Serum bilirubin may serve as a marker for increased heme oxygenase activity and inducibility in tissues - A rationale for the versatile health protection associated with elevated plasma bilirubin
Serum bilirubin may serve as a marker for increased heme oxygenase activity and inducibility in tissues - A rationale for the versatile health protection associated with elevated plasma bilirubin
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DOI：
10.1016/j.mehy.2013.07.013
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发表时间：
2013-10-01
影响因子：
4.7
通讯作者：
McCarty, Mark F.
中科院分区：
文献类型：
--
作者：
McCarty, Mark F.
未结合胆红素在细胞内作为NADPH氧化酶复合物的有效抑制剂发挥作用，白蛋白结合胆红素显著促进血浆的氧化剂清除活性。因此，血清胆红素水平被发现与血管疾病和许多其他疾病的风险呈负相关也就不足为奇了。尽管如此，最近的孟德尔随机化分析显示，携带肝胆红素结合酶UGT 1A 1的低表达等位基因的个体，因此在整个生命中血浆胆红素水平有所升高，血管疾病的风险并没有降低。这可能反映了这样一个事实，即在大多数人中，血浆中未结合的未结合胆红素（能够回流到细胞中的胆红素部分）水平非常低（接近1 nM），以至于它们只能对细胞产生微不足道的抗氧化作用。根据这些发现，可以合理地提出，许多研究中观察到的血浆胆红素和疾病风险的负相关性通常反映了这样一个事实，即血浆胆红素升高可以作为细胞内生成胆红素倾向增加的标志物。与这一观点一致，胆红素主要酶源血红素加氧酶-1（HO-1）的高表达等位基因在大多数研究中确实与血管风险降低相关，并且在这些等位基因携带者中报告了血浆胆红素升高。因此，在患有吉尔伯特综合征（传统上定义为血清胆红素超过20 μ M）的人中观察到的血管风险的持续降低可能归因于组织内胆红素生成速率的增加，而不是这种综合征的特征性肝脏UGT 1A 1活性的降低。然而，有充分的理由怀疑，在某些足够高的血浆胆红素水平下--如在患有非常严重的吉尔伯特综合征的个体中或在缺乏UGT 1A 1活性的古恩大鼠中--血浆胆红素池确实为细胞提供了一些抗氧化保护。通过HO-1诱导促进细胞内胆红素产生的策略，或用蓝藻藻胆素模拟胆红素的抗氧化活性的策略，可能对促进健康具有重要的潜力。(C)2013爱思唯尔有限公司保留所有权利。
Unconjugated bilirubin functions intracellularly as a potent inhibitor of NADPH oxidase complexes, and albumin-bound bilirubin contributes significantly to the oxidant scavenging activity of plasma. So it is not surprising that serum levels of bilirubin have been found to correlate inversely with risk for vascular diseases and a host of other disorders. Nonetheless, recent Mendelian randomization analyses reveal that individuals who carry low expression alleles of the hepatic bilirubin conjugating enzyme UGT1A1, and hence have somewhat elevated levels of plasma bilirubin throughout life, are not at decreased risk for vascular disorders. This likely reflects the fact that, in most people, plasma levels of unconjugated, unbound bilirubin - the fraction of bilirubin capable of fluxing back into cells - are so low (near 1 nM) that they can exert only a trivial antioxidant influence on cells. In light of these findings, it is reasonable to propose that the inverse correlation of plasma bilirubin and disease risks noted in many studies often reflect the fact that elevated plasma bilirubin can serve as a marker for an increased propensity to generate bilirubin within cells. Consistent with this view, high expression alleles of the major enzymatic source of bilirubin, heme oxygenase-1 (HO-1), do associate with decreased vascular risk in the majority of studies that have addressed this issue, and increased plasma bilirubin has been reported in carriers of these alleles. Hence, the consistent reduction in vascular risk noted in people with Gilbert syndrome (traditionally defined as having serum bilirubin in excess of 20 mu M) is likely attributable to an increased rate of bilirubin generation within tissues, rather than to the decreased hepatic UGT1A1 activity that characterizes this syndrome. However, there is good reason to suspect that, at some sufficiently high plasma bilirubin level - as in individuals with very intense Gilbert syndrome or in Gunn rats lacking UGT1A1 activity - the plasma bilirubin pool does indeed provide some antioxidant protection to cells. Strategies for boosting bilirubin production within cells via HO-1 induction, or for mimicking bilirubin's antioxidant activity with cyanobacterial phycobilins, may have important potential for health promotion. (C) 2013 Elsevier Ltd. All rights reserved.