For long time bilirubin was only considered as a potentially dangerous sign of liver diseases, but it now appears clear that it is also a powerful signaling molecule. Together with potent antioxidant activities that were only reported in the last few decades, many other biological effects have now been clearly described. These include especially profound inhibitory effects on almost all effectors of the immune system, with their clinical consequences in the bilirubin‐mediated protection against autoimmune and inflammatory diseases. Separate from these, bilirubin activates various nuclear and cytoplasmic receptors, resembling the endocrine activities of actual hormonal substances. This is true for the “classical” hepatic nuclear receptors, including the aryl hydrocarbon receptor, or the constitutive androstane receptor; and also for some lesser‐explored receptors such as peroxisome proliferator‐activated receptors α and γ; Mas‐related G protein‐coupled receptor; or other signaling molecules including fatty acid binding protein 1, apolipoprotein D, or reactive oxygen species. All of these targets have broad metabolic effects, which in turn may offer protection against obesity, diabetes mellitus, and other metabolic diseases. The (mostly experimental) data are also supported by clinical evidence. In fact, data from the last three decades have convincingly demonstrated the protective effects of mildly elevated serum bilirubin concentrations against various “diseases of civilization.” Additionally, even tiny, micromolar changes of serum bilirubin concentrations have been associated with substantial alteration in the risks of these diseases. It is highly likely that all of the biological activities of bilirubin have yet to be exhaustively explored, and thus we can expect further clinical discoveries about this evolutionarily old molecule into the future.

中文翻译：

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胆红素作为信号分子。

长期以来，胆红素仅被认为是肝脏疾病的潜在危险信号，但现在看来，它也是一种强大的信号分子。连同仅在最近几十年才报道的有效抗氧化活性，现在已经清楚地描述了许多其他生物效应。这些包括对免疫系统的几乎所有效应物的特别深刻的抑制作用，以及它们在胆红素介导的针对自身免疫和炎症疾病的保护中的临床后果。与这些不同的是，胆红素激活各种核和细胞质受体，类似于实际激素物质的内分泌活动。这适用于“经典”肝核受体，包括芳烃受体或组成型雄甾烷受体；以及一些鲜为人知的受体，例如过氧化物酶体增殖物激活受体 α 和 γ；Mas相关G蛋白偶联受体；或其他信号分子，包括脂肪酸结合蛋白 1、载脂蛋白 D 或活性氧。所有这些目标都具有广泛的代谢作用，这反过来又可以预防肥胖、糖尿病和其他代谢疾病。（主要是实验）数据也得到临床证据的支持。事实上，过去三年的数据已经令人信服地证明了轻度升高的血清胆红素浓度对各种“文明病”的保护作用。此外，即使血清胆红素浓度的微小、微摩尔变化也与这些疾病风险的实质性改变有关。