma-linolenic acid (DGLA, n-6) and arachidonic acid (AA, n-6). The activities of carnitine acyltransferase and acyl-CoA dehydrogenase in liver mitochondria were enhanced by the intake of the high-fat diet, and were further enhanced by the administration of sesamin. Peroxisomal acyl-CoA oxidase activity was also enhanced by sesamin, while it was not affected by the dietary fat level. These results suggest that sesamin suppressed the increase of hepatic PUFA concentration caused by feeding the high-fat diet through enhancing the enzyme activities of fatty acid beta-oxidation and PUFA metabolism from LA and ALA.

The metabolism and n-6/n-3 ratio of essential fatty acids in rats: effect of dietary arachidonic acid and a mixture of sesame lignans (sesamin and episesamin).

In this study, we examined the effect of dietary arachidonic acid (AA) and sesame lignans on the content and n-6/n-3 ratio of polyunsaturated fatty acid (PUFA) in rat liver and the concentrations of triglyceride (TG) and ketone bodies in serum. For 4 wk, rats were fed two types of dietary oils: (i) the control oil diet groups (CO and COS): soybean oil/perilla oil = 5:1, and (ii) the AA-rich oil group (AO and AOS): AA ethyl esters/palm oil/perilla oil = 2:2:1, with (COS and AOS) or without (CO and AO) 0.5% (w/w) of sesame lignans. Dietary AA and sesame lignans significantly affected hepatic PUFA metabolism. AA content and n-6/n-3 ratio in the liver were significantly increased in the AO group, despite the dietary total of n-6 PUFA being the same in all groups, while AOS diet reduced AA content and n-6/n-3 ratio to a level similar to the CO and COS groups. These results suggest that (i) dietary AA considerably affects the hepatic profile and n-6/n-3 ratio of PUFA, and (ii) dietary sesame lignans reduce AA content and n-6/n-3 ratio in the liver. In the AO group, the concentration of acetoacetate was significantly increased, but the ratio of beta-hydroxybutyrate/acetoacetate was decreased. On the other hand, the AO diet increased the concentration of TG in serum by almost twofold as compared to other groups. However, the AOS diet significantly reduced serum TG level as compared to the AO group. In addition, the AOS diet significantly increased the acetoacetate level, but reduced the beta-hydroxybutyrate/acetoacetate ratio. These results suggest that dietary sesame lignans promote ketogenesis and reduce PUFA esterification into TG. This study resulted in two findings: (i) sesame lignans inhibited extreme changes of the n-6/n-3 ratio by reducing hepatic PUFA content, and (ii) the reduction of hepatic PUFA content may have occurred because of the effects of sesame lignans on PUFA degradation (oxidation) and esterification.

Muscle and hepatic fatty acid profiles and α-tocopherol status in African catfish (Clarias gariepinus) given diets varying in oxidative state and vitamin E inclusion level

AbstractOn termination of a 56-day feeding trial, the effect of dietary oxidized oil and all-rac-α-tocopheryl acetate on fatty acid and α-tocopherol status of juvenile African catfish (Clarias gariepinusj muscle and liver was investigated. Clarias of mean initial weight 15·8 (s.e. 0·29) g were given food at -proportionately 0·03 body weight per day on diets of two oxidative states (fresh or oxidized) at two levels of supplemental α-tocopheryl acetate (20 or 100 mg/kg dry matter).As well as having a significant detrimental effect on final body weight (P < 0·001), oxidation of the dietary lipid source was responsible for decreasing muscle but not hepatic polyunsaturated fatty acids (PUTAs). Liver tissue was suspected of actively synthesizing longer chain PUT As in response to consumption of oxidized oils, as indicated by decreases in the proportions of linoleate (18:2 n-6) and linolenate (18:3 n-3) and the increased abundance of eicosatetraenoic acid (20:4 n-6, arachidonate) and docosahexaenoic acid (22: 6 n-3, DHA). This phenomenon has not been described in fish nutrition and therefore possible mechanisms are discussed. Additionally, oxidized oils in catfish diets caused significant depletion of a-tocopherol from both muscle and liver (P < 0·05).Modulation of the effects of oxidized lipids was achieved at the higher dietary tocopherol concentration. Appearance of an unknown aliphatic compound (equivalent chain length (ECL) = 13·1), believed to be a product of lipid peroxidation, demonstrated that catfish given rancid/low-tocopherol diets had been subjected to heightened oxidative nutritional stress. Values obtained for this peak were significantly correlated with dietary regime (P < 0·02), Once more, dietary α-tocopheryl acetate moderated this effect. It was concluded that elevated inclusion of all-rac-α-tocopheryl acetate into diets for African catfish could abrogate the effects of oxidized dietary lipids on muscle and liver fatty acids and α-tocopherol.

Influence of dietary n-3 fatty acids on the biosynthesis of polyunsaturated fatty acids in STZ-diabetic rats

Experimental diabetes in rats produces a generalized defect in liver microsomal polydesaturase activity and hence in the total fatty-acid composition. The present study was devised to determine whether or not those enzymic defects in the diabetic animal might be offset by alterations in the profile of fatty acids consumed in the diet. Accordingly, streptozotocin-induced diabetic rats were fed nutritionally adequate basal diets for 2 weeks supplemented with equivalent amounts of free fatty acids from either corn oil, rich in n-6 species, or cod-liver oil, abundant in n-3 acids. Both classes of dietary polyunsaturates were incorporated into hepatic microsomes and caused elevations in the respective levels of those acids in cellular membranes. The unsaturation indices, however, were higher under the latter regime than under the former. Dietary supplementation with the n-3, but not the n-6, fatty acids increased plasma glucose levels in both control and diabetic rats. Neither regime, however, affected microsomal desaturase or fatty acyl-CoA synthetase activity in either experimental group. Therefore, we conclude that the deficiency in hepatic-desaturase activity accompanying diabetes occurs independently of the nature of the fatty acids present in the hepatic membranes. An enhanced dietary intake of n-3 fatty acids thus fails to alleviate the depression in the enzymes involved in hepatic polyunsaturated fatty acid biosynthesis in diabetic rats.

N-3 fatty acids inhibit defects and fatty acid changes caused by phenytoin in early gestation in mice.

Our previous work has shown that n-3 fatty acids exert a protective effect against phenytoin-induced cleft palate when phenytoin was administered midgestation [gestational days (GD) 12 and 13] to CD-1 mice. The effects of dietary n-3 fatty acids on phenytoin teratogenicity were investigated at an earlier gestational period (GD 9) to examine whether n-3 fatty acids could exert protective action against other teratogenic effects of phenytoin apart from cleft palate. The effect of phenytoin exposure on maternal hepatic polyunsaturated fatty acid composition was also studied since delta 6 desaturase activity has been shown to be modified by pharmacological action. Female CD-1 mice were fed a standard laboratory diet (SLD), safflower oil (SAFF) or a cod liver/linseed oil (CLO/LO)-based diet for three weeks prior to impregnation and throughout pregnancy. Pregnant mice were administered a single i.p. dose of phenytoin on GD 9, and teratological assessments were performed on GD 19. Tissues were harvested on GD 10 for maternal hepatic phospholipid fatty acid analysis from another group of phenytoin-treated mice. The CLO/LO and the SLD mice, as compared to the SAFF-fed animals, showed a reduction in total malformations and fetal growth retardation due to phenytoin. Open eye defect was the only anomaly induced by phenytoin in the CLO/LO fetuses while phenytoin produced a variety of malformations in the SAFF fetuses such as tail defects, cleft palate, open eye and absence or blockage of the ureter.(ABSTRACT TRUNCATED AT 250 WORDS)