维生素A缺乏对肝脏铁代谢的影响及机制研究

发布时间：2018-05-09 00:10

本文选题：维生素A + 铁代谢　；参考：《重庆医科大学》2009年博士论文

【摘要】： 第一部分人群维生素A营养状况与铁代谢稳态相关性研究目的:横断面调查学龄前儿童维生素A营养状况与铁代谢动态平衡及机体总铁含量之间的关系,并评估不同维生素A营养状况下贫血与储铁不足的患病风险。方法:利用整群抽样和分层抽样相结合的方法从巴南区鱼洞镇共20多所幼儿园随机抽取其中4所进行调查,同时问卷调查其人口学资料、社会经济状况以及饮食习惯等。利用高效液相色谱法测定血清维生素A浓度,酶联免疫法测定血清铁蛋白(serum ferritin, SF)水平、微粒子增强透射免疫法检测可溶性转铁蛋白受体(serum transferrin receptor, sTfR)水平、透射免疫比浊法测定血清C-反应蛋白(C- reactive protein, CRP)水平以及高铁氰化法测定血红蛋白(hemoglobin, HB)浓度,并计算sTfR-SF指数(TFR-F指数)以及机体总铁含量。结果:共471名学龄前儿童纳入研究,其中男童236名,女童235名,年龄范围为2～7岁,平均年龄为(4.0±0.85)(均数±标准差)岁。HB水平为(115.8±9.2)g/L ,贫血患病率为23.5 %; SF水平为(24.75±14.71)μg/L,sTfR水平为(1.28±0.33)mg/L,储铁不足发生率为45.1%。血清维生素A水平为(1.21±0.36)μmol/L,维生素A缺乏(vitamin A deficiency, VAD)患病率为6.5%,可疑亚临床维生素A缺乏( suspect sub-clinic vitamin A deficiency, SSVAD)患病率为26.0%。TFR-F指数0.9595 (0.7257,1.2226)[中位数(P25,P75)] ,机体铁含量8.868 (6.986,10.470) mg/kg。校正儿童年龄、性别、不同幼儿园来源、家庭经济状况以及膳食模式等因素后,血清维生素A与HB、SF对数浓度、sTfR水平、TFR-F指数以及机体铁含量的偏相关系数(radjust)分别是0.16(p0.001), -0.13 (p=0.037), 0.17 (p=0.0011), -0.013 (p=0.7935)以及-0.05 (p=0.3652)。Logitic回归分析显示,VAD是导致储铁不足(以SF水平作为判断标准)的独立危险因素[优势比(odds ratio, OR)(95% CI): 1.88(1.01, 2.97)。若以TFR-F为判断指标,VAD则不是储铁不足患病危险因素[OR(95% CI): 1.365(0.286,6.513)]。VAD儿童患贫血的危险性[OR (95% CI): 2.56(1.15,5.70)]是NVA儿童贫血患病风险的2.56倍;若对SF和sTfR校正以后,VAD儿童贫血患病风险则明显下降[OR (95% CI): 1.53(1.01,1.88)]。结论: 1学龄前儿童血清维生素A水平与反映机体铁储备和铁利用的生化指标密切相关,而与铁吸收及机体总铁含量无明显关系。 2 VAD是储铁不足患病的独立危险因素,其可能主要通过影响铁储备和铁利用产生作用,而对铁吸收影响不大。 3 VAD是贫血患病的独立危险因素,除主要影响铁代谢外,还可能通过其他途径产生作用。第二部分维生素A等多种微量营养素干预对铁代谢稳态的影响目的:观察单独维生素A补充、维生素A+铁以及多种微量营养素联合补充等干预方式对铁代谢相关生化指标的影响,并评估不同干预方式对贫血以及储铁不足发病的保护作用。方法:本研究为随机、对照、盲法现场干预试验,对象来源于第一部分研究。从该地区共20多所幼儿园中随机选取3所中的全部226名2-7岁学龄前儿童纳入计划干预对象。对其分别补充100%RDA的维生素A(Ⅰ组),维生素A加铁(Ⅱ组)以及维生素A,铁,维生素B1,核黄素,叶酸,尼克酸,锌以及钙(Ⅲ组)。干预前后分别测定利用高效液相色谱法测定血清维生素A浓度,酶联免疫法测定血清铁蛋白(serum ferritin, SF)水平、微粒子增强透射免疫法检测可溶性转铁蛋白受体(serum transferring receptor, sTfR)水平、透射免疫比浊法测定血清C-反应蛋白(C- reactive protein, CRP)水平以及高铁氰化法测定血红蛋白(hemoglobin, HB)浓度,并计算sTfR-SF指数(TFR-F指数)及机体总铁含量。同时利用问卷方式调查这些儿童的人口学治疗、社会经济状况以及饮食习惯等。结果:三种干预方式均可使HB水平均较干预前明显升高(P0.0001),但各干预组间无显著差异(p0.05)。干预后各组维生素A水平均有所提高,而以维生素A+铁组以及多种微量营养素补充组最为明显(p0.05)。干预后各组SF值均较干预前明显下降(P0.01),而维生素A+铁补充组以及多种微量营养素补充组下降最为明显(P0.05)。干预后各组sTfR水平均出现明显降低(P0.01),尤以单独维生素A补充组最明显(P0.05)。单独维生素A补充组其TFR-F指数以及机体总铁含量于干预前后并无明显变化(P0.05)。在校正了儿童性别、年龄、被动吸烟、社会经济状况以及膳食模式以后,三种干预方式对贫血发病的保护作用并无明显差异(P0.05)。若以铁蛋白作为储铁不足乏判断的指标,三种干预方式对储铁不足保护作用也无差异(P0.05);但若以TFR-F指数作为判定指标,则相对于单独维生素A补充而言,维生素A+铁以及多种微量营养素的联合补充是储铁不足更好的保护因素[相对危险度(relative risk, RR)(95% CI): 0.410(0.218,0.992)]。结论: 1维生素A干预对铁储备及铁利用过程均有影响。 2维生素A干预对TFR-F指数以及机体总铁含量无明显影响,表明维生素A对铁在肠道的吸收无明显作用。 3维生素A联合铁剂等多种微量营养素的补充可能是改善储铁不足状态的较好干预方式。第三部分维生素A营养状况对铁调节模式的影响及其相关机制目的:了解不同维生素A营养状况下大鼠贫血的性质及其对铁效应元件-铁调节蛋白作用模式(iron responsive element-iron regulated protein, IRE-IRP模式)和肝调素-膜铁转运蛋白作用模式(hepcidin- ferroportin,Hepc-FPN模式)各组件在肝脏mRNA和蛋白水平表达的影响。方法:清洁级健康雌性Wistar大鼠30只随机分为3组,饲以相应饲料,3周后与健康雄性Wistar大鼠交配,1:2雌雄合笼::(1)正常维生素A饲喂组母鼠(normal vitamin A status, NVA)(10只),给予维生素A充足饲料(含维生素A 6500 U/kg),随机从10窝中每窝各抽取雌雄仔鼠各1只共计20只用于本实验,仔鼠饲料同母鼠;(2)低维生素A饲喂组母鼠(low vitamin A status, LVA)(10只),给予低维生素A饲料(含维生素A 400IU/kg) ,随机从10窝中每窝各抽取雌雄仔鼠各1只共计20只用于本实验,仔鼠饲料同母鼠,其幼鼠为维生素A缺乏鼠(vitamin A deficiency, VAD);(3)生后4周干预组母鼠(vitamin A intervention, VAI)(10只),给予低维生素A饲料饲喂至分娩,随机从10窝中每窝各抽取雌雄仔鼠各1只共计20只用于本实验,仔鼠饲料同母鼠,4周龄大小后改饲维生素A充足饲料。各组仔鼠于8周龄处死。用高效液相色谱法(HPLC)检测血清维生素A浓度,利用全自动血细胞分析仪测定全血红细胞指数,荧光定量PCR法、Western blotting法以及酶联免疫法分别测定铁调节IRE-IRP模式和Hepc-FPN模式各组件在肝脏mRNA和蛋白水平表达的水平。结果:①仔鼠在第八周时,NVA组和VAD组大鼠外周血红细胞计数、血红蛋白浓度以及红细胞压积均无显著差异(p0.05),而VAI大鼠上述指标均显著高于前两组(p0.05)。VAD组红细胞平均容积最低(p0.05),NVA组和VAI组大鼠之间则无显著差异(p0.05);VAI组大鼠红细胞分布宽度显著高于NVA组和VAD组(p0.05),后两组该值无显著差异(p0.05)。三个组大鼠平均血红蛋白含量组间无差异(p0.05),而VAI组平均血红蛋白浓度则显著低于VAN组和MVAD组(p0.05),后两组该指标之间无显著差异(p0.05)。②Hepc-FPN模式中肝调素、骨形成蛋白-4以及白细胞介素-6在不同维生素A营养状况下其在肝脏的mRNA及蛋白水平的表达均出现差异。③IRE-IRP模式中铁调节蛋白-1、膜铁转运蛋白-1、铁蛋白轻链以及转铁蛋白受体-1在不同维生素A营养状况下在肝脏的mRNA及蛋白水平的表达均出现差异,而二价金属离子转运体-1的表达则差异不明显。结论: 1维生素A缺乏时外周血主要为小细胞低色素表现,补充维生素A可使上述改变有所恢复;维生素A缺乏对平均血红蛋白量以及平均血红蛋白浓度影响不大; 2不同维生素A营养状况对铁代谢Hepc-FPN模式具有明显影响,而其可能途径是从转录水平调节IL-6和BMP-4生成从而影响Hepcidin的合成的; 3不同维生素A营养状况对铁代谢IRE-IRP模式具有明显影响,而其可能途径之一是通过从转录水平调节IRP-1的合成起作用的。
[Abstract]:Study on the relationship between the nutritional status of vitamin A and iron metabolism in the first part of the population

Objective : To investigate the relationship between the nutritional status of vitamin A and the dynamic balance of iron metabolism and the total iron content of iron metabolism in preschool children before school age , and to evaluate the risk of anemia and deficiency of iron in nutritional status of different vitamin A .

Methods : Four of 20 kindergartens were randomly selected from 20 kindergartens in fish - hole town in southern Brazil by cluster sampling and stratified sampling . The levels of serum vitamin A , serum ferritin ( SF ) , serum ferritin ( SF ) and serum C - reactive protein ( sTfR ) were measured by high performance liquid chromatography . Serum C - reactive protein ( CRP ) and hemoglobin ( HB ) were measured by radioimmunoturbidimetry , and the sTfR - SF index ( TFR - F index ) and total iron content were calculated .

Results : The prevalence of serum vitamin A and HB , SF , sTfR , TFR - F and serum iron content were ( 1 . 21 卤 0 . 36 ) 渭mol / L , 0 . 17 ( p = 0.0011 ) , - 0 . 013 ( p = 0 . 7935 ) and - 0.05 ( p = 0.3652 ) . OR)(95% CI): 1.88(1.01, 2.97). If TFR - F was used as the criterion , VAD was not a risk factor for iron deficiency ( 95 % CI ) : 1.365 ( 0.286 , 6.513 ) , and the risk of anemia in VAD children was 2.56 times ( 95 % CI ) : 2.56 ( 1.15 , 5.70 ) , which was 2.56 times the risk of anemia in NVA children .

Conclusion :

The level of serum vitamin A in preschool children was closely related to the biochemical indexes reflecting the iron reserve and iron utilization of the organism , and there was no obvious relation between the iron absorption and the total iron content of the body .

2 VAD is an independent risk factor for the deficiency of iron storage , which may affect the iron absorption and iron utilization , and has little effect on iron absorption .

The 3 VAD is an independent risk factor for anemia , which may affect iron metabolism , but may also act through other pathways .

Effect of Various Kinds of Trace Nutrients Intervention on the Steady State of Iron Metabolism in the Second Part of Vitamin A

Objective : To observe the effects of vitamin A supplementation , vitamin A + iron and multiple trace nutrients supplementation on iron metabolism related biochemical indexes , and to evaluate the protective effects of different intervention methods on anemia and iron deficiency .

Methods : The level of serum vitamin A , serum ferritin ( SF ) level , serum C - reactive protein ( SF ) level , serum C - reactive protein ( SF ) level , serum C - reactive protein ( SF ) level , serum C - reactive protein ( SF ) level , serum C - reactive protein ( SF ) level , serum C - reactive protein ( CRP ) level and total iron content were measured by high performance liquid chromatography .

Results : There was no significant difference in the levels of serum levels of vitamin A ( P < 0 . 05 ) , but there was no significant difference in the levels of vitamin A + iron ( P < 0 . 05 ) . However , there was no significant difference in the levels of vitamin A + iron ( P < 0 . 05 ) .

Conclusion :

1 Vitamin A intervention had an impact on iron reserves and iron utilization .

There was no obvious effect on TFR - F index and total iron content of the body , indicating that vitamin A had no obvious effect on the absorption of iron in intestinal tract .

3 . The supplements of vitamin A and iron supplements may be a good way to improve the state of iron storage deficiency .

Effect of the third part of vitamin A nutritional status on iron regulation mode and its related mechanism

Objective : To investigate the effects of various components of iron responsive element - iron regulated protein ( IRE - IRPs ) on liver mRNA and protein level in rats with different vitamin A nutritional status and their effects on iron responsive element - iron regulated protein ( IRE - IRPs ) and hepcidin - ferroportin ( Hepc - FPN ) .

Methods : 30 healthy female Wistar rats were randomly divided into three groups : 1 ) normal vitamin A status ( NVA ) ( 10 rats ) , vitamin A deficiency rats ( vitamin A 400IU / kg ) .

Results : ( 1 ) There was no significant difference ( p < 0.05 ) between group A and VAD group ( p < 0.05 ) . There was no significant difference between the two groups ( p < 0.05 ) .

Conclusion :

In the absence of vitamin A , peripheral blood was mainly the low - pigment expression of small cells , and vitamin A supplementation could restore the above - mentioned changes ; vitamin A deficiency had little effect on average hemoglobin concentration and mean hemoglobin concentration ;

2 The nutritional status of different vitamin A has an obvious effect on the Hepc - FPN model of iron metabolism , and its possible pathway is to regulate the production of IL - 6 and BMP - 4 from the level of transcription , thus affecting the synthesis of hepcidin ;

3 The nutritional status of different vitamin A has an obvious effect on the IRE - IRPs model of iron metabolism , and one of the possible ways is by regulating the synthesis of IRPs - 1 from the transcription level .

【学位授予单位】：重庆医科大学
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R341

【参考文献】