Vecka Marek, Zak Ales, Tvrzická Eva
Charles University in Prague, First Faculty of Medicine, Clinical Department of Gastroenterology and Hepatology, Prague.
Acta Univ Carol Med Monogr. 2008;154:5-101.
Although most of us are more or less familiar with the term "cholesterol", the world of sterols is far more complicated and interesting. Apart from cholesterol, many non-cholesterol sterols can be found in human plasma and these sterols serve many important functions in human organism. They are either derived from endogenous biosynthesis of cholesterol or they come from dietary sources (phytosterols). The sole cholesterol molecule is used for keeping our cell membranes fit, for signalization purposes as well as a precursor for bile acids and steroid hormones. The compounds prior to cholesterol in its biosynthetic pathway were identified as vitamin D3 precursor, meiosis activating sterols and nowadays it seems that they could play a role in cholesterol homeostasis. The sterols from ingested vegetable sources, the phytosterols, are expelled from enterocytes and thus indirectly help our gut in coping with abundant cholesterol in the lumen. Higher plants synthesize many phytosterols, but in marine organisms, we can find other innumerous sterol molecules. The diversity of sterol molecules produced and resistance of their tetracyclic core to enzymatic activities implies crucial importance of sterols during the ontogenesis of multicellular organisms. First oxygen appeared on the Earth app. 2.7 billion years ago and since that time, every new life form took the advantage of oxygen needed also for build-up of sterol molecules. The last decades changed our view to the sterol molecules on almost at all levels of their appearance in human body. In the gut, the absorption of sterols was proven to be protein dependent and the quest for the transporter was successful. The general concepts of intracellular homeostasis of cholesterol have been described including the covalent interaction unbelievable so far - cholesterol and a protein. The clinical importance of non-cholesterol sterols rises with the effort to discover underlying facts about the causes of atherosclerosis. The compound in question, cholesterol, seems to be involved, but it sounds not to be crucial per se. The fact that the accumulation of phytosterols in sitosterolemia enhances the probability of early atherosclerosis onset further supports the hypothesis about some sterol (or steroid) compound being responsible on the molecular level for triggering the pathobiochemical cascade of events leading to atherosclerosis. Understanding the processes taking place in the enterocyte during the absorption of sterols resulted in synthesis of selective inhibitors at the level of sterol translocation into the enterocyte, sterol esterification and chylomicron packing, which are in different phases of clinical testing. The studies in the last part of the monograph represent the clinical potential of the analyses of non-cholesterol sterols. In well-defined groups, these analytes enables us to assess the changes in the homeostasis of cholesterol, which can be reflected in the concentration of total cholesterol. Furthermore, the high concentrations of some plasma sterols could point to the inborn errors of cholesterol biosynthesis (Smith-Laemli-Opitz syndrome), transport (sitosterolemia) or metabolization (cerebrotendinous xanthomatosis). Some issues concerning the research on the non-cholesterol sterols still remain unanswered - it is not known why some of the enzymes of the cholesterol biosynthesis (seladin-1, sterol D14 reductase) have other functions, qualitative aspects of sterol absorption are not satisfactorily explained and exact reason for expulsion of phytosterols from human body is not clear. Nevertheless, the authors hope that the presented facts can broaden the reader's perspective about the area, which is usually hidden beneath the cholesterol molecule.
尽管我们大多数人或多或少都熟悉“胆固醇”这个术语,但甾醇的世界要复杂和有趣得多。除了胆固醇外,人体血浆中还能发现许多非胆固醇甾醇,这些甾醇在人体中发挥着许多重要功能。它们要么源自胆固醇的内源性生物合成,要么来自饮食来源(植物甾醇)。单一的胆固醇分子用于维持我们细胞膜的健康,用于信号传导,也是胆汁酸和类固醇激素的前体。在其生物合成途径中先于胆固醇的化合物被鉴定为维生素D3前体、减数分裂激活甾醇,如今看来它们可能在胆固醇稳态中发挥作用。从摄入的植物来源中获取的甾醇,即植物甾醇,会从肠细胞中排出,从而间接帮助我们的肠道应对肠腔内大量的胆固醇。高等植物合成许多植物甾醇,但在海洋生物中,我们可以发现其他无数的甾醇分子。所产生的甾醇分子的多样性及其四环核心对酶活性的抗性意味着甾醇在多细胞生物的个体发育过程中至关重要。大约在27亿年前,地球上首次出现氧气,从那时起,每一种新的生命形式都利用了构建甾醇分子所需的氧气。过去几十年几乎在甾醇分子在人体中出现的各个层面上改变了我们对它们的看法。在肠道中,已证明甾醇的吸收依赖于蛋白质,并且对转运蛋白的寻找取得了成功。已经描述了胆固醇细胞内稳态的一般概念,包括迄今为止令人难以置信的共价相互作用——胆固醇和一种蛋白质。随着努力发现动脉粥样硬化病因背后的事实,非胆固醇甾醇的临床重要性日益增加。所讨论的化合物胆固醇似乎与之有关,但本身似乎并非至关重要。植物甾醇在谷甾醇血症中的积累增加了早期动脉粥样硬化发病的可能性,这一事实进一步支持了关于某种甾醇(或类固醇)化合物在分子水平上导致引发动脉粥样硬化的病理生化事件级联反应的假设。对甾醇吸收过程中肠细胞内发生的过程的理解导致了在甾醇转运到肠细胞、甾醇酯化和乳糜微粒包装水平上的选择性抑制剂的合成,这些抑制剂正处于临床试验的不同阶段。专著最后一部分的研究代表了非胆固醇甾醇分析的临床潜力。在明确界定的群体中,这些分析物使我们能够评估胆固醇稳态的变化,这可以反映在总胆固醇浓度中。此外,某些血浆甾醇的高浓度可能指向胆固醇生物合成(史密斯-莱姆利-奥皮茨综合征)、转运(谷甾醇血症)或代谢(脑腱性黄瘤病)的先天性缺陷。关于非胆固醇甾醇的一些研究问题仍然没有答案——尚不清楚为什么胆固醇生物合成的某些酶(seladin-1、甾醇D14还原酶)具有其他功能,甾醇吸收的定性方面没有得到令人满意的解释,以及植物甾醇从人体排出的确切原因尚不清楚。然而,作者希望所呈现的事实能够拓宽读者对这个通常隐藏在胆固醇分子之下的领域的视野。