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Studies on biosynthetic pathways to bile acids in human liver cells

机译:人肝细胞中生物合成途径对胆汁酸的研究

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The hepatic conversion of cholesterol to bile acids involves many enzymes with broad substrate specificities, permitting at least in theory a large number of biosynthetic pathways to exist . Furthermore, the enzymes efficiently convert the substrates, resulting in low and usually undetectable concentrations of intermediates in human liver tissue. Because of this, major biosynthetic pathways to cholic acid (CA) and chenodeoxycholic acid (CDCA) have been difficult to establish. Based on our studies on circulating bile acid precursors7'8 we could propose a model for the biosynthesis of bile acids in humans about a decade ago2' . Briefly, under normal conditions two major pathways, one starting with 7a-hydroxylation of cholesterol (neutral pathway) and the other with 27-hydroxylation (acidic pathway), lead to the formation of preferentially CA and CDCA, respectively (Figure 1). When the activity of cholesterol 7a-hydroxylase is high the neutral pathway dominates, whereas the acidic dominates when this activity is low. Since the two pathways had to be independently regulated, the existence of another 7a-hydroxylase being active on oxidized sterols could be predicted. This was subsequently confirmed.
机译:胆固醇与胆汁酸的肝转化率涉及许多具有宽底物特异性的酶,至少在理论上允许存在大量的生物合成途径。此外,酶有效地转化基质,导致人肝组织中的中间体的低且通常不可检测的浓度。因此,对胆酸(CA)和陈脱氧胆酸(CDCA)的主要生物合成途径难以建立。基于我们对循环胆汁酸前体的研究7'8,我们可以提出大约十年前的人类胆汁酸生物合成的模型。简而言之,在正常条件两个主要途径,一种起始与胆固醇(中性途径)的图7a-羟基化和另一个具有27羟基化(酸性途径),铅优先CA和CDCA,分别为(图1)的形成下。当胆固醇7A-羟化酶的活性高,中性途径占主导地位,而当该活性低时,酸性占主导地位。由于必须独立调节两种途径,因此可以预测氧化甾醇上活性的另一7A-羟化酶的存在。随后证实了这一点。

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