n-3多不饱和脂肪酸和肾脏疾病

慢性肾脏疾病（CKD）已成为一个威胁公众健康的重要问题，如不及早预防与干预，将导致进行性肾脏纤维化和肾功能减退，直至进入终末期肾衰竭，而不得不依赖透析或肾移植生存。原发病的类型是决定肾功能减退速度的重要因素，除此之外，目前的研究显示许多心血管疾病的危险因素如高血压、糖尿病、吸烟和脂质代谢紊乱等亦能影响CKD的进展。鱼油中的主要成分n-3多不饱和脂肪酸（n-3PUFA）被证实具有心血管保护作用，饮食富含n-3PUFA的爱斯基摩人和日本人群中动脉粥样硬化引起的死亡比例较其他人群明显降低。CKD的病理生理学特征与动脉粥样硬化有许多相似之处，近来一些研究提示n-3PUFA对于肾脏疾病亦有益处，我们就此作一综述。     

Modulation of human hepatocyte acute phase protein production in vitro by n-3 and n-6 polyunsaturated fatty acids.

OBJECTIVE: The authors investigate the role of a variety of essential polyunsaturated fatty acids on the spontaneous and interleukin-6 stimulated production of acute phase proteins by isolated human hepatocytes. SUMMARY BACKGROUND DATA: The altered production of acute phase proteins by the liver is one of the principal effects of the systemic inflammatory response in human disease. It has been shown that polyunsaturated fatty acids have certain anti-inflammatory properties that potentially are mediated through altered prostaglandin or proinflammatory cytokine production. However, the effect of polyunsaturated fatty acids on the responsiveness of the human hepatocyte to proinflammatory cytokines has not been studied in detail. METHODS: Hepatocytes isolated from human livers were maintained in primary culture in the presence of a variety of bovine serum albumin-complexed fatty acids. The influence of these fatty acids on hepatocyte acute phase protein production was assessed, in the presence and absence of recombinant interleukin-6, by measurement of acute phase proteins by enzyme-linked immunosorbent assay. RESULTS: Eicosapentaenoic and gammalinolenic acid increased spontaneous production of alpha 1-antichymotrypsin and prealbumin but decreased spontaneous production of transferrin and haptoglobin from isolated human hepatocytes. Eicosapentaenoic and gammalinolenic significantly increased interleukin-6-stimulated production of C-reactive protein and alpha 1-antichymotrypsin but reversed the stimulatory effect of interleukin-6 on haptoglobin production. These fatty acids also reversed the inhibitory effect of interleukin-6 on prealbumin production. CONCLUSIONS: These results show that certain fatty acids have the potential to modulate spontaneous and cytokine-induced alterations in human hepatic acute phase protein metabolism. These data indicate the presence of complex mechanisms of regulation of human hepatic protein metabolism by fatty acids, and further study will be required to establish the nature of their influence in vivo.     

Supplementation with n-3 and n-6 polyunsaturated fatty acids: effects on lipoxygenase activity and clinical symptoms of pruritus in hemodialysis patients.

OBJECTIVE: To investigate the effect of supplementation with different sources of oils rich in long chain fatty acids, ie, fish oil (FO) and safflower oil (SO), on the production of leukotriene B4 (LTB4) by polymorphonuclear leukocytes (PMNLs) in hemodialysis patients and the consequent effects on the symptoms of pruritus. DESIGN: Randomized, prospective, double-blind study for 2 treatment groups. SETTING: Three Medical Center-affiliated units. PATIENTS: Twenty-two patients on maintenance hemodialysis, of both sexes, age > or = 20 years with complaint of dry and/or itchy skin. INTERVENTION: Two groups of patients receiving daily supplements of 6 g ethyl ester of FO or SO for 16 weeks. MAIN OUTCOME MEASURES: Red blood cell (RBC) fatty acid profile, LTB 4 production by PMNLs, and pruritus symptoms at baseline and after supplementation. RESULTS: After supplementation, the FO group had a higher RBC 22:6n3, total n-3 fatty acids, and ratio of total n-3 to total n-6 fatty acids (P < .05) than the SO group. The change in LTB4 production (pg/mL) from baseline to week 16 was 240.7 +/- 200.2 to 29.2 +/- 14.6 in the FO group and from 171.1 +/- 121.7 to 31.9 +/- 14.7 in the SO group. The overall pruritus score change was 16.7 +/- 11.4 to 8.9 +/- 9.2 in the FO group and from 17.5 +/- 8.8 to 13.1 +/- 5.6 in the SO group. FO supplementation did not result in a significant specific effect on LTB4 production by the PMNLs. There was a nonsignificant decrease in the pruritus scores that could be clinically significant and important to patients suffering with this condition. CONCLUSION: Supplementation with FO results in significant incorporation of n-3 fatty acids in the RBCs. Intervention with both FO and SO resulted in a nonsignificant improvement of clinical symptoms of pruritus and a nonsignificant reduction in LTB 4 production by PMNLs in the hemodialysis patients. The percent decrease in total puritus score was greater for the FO group compared with the SO group.     

Improved survival of heterotopic cardiac allografts in rats with dietary n-3 polyunsaturated fatty acids

A heterotopic cardiac transplant model, with male Fischer 344 rats as donors and Long Evans rats as recipients, was utilized to investigate the effect of dietary n-3 polyunsaturated fatty acids on acute rejection. Both donor and recipient rats were fed purified diets high in either n-3 polyunsaturated fatty acids (from concentrated n-3 ethyl esters [EE] or fish oil [FO]) or n-6 polyunsaturated fatty acids (from corn oil [CO]) for either 2-3 or 3-4 weeks before transplant. The recipient rats continued on their diets until rejection. The AIN-76A-based diets (with 30% of calories as fat) had adequate essential fatty acids and were balanced for sterols and antioxidants. Allograft survival was significantly increased by 45% when recipient rats were fed EE as compared to the control (CO diet fed to both donor and recipient), regardless of the diet fed to the donor. There was a slight but significant increase in allograft survival when only donor rats were fed the EE diet 2-3 weeks before transplant. With the FO diet (containing one third of the n-3 fatty acids in the EE diet), only the group fed FO to both donor and recipient (starting 2-3 weeks before transplant) showed a significant increase in allograft survival over the control. However, if the FO diets were fed for 3-4 weeks before transplant, increased survival was seen in groups fed FO to either the donor or recipient alone. In this case, allograft survival with FO feeding to both donor and recipient was not different from recipient treatment alone. In all the studies there was a significant and direct correlation between allograft survival and the donor heart phospholipid n-3/n-6 fatty acid ratio and the n-3 fatty acid content (at rejection). There was an indirect relationship with the n-6 fatty acid content. There was no detectable 20:3 (n-9) in the cardiac phospholipids, indicating the absence of essential fatty acid deficiency. Recipient diets were the strongest determinant of the fatty acid composition in the transplanted donor heart. The data indicate that providing dietary n-3 polyunsaturated fatty acids before and after cardiac transplant to recipient animals provides a significant protection against acute rejection.     

Modulation of Kupffer cell membrane phospholipid function by n-3 polyunsaturated fatty acids

Dietary n-3 polyunsaturated fatty acids (PUFAs) have been reported to improve clinical outcome in a number of inflammatory diseases including burns and sepsis. One mechanism contributing to the anti-inflammatory effect is the incorporation of n-3 PUFAs into membrane phospholipids which decreases macrophage eicosanoid production. We hypothesize that an additional mechanism for their effects is an alteration of membrane signal transduction that decreases macrophage responsiveness to inflammatory stimuli. Kupffer cells, the fixed macrophages of the liver, were obtained from rats pair fed diets for 6 weeks with 15% of calories supplied as menhaden (high n-3), corn (control), or safflower (high n-6) oils. The effects of the dietary oils on Kupffer cell membrane signal transduction and eicosanoid production were assessed by measuring inositol phospholipid (PI) metabolism, intracellular calcium responses, and prostaglandin E2 (PGE2) production to the inflammatory signals endotoxin (LPS) and platelet activating factor (PAF). The menhaden oil diet resulted in significant incorporation of n-3 PUFAs into total cellular PUFAs compared to corn and safflower oil. (total n-3 PUFAs, 28.1% menhaden vs 2.1% corn vs 1.2% safflower, P less than 0.03). This incorporation altered signal transduction of PAF as both PI turnover (65% +/- 10% of corn oil) and calcium response (0.6-fold vs 5.0-fold for corn oil) were significantly reduced in the menhaden oil group. (P less than 0.05) The menhaden oil diet also reduced significantly PGE2 production in response to PAF and LPS (corn, 348 +/- 23 pg/ml; menhaden, 48 +/- 6 pg/ml, P less than 0.01). We conclude that, in addition to modulating eicosanoid production, n-3 PUFAs can also alter macrophage membrane signal transduction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduction of delayed-type hypersensitivity by the injection of n-3 polyunsaturated fatty acids in mice.

The effects of injection of n-3 polyunsaturated fatty acids (PUFAs) on the delayed-type hypersensitivity (DTH) response was investigated in mice. Mice were immunized with sheep red blood cells (SRBCs). Six days later 50 microliters of a 20% SRBC suspension was injected into the right hind footpad of each mouse. Just before the challenge of SRBCs, various amount of a trieicosapentaenoyl-glycerol emulsion (10%) was injected through tail veins (5 mice per each dose). Then 24 hr later the dorsoventral thickness of the right hind footpad was measured and compared with that of the left hind footpad. The difference in thickness between both footpads was regarded as the DTH response. The effect of the emulsion on DTH was dose-dependent; the DTH responses (in mm) in the control group (injected with 0.5 ml of a 2.5% glycerol solution through tail veins) and EPA-injected groups (with 5 mg, 10 mg, and 20 mg) were 1.53 +/- 0.16 (mean +/- SEM), 1.09 +/- 0.14, 0.43 +/- 0.07 (P less than 0.005), and 0.36 +/- 0.13 (P less than 0.005), respectively. The DTH response was also depressed by the injection of a tridocosahexaenoyl-glycerol emulsion. Consequently, n-3 PUFA emulsions have clinical implication in DTH-related diseases such as rejection of allografts.     

302例军校学员n6和n3系多烯脂酸和n6/n3比值的调查

目的:调查302例军校学员的 n3系多烯不饱和脂肪酸(n3-PUFAs,n3系多烯脂酸)、n6系多烯不饱和脂肪酸(n6-PUFAs,n6系多烯脂酸)和 n6/n3比值。方法:用气相色谱法测定302例军校学员血浆脂肪酸中n3-PUFAs 和 n6-PUFAs 组分和含量,并对不同性别组的各种脂肪酸含量进行 t 检验。结果:n6-PUFAs 为45.74%,n3-PUFAs 为2.90%,n6/n3比值为16:12;饱和脂肪酸(S):单烯脂酸(M):多烯脂酸(P)比值为1:0.67:1.58;男学员的油酸和单烯脂酸(MUFA)高于女学员(P<0.01),而二十二碳六烯酸(22:6n-3,DHA)、n3-PU-FAs 和多烯脂酸低于女学员。结论:应适当减少 n6-PUFAs 摄入,增加油酸摄入,并补充22:6n-3,使n6/n3和 S:M:P 比值趋于合理的水平。     

n-3多不饱和脂肪酸对人结肠癌细胞增殖与凋亡的影响

目的探讨n-3多不饱和脂肪酸（n-3PUFA）对人结肠癌细胞HT．29的作用及其机制。方法应用MTT比色法、细胞的形态学观察（Hochest33258染色）、DNA凝胶电泳、流式细胞技术检测二十二碳六烯酸（DHA）对HT．29增殖和凋亡的影响：气相色谱分析的方法检测DHA对HT-29细胞n-3PUFA和n．6PUFA含量及n-6／n-3PUFA比例的影响。结果DHA在体外对HT．29有明显的增殖抑制作用,10、20、40和80mg儿DHA作用24h时的细胞增殖抑制率分别为16．8％、24．7％、50．0％和60．1％。40mg／LDHA作用24、48和72h的细胞增殖抑制率分别为50．0％、69．9％和77．0％：呈现明显的剂量和时间效应关系。荧光染色可观察到细胞核染色质浓集,核浓缩核碎裂．并出现典型的凋亡小体：DNA凝胶电泳呈现特征性的梯形条带（DNALadder）：流式细胞仪检测显示经DHA处理后HT-29DNA合成前期（G,期）细胞比例较对照组增加（72．1％比51．3％）,DNA合成期（S期）细胞比例明显减少（19．9％比38．9％）,细胞呈现明显的G,期阻滞;气相色谱分析显示．DHA可以降低HT-29细胞内n-6PUFA而提高n-3PUFA含量,降低n-6／n-3PUFA比率。结论n-3PUFA通过抑制细胞增殖和诱导细胞凋亡来阻遏结肠癌细胞的生长．这种作用的机制可能为降低了细胞的n-6／n-3PUFA的比例。     

Effects of n-3 polyunsaturated fatty acids on hepatic tight junction after partial hepatectomy in rats

Objective

To explore the effects of n-3 polyunsaturated fatty acid (PUFA) on the hepatic tight junction in rat liver after partial hepatectomy.

Materials and Methods

Male Sprague-Dawley rats were divided into 4 groups: sham operation, 70% hepatectomy, 70% hepatectomy with administration of 1 mL/kg n-3 PUFA, and 70% hepatectomy with administration of 2 mL/kg n-3 PUFA. Morphologic features of the hepatic tight junction were observed at transmission electron microscopy, and expression of the tight junction proteins occludin, claudin-3, and ZO-1 was studied using Western blot analysis.

Results

The hepatic tight junction structure became loosened 3 days after 70% hepatectomy. The levels of tight junction occludin decreased markedly, whereas claudin-3 and ZO-1 levels increased 2- or 3-fold over control levels. Supplementation of n-3 PUFA alleviated the changes in tight junction structure and occludin expression.

Conclusion

n-3 PUFA has protective effects on hepatic tight junction structure after 70% hepatectomy, which were attributed in part to modulation of occludin expression.     

Prostate tissue and leukocyte levels of n-3 polyunsaturated fatty acids in men with benign prostate hyperplasia or prostate cancer

OBJECTIVE: To compare the levels of n-3 polyunsaturated fatty acids (PUFAs) in leukocytes and prostate tissue in men with prostate cancer or benign prostatic hyperplasia (BPH), as dietary intake of n-3 PUFAs has been linked to the risk of prostate cancer; the prostate-specific antigen (PSA) level was also compared to prostate tissue levels of n-3 PUFAs. PATIENTS AND METHODS: Prostate tissue was obtained and leukocytes isolated from 20 men with prostate cancer and 35 with BPH. The n-3 PUFAs alpha-linolenic acid (ALA), eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) were measured in prostate tissue and in peripheral blood leukocytes using gas chromatography. PSA levels were measured in all of the men. RESULTS: There was a strong positive correlation between EPA and DHA in leukocytes and in prostate tissue (EPA: r = 0.80, DHA: r = 0.53, both P < 0.001) in all the men, whereas there was no association between the content of ALA in leukocytes and in prostate tissue (r = -0.15). Men with BPH had similar levels of ALA in leukocytes and in prostate tissue, but men with prostate cancer had more ALA in prostate tissue than in leukocytes. The PSA level was significantly positively correlated with ALA level in prostate tissue (r = 0.42, P < 0.01) but there was no significant correlation between PSA level and EPA and DHA levels. There were no significant correlations between PSA level and n-3 PUFA levels in leukocytes. CONCLUSION: Dietary intake of the marine n-3 PUFAs reflected in EPA and DHA levels in leukocytes are also reflected in EPA and DHA levels in prostate tissue in men with and without prostate cancer. However, there is a discrepancy between the levels of ALA in leukocytes and in prostate tissue, with higher levels in men with prostate cancer. This is in accordance with the strong positive association between PSA and ALA levels in prostate tissue. This study therefore does not support the hypothesis that intake of marine n-3 PUFAs might protect against prostate cancer, but lends support to the deleterious role of ALA in the development of prostate cancer.     

n一3多不饱和脂肪酸与骨代谢

骨质疏松是当今老龄社会的主要健康和经济问题,影响人类生活质量和寿命,基因因素、脂肪酸营养摄入等影响骨质疏松及其并发症。脂肪酸是细胞膜的重要组成部分,通过调节钙吸收、破骨细胞形成、前列腺素的合成、细胞膜n-6/n-3脂肪酸比率、细胞因子及脂质过氧化等可影响骨代谢。本文综述了膳食中n-3脂肪酸的重要性及fat-1基因对骨代谢的影响,n-3脂肪酸影响人类和鼠的骨代谢,分析n-3脂肪酸对骨代谢影响的细胞与分子机制。     

Influence of topical administration of n-3 and n-6 essential and n-9 nonessential fatty acids on the healing of cutaneous wounds.

Injury triggers a series of physiological events at the wound site. These include an inflammatory response that is established shortly after the injury, which is then followed by an intense formation of tissue over a period of days. Poly- and monounsaturated fatty acids exert major functions on the inflammatory responses, either in the form of phospholipids anchored in the cell membrane or as soluble lipoic mediators. We present evidence that linolenic (n-3), linoleic (n-6), and oleic (n-9) fatty acids can modulate the closure of surgically induced skin wounds. We found that n-9 fatty acids induced faster wound closure when compared to n-3, n-6, and control. In addition, n-9 fatty acids strongly inhibited the production of nitric oxide at the wound site. A mild improvement on wound closure was observed in the n-6 fatty acid-treated animals concurrent with a peak in nitric oxide production at 48 hours postsurgery. N-3 fatty acid treatment significantly delayed wound closure. Furthermore, we showed that n-3 fatty acid induced a peak in nitric oxide at 3 hours postsurgery and an intense deposition of extracellular matrix after 5 days of treatment. Thus, our results suggest a relevant role and potential therapeutic implication for fatty acids on skin wound healing.