高脂膳食性氧化应激对钙代谢的影响及其分子机制
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摘要
随着生活水平的提高,城乡居民的膳食结构发生了巨大变化,膳食中油脂的比例不断增多。能量摄入的增加,体内能量代谢旺盛,其副产物ROS也随之增加,可诱发机体氧化应激。氧化应激又是许多疾病发病过程中共同的作用机制,如:骨质疏松症等。血脂代谢紊乱人群中骨质疏松的发病率高于正常人群,特别在老年人中骨质疏松症的发病率超过60%。现已发现雌激素缺乏引发氧化应激在骨质疏松发生过程中发挥了重要的作用,但目前未见营养性氧化应激对钙代谢异常作用的研究,也鲜有其分子机制的报道。本文旨在探讨高脂膳食性氧化应激及抗氧化剂硫辛酸干预对钙吸收和骨代谢的影响及其分子机制。
1.氧化还原状态对钙吸收机制的影响
C57BL/6雄性小鼠随机分为四组(每组8只):对照组(2%猪油、0.65% Ca);高脂组(HFD、19.5%猪油、0.7% Ca);硫辛酸干预组(HFD+0.1% LA、0.7% Ca);钙补充组(HFD+CS, 1.6% Ca),饲养9wk。结果显示高脂膳食导致肠钙吸收和骨钙含量减少,且引起十二指肠氧化应激、使氧化还原状态失衡。硫辛酸干预和膳食钙补充对钙吸收和抗氧化能力等可部分或完全恢复至对照组水平。相关性分析表明钙净吸收率与十二指肠ROS水平呈现显著负相关(r = -0.729, P < 0.01),与GSH/GSSG比值呈现显著正相关(r = 0.805, P < 0.01),但与膳食脂肪含量无显著相关(P > 0.05)。此外,HFD组小鼠十二指肠中calbindin-D9K、PMCA (plasma membrance calcium ATPase)、NCX (sodium-calcium exchanger)基因表达分别下调1.9、2.7、1.5倍。而HFD组血浆中钙三醇水平和十二指肠中VDR基因表达水平均显著高于对照水平。以上结果表明高脂膳食引发十二指肠氧化还原状态失衡,抑制钙吸收相关基因的表达,从而抑制肠道钙吸收。
2.高脂膳食性氧化应激对骨代谢的影响
C57BL/6雄性小鼠随机分为三组(每组9只):对照组;高脂组;硫辛酸干预组,饲养13wk,探究高脂膳食是否会引起骨组织氧化应激,以及高脂膳食性氧化应激与异常骨代谢之间的关系。结果显示高脂膳食引发骨组织抗氧化能力受损,氧化损伤指标MDA显著增加,氧化还原状态呈现向氧化态的转变。高脂膳食导致骨代谢异常——抑制骨形成且刺激骨再吸收。此外,HFD组小鼠血浆中IGF-1水平显著低于对照组,而TNF-α水平显著高于对照组。硫辛酸的干预可完全或部分恢复上述指标至对照水平。骨组织中GSH/ GSSG比值与骨形成指标P1CP呈现显著正相关(r = 0.565, P < 0.003),与骨再吸收指标NTx呈现显著负相关(r = -0.786, P < 0.001)。相反,脂质过氧化物指标MDA与P1CP呈现显著负相关(r = -0.687, P < 0.001),与NTx呈现显著正相关(r = 0.516, P < 0.007)。以上结果提示高脂膳食可造成骨组织抗氧化能力减弱、氧化还原状态失衡。骨组织的氧化还原状态失衡可能是发生高脂膳食性骨质疏松重要的作用机制。
3.高脂膳食性骨代谢异常的分子机制
通过分析小鼠股骨(近端)基因表达谱的变化,更全面地阐述髙脂膳食性骨质流失以及抗氧化剂硫辛酸干预作用可能的分子机制。Affymetrix mouse 430A表达芯片数据显示骨形成相关的多数基因表达下调(如:COL1a1、ALP1、FOS),而骨再吸收相关的多数基因表达上调(如:NOX2、RANKL、CTSK等)。另外,参与抗氧化防御的基因表达也呈现下调趋势(除NQO1上调),脂肪合成与脂肪酸氧化相关基因的表达也呈现下调趋势(如:PPARg和APOE等)。而硫辛酸干预可部分恢复骨形成相关基因的表达,而骨再吸收、抗氧化和脂代谢相关多数基因的表达水平与对照组无显著变化。
此外,本研究也分析了涉及信号转导相关基因表达的变化。IGF能刺激成骨细胞增殖和增强骨形成作用,而芯片数据中IGF信号通路中多数基因表达下调(如IGF1、IGF1R、IGFBP4等)。P53负调控成骨细胞分化和骨形成作用,本研究中高脂膳食显著上调P53凋亡通路中多数基因的表达。另外,芯片数据中HFD组的TGFbR1和IL-17等基因表达强烈上调,IL-4表达下调,这些细胞因子可通过改变RANK/RANKL/OPG系统来调控破骨细胞的形成和骨再吸收的过程。上述信号转导的基因表达在硫辛酸干预下呈现恢复至对照水平的趋势。
以上结果表明HFD导致骨组织氧化应激,促进P53表达,可能由此导致成骨细胞凋亡,抑制成骨细胞的骨基质形成作用。而高脂膳食性氧化应激又可促进炎症因子或其受体的表达,RANKL/OPG表达比值增加,促进破骨细胞增殖,增强了骨再吸收的作用。
4.氧化还原状态对成骨细胞基质矿化的影响
通过400μM过氧化氢诱导MC3T3-E1细胞(小鼠成骨样细胞)氧化损伤和硫辛酸的干预,来探讨氧化还原状态对MC3T3-E1细胞基质矿化的作用,并且进一步阐述硫辛酸干预作用的机制。结果表明硫辛酸可有效防止过氧化氢导致MC3T3-E1细胞的氧化损伤,并且干预由氧化应激导致NQO1基因的高表达。NQO1的高表达可增加P53表达的稳定性,可能由此增强P53对成骨细胞凋亡作用,硫辛酸通过维持成骨细胞内氧化还原状态的平衡可防止氧化损伤导致P53凋亡。适宜剂量的硫辛酸(0.1-0.5mM)能显著改善因氧化损伤导致受损的MC3T3-E1细胞基质矿化功能。
综上所述,髙脂膳食性氧化应激导致氧化还原状态失衡是肠道钙吸收减少和骨代谢异常的重要原因。抗氧化剂硫辛酸能有效地干预高脂膳食性氧化应激的发生,改善钙代谢异常。
With growth in the living standard, the great changes in dietary patterns occur in urban and rural residents. Fat intakes are increasing in China, bringing about many health problems, such as osteoporosis. The increased energy intake can cause strong energy metabolic rate, which produces numerous ROS and consequently induces oxidative stress. Further, oxidative stress is one cause for pathogensis of many diseases. Although increasing evidences in postmenopausal models have demonstrated that oxidative stress plays a key role in abnormal calcium metabolism, previous studies have not addressed role of oxidative stress in high-fat diet (HFD)-induced bone mass loss. In contrast, antioxidant lipoic acid (LA), which not only scavenges ROS directly but also provides the reducing medium for the regeneration of the antioxidant from oxidized form, can prevent or at least attenuate oxidative injure. Therefore, the prevent study investigated the roles of HFD-induced oxidative stress in intestinal calcium absorption and bone metabolism and preventive effects of LA on them. Furthermore, their molecular mechamisms were also addressed.
1. HFD-indcued oxidative stress inhibits intestinal calcium absorption
Male C57BL/6 mice were randomly assigned to one of four groups with eight mice in each group. The control group consumed an ordinary diet (4.9% fat, w/w). The other three groups were fed an HFD (21.2% fat), the HFD plus 0.1% lipoic acid (LA), or the HFD plus additional 0.9% calcium supplement (CS). After 9 wk, plasma and duodenal oxidative stress biomarkers including malondialdehyde, superoxide dismutase, catalase, total antioxidant capacity, reduced glutathione/oxidized glutathione ratio, and reactive oxygen species (ROS) were examined. The intestinal calcium absorption state was evaluated through examining the calcium balance, bone mineral density (BMD), and calcium metabolism biomarkers. Furthermore, quantitative RT-PCR was carried out to analyze the changes in expression of transcellular calcium absorption-related genes.
The HFD induced marked decreases in intestinal calcium absorption and BMD of whole body, accompanied by redox imbalance and increased oxidative damage in duodenum; duodenal expression of calbindin-D9K, PMCA1b, and NCX was significantly down-regulated by 1.9-, 2.7-, and 1.5-fold, respectively. Furthermore, duodenal GSH/GSSG ratios were strongly positively correlated with the apparent calcium absorption rate a, ROS levels were negatively correlated with it, but dietary fat levels were not significantly correlated with it. Our results demonstrated that HFD-induced duodenal oxidation state could significantly down-regulate expression of calbindin-D9K, PMCA1b, and NCX, thus causing an inhibitory effect on intestinal calcium absorption.
2. HFD-induced abnormal bone metabolism associated with bone oxidative stess
Male C57BL/6 mice (4 wk old) were fed with normal diet, high-fat diet (HFD), or HFD supplemented with 0.1% antioxidant LA. After 13-wk feeding, the markers of bone metabolism in plasma and in urine, and femora oxidative stress were measured. Moreover, IGF-1 and TNF-a in plasma were measured. The feeding dyslipidemic HFD induced both inhibitory bone formation reactions and enhancive bone resorption reactions, accompanied by impaired bone antioxidant system, low levels of IGF-1 in plasma, and high levels of TNF-a in plasma. In contrast, these alternatives were prevented completely or partially in mice fed LA supplement. Further, plasma propeptide of ? collagen C-propeptide as a marker of bone formation was positively correlated with both MDA (r=-0.687, P<0.001) and reduced glutathione/ oxidized glutathione (GSH/GSSG) ratio (r=0.565, P<0.003) of bone. Cross-linked N-telopeptides of bone type ? collagen as a marker of bone resorption was negatively correlated with both MDA (r=0.516, P<0.007) and GSH/GSSG ratio (r=-0.786, P<0.001). Dyslipidemia induces impaired bone antioxidant system. Oxidative stress could be an important mediator of hyperlipidemia-induced bone loss.
3. Molecular mechanism for HFD-induced low bone mass
High-fat diet (HFD) leads to an increased risk of osteoporosis-related fracture, but the molecular mechanisms for its effects on bone metabolism have rarely been addressed. The present study investigated the possible molecular mechanisms for the dyslipidemic HFD-induced bone loss through comparing femoral gene expression profiles in the HFD-fed mice vs. the normal diet-fed mice during growth stage. We used Affymetrix 430A Gene Chips to identify the significant changes in genes expression involved in bone metabolism, lipids metabolism, and the related signal transduction pathways. Quantitative RT-PCR was carried out on some significant genes for corroboration of the microarray results. At the conclusion of the 13-wk feeding, the down-regulation of most of the genes related to bone formation and the up-regulation of most of the genes related to bone resorption were observed in the HFD-fed mice, according with the changes in plasma bone metabolic biomarkers. Together, the HFD induced a decrease in the majority of the adipogenesis-, lipid biosynthesis-, and fatty acid oxidation-related genes expression, such as PPARg and APOE. Furthermore, some genes engaged in the related signal transduction pathway were strongly regulated at transcript level, including IGFBP4, TGFbR1, IL17a, IL-4, and P53. These results indicate that the HFD may induce inhibitory bone formation and enhanced bone resorption, thus causing adverse bone status.
Supplemental LA can attenuate HFD-induced negative effects on bone formation and prevent its enhancement effects on bone resorption associated with decreased oxidative stress. Furthermore, antioxidant LA can up-regulate genes involved in IGF-1 signaling pathway and down-regulate genes involved in P53 apoptotic pathway, thus contributing to attenuating inhibitory bone formation caused by HFD. Moreover, LA-induced the strong up-regulation of IL12a and down-regulation of PTHR1, TGFbR1, and IL17a may lead to depressing bone resorption.
4. Effect of redox status onmatrix mineralizetion of osteoblast-like cell (MC3T3-E1)
The role of redox status in matrix mineralization of MC3T3-E1 cells and preventive effect of antioxidant LA was studied. Our results suggested that LA prevented oxidative injure of MC3T3-E1 cells induced by hydrogen peroxide and down-regulated high NQO1 expression, which is involved in response to oxidative stress. The high NQO1 expression can increase stabilization of P53 expreesion, thus maybe induced osteoblastic apoptosis. This study demonstrated that LA can prevent P53-dependent MC3T3-E1 cells apoptosis induced by oxidative stress, associated with maintaing redox status. Moderate levels of LA (0.1-0.5mM) attenuate the impaired MC3T3-E1 cell proliferation and mineralization levels induced by hydrogen peroxide, but high levels of LA (2.5mM) can not prevent significantly its functions.
1.氧化还原状态对钙吸收机制的影响
C57BL/6雄性小鼠随机分为四组(每组8只):对照组(2%猪油、0.65% Ca);高脂组(HFD、19.5%猪油、0.7% Ca);硫辛酸干预组(HFD+0.1% LA、0.7% Ca);钙补充组(HFD+CS, 1.6% Ca),饲养9wk。结果显示高脂膳食导致肠钙吸收和骨钙含量减少,且引起十二指肠氧化应激、使氧化还原状态失衡。硫辛酸干预和膳食钙补充对钙吸收和抗氧化能力等可部分或完全恢复至对照组水平。相关性分析表明钙净吸收率与十二指肠ROS水平呈现显著负相关(r = -0.729, P < 0.01),与GSH/GSSG比值呈现显著正相关(r = 0.805, P < 0.01),但与膳食脂肪含量无显著相关(P > 0.05)。此外,HFD组小鼠十二指肠中calbindin-D9K、PMCA (plasma membrance calcium ATPase)、NCX (sodium-calcium exchanger)基因表达分别下调1.9、2.7、1.5倍。而HFD组血浆中钙三醇水平和十二指肠中VDR基因表达水平均显著高于对照水平。以上结果表明高脂膳食引发十二指肠氧化还原状态失衡,抑制钙吸收相关基因的表达,从而抑制肠道钙吸收。
2.高脂膳食性氧化应激对骨代谢的影响
C57BL/6雄性小鼠随机分为三组(每组9只):对照组;高脂组;硫辛酸干预组,饲养13wk,探究高脂膳食是否会引起骨组织氧化应激,以及高脂膳食性氧化应激与异常骨代谢之间的关系。结果显示高脂膳食引发骨组织抗氧化能力受损,氧化损伤指标MDA显著增加,氧化还原状态呈现向氧化态的转变。高脂膳食导致骨代谢异常——抑制骨形成且刺激骨再吸收。此外,HFD组小鼠血浆中IGF-1水平显著低于对照组,而TNF-α水平显著高于对照组。硫辛酸的干预可完全或部分恢复上述指标至对照水平。骨组织中GSH/ GSSG比值与骨形成指标P1CP呈现显著正相关(r = 0.565, P < 0.003),与骨再吸收指标NTx呈现显著负相关(r = -0.786, P < 0.001)。相反,脂质过氧化物指标MDA与P1CP呈现显著负相关(r = -0.687, P < 0.001),与NTx呈现显著正相关(r = 0.516, P < 0.007)。以上结果提示高脂膳食可造成骨组织抗氧化能力减弱、氧化还原状态失衡。骨组织的氧化还原状态失衡可能是发生高脂膳食性骨质疏松重要的作用机制。
3.高脂膳食性骨代谢异常的分子机制
通过分析小鼠股骨(近端)基因表达谱的变化,更全面地阐述髙脂膳食性骨质流失以及抗氧化剂硫辛酸干预作用可能的分子机制。Affymetrix mouse 430A表达芯片数据显示骨形成相关的多数基因表达下调(如:COL1a1、ALP1、FOS),而骨再吸收相关的多数基因表达上调(如:NOX2、RANKL、CTSK等)。另外,参与抗氧化防御的基因表达也呈现下调趋势(除NQO1上调),脂肪合成与脂肪酸氧化相关基因的表达也呈现下调趋势(如:PPARg和APOE等)。而硫辛酸干预可部分恢复骨形成相关基因的表达,而骨再吸收、抗氧化和脂代谢相关多数基因的表达水平与对照组无显著变化。
此外,本研究也分析了涉及信号转导相关基因表达的变化。IGF能刺激成骨细胞增殖和增强骨形成作用,而芯片数据中IGF信号通路中多数基因表达下调(如IGF1、IGF1R、IGFBP4等)。P53负调控成骨细胞分化和骨形成作用,本研究中高脂膳食显著上调P53凋亡通路中多数基因的表达。另外,芯片数据中HFD组的TGFbR1和IL-17等基因表达强烈上调,IL-4表达下调,这些细胞因子可通过改变RANK/RANKL/OPG系统来调控破骨细胞的形成和骨再吸收的过程。上述信号转导的基因表达在硫辛酸干预下呈现恢复至对照水平的趋势。
以上结果表明HFD导致骨组织氧化应激,促进P53表达,可能由此导致成骨细胞凋亡,抑制成骨细胞的骨基质形成作用。而高脂膳食性氧化应激又可促进炎症因子或其受体的表达,RANKL/OPG表达比值增加,促进破骨细胞增殖,增强了骨再吸收的作用。
4.氧化还原状态对成骨细胞基质矿化的影响
通过400μM过氧化氢诱导MC3T3-E1细胞(小鼠成骨样细胞)氧化损伤和硫辛酸的干预,来探讨氧化还原状态对MC3T3-E1细胞基质矿化的作用,并且进一步阐述硫辛酸干预作用的机制。结果表明硫辛酸可有效防止过氧化氢导致MC3T3-E1细胞的氧化损伤,并且干预由氧化应激导致NQO1基因的高表达。NQO1的高表达可增加P53表达的稳定性,可能由此增强P53对成骨细胞凋亡作用,硫辛酸通过维持成骨细胞内氧化还原状态的平衡可防止氧化损伤导致P53凋亡。适宜剂量的硫辛酸(0.1-0.5mM)能显著改善因氧化损伤导致受损的MC3T3-E1细胞基质矿化功能。
综上所述,髙脂膳食性氧化应激导致氧化还原状态失衡是肠道钙吸收减少和骨代谢异常的重要原因。抗氧化剂硫辛酸能有效地干预高脂膳食性氧化应激的发生,改善钙代谢异常。
With growth in the living standard, the great changes in dietary patterns occur in urban and rural residents. Fat intakes are increasing in China, bringing about many health problems, such as osteoporosis. The increased energy intake can cause strong energy metabolic rate, which produces numerous ROS and consequently induces oxidative stress. Further, oxidative stress is one cause for pathogensis of many diseases. Although increasing evidences in postmenopausal models have demonstrated that oxidative stress plays a key role in abnormal calcium metabolism, previous studies have not addressed role of oxidative stress in high-fat diet (HFD)-induced bone mass loss. In contrast, antioxidant lipoic acid (LA), which not only scavenges ROS directly but also provides the reducing medium for the regeneration of the antioxidant from oxidized form, can prevent or at least attenuate oxidative injure. Therefore, the prevent study investigated the roles of HFD-induced oxidative stress in intestinal calcium absorption and bone metabolism and preventive effects of LA on them. Furthermore, their molecular mechamisms were also addressed.
1. HFD-indcued oxidative stress inhibits intestinal calcium absorption
Male C57BL/6 mice were randomly assigned to one of four groups with eight mice in each group. The control group consumed an ordinary diet (4.9% fat, w/w). The other three groups were fed an HFD (21.2% fat), the HFD plus 0.1% lipoic acid (LA), or the HFD plus additional 0.9% calcium supplement (CS). After 9 wk, plasma and duodenal oxidative stress biomarkers including malondialdehyde, superoxide dismutase, catalase, total antioxidant capacity, reduced glutathione/oxidized glutathione ratio, and reactive oxygen species (ROS) were examined. The intestinal calcium absorption state was evaluated through examining the calcium balance, bone mineral density (BMD), and calcium metabolism biomarkers. Furthermore, quantitative RT-PCR was carried out to analyze the changes in expression of transcellular calcium absorption-related genes.
The HFD induced marked decreases in intestinal calcium absorption and BMD of whole body, accompanied by redox imbalance and increased oxidative damage in duodenum; duodenal expression of calbindin-D9K, PMCA1b, and NCX was significantly down-regulated by 1.9-, 2.7-, and 1.5-fold, respectively. Furthermore, duodenal GSH/GSSG ratios were strongly positively correlated with the apparent calcium absorption rate a, ROS levels were negatively correlated with it, but dietary fat levels were not significantly correlated with it. Our results demonstrated that HFD-induced duodenal oxidation state could significantly down-regulate expression of calbindin-D9K, PMCA1b, and NCX, thus causing an inhibitory effect on intestinal calcium absorption.
2. HFD-induced abnormal bone metabolism associated with bone oxidative stess
Male C57BL/6 mice (4 wk old) were fed with normal diet, high-fat diet (HFD), or HFD supplemented with 0.1% antioxidant LA. After 13-wk feeding, the markers of bone metabolism in plasma and in urine, and femora oxidative stress were measured. Moreover, IGF-1 and TNF-a in plasma were measured. The feeding dyslipidemic HFD induced both inhibitory bone formation reactions and enhancive bone resorption reactions, accompanied by impaired bone antioxidant system, low levels of IGF-1 in plasma, and high levels of TNF-a in plasma. In contrast, these alternatives were prevented completely or partially in mice fed LA supplement. Further, plasma propeptide of ? collagen C-propeptide as a marker of bone formation was positively correlated with both MDA (r=-0.687, P<0.001) and reduced glutathione/ oxidized glutathione (GSH/GSSG) ratio (r=0.565, P<0.003) of bone. Cross-linked N-telopeptides of bone type ? collagen as a marker of bone resorption was negatively correlated with both MDA (r=0.516, P<0.007) and GSH/GSSG ratio (r=-0.786, P<0.001). Dyslipidemia induces impaired bone antioxidant system. Oxidative stress could be an important mediator of hyperlipidemia-induced bone loss.
3. Molecular mechanism for HFD-induced low bone mass
High-fat diet (HFD) leads to an increased risk of osteoporosis-related fracture, but the molecular mechanisms for its effects on bone metabolism have rarely been addressed. The present study investigated the possible molecular mechanisms for the dyslipidemic HFD-induced bone loss through comparing femoral gene expression profiles in the HFD-fed mice vs. the normal diet-fed mice during growth stage. We used Affymetrix 430A Gene Chips to identify the significant changes in genes expression involved in bone metabolism, lipids metabolism, and the related signal transduction pathways. Quantitative RT-PCR was carried out on some significant genes for corroboration of the microarray results. At the conclusion of the 13-wk feeding, the down-regulation of most of the genes related to bone formation and the up-regulation of most of the genes related to bone resorption were observed in the HFD-fed mice, according with the changes in plasma bone metabolic biomarkers. Together, the HFD induced a decrease in the majority of the adipogenesis-, lipid biosynthesis-, and fatty acid oxidation-related genes expression, such as PPARg and APOE. Furthermore, some genes engaged in the related signal transduction pathway were strongly regulated at transcript level, including IGFBP4, TGFbR1, IL17a, IL-4, and P53. These results indicate that the HFD may induce inhibitory bone formation and enhanced bone resorption, thus causing adverse bone status.
Supplemental LA can attenuate HFD-induced negative effects on bone formation and prevent its enhancement effects on bone resorption associated with decreased oxidative stress. Furthermore, antioxidant LA can up-regulate genes involved in IGF-1 signaling pathway and down-regulate genes involved in P53 apoptotic pathway, thus contributing to attenuating inhibitory bone formation caused by HFD. Moreover, LA-induced the strong up-regulation of IL12a and down-regulation of PTHR1, TGFbR1, and IL17a may lead to depressing bone resorption.
4. Effect of redox status onmatrix mineralizetion of osteoblast-like cell (MC3T3-E1)
The role of redox status in matrix mineralization of MC3T3-E1 cells and preventive effect of antioxidant LA was studied. Our results suggested that LA prevented oxidative injure of MC3T3-E1 cells induced by hydrogen peroxide and down-regulated high NQO1 expression, which is involved in response to oxidative stress. The high NQO1 expression can increase stabilization of P53 expreesion, thus maybe induced osteoblastic apoptosis. This study demonstrated that LA can prevent P53-dependent MC3T3-E1 cells apoptosis induced by oxidative stress, associated with maintaing redox status. Moderate levels of LA (0.1-0.5mM) attenuate the impaired MC3T3-E1 cell proliferation and mineralization levels induced by hydrogen peroxide, but high levels of LA (2.5mM) can not prevent significantly its functions.
引文
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