Häussinger D, Lamers W H, Moorman A F
Medizinische Klinik, Universität Freiburg, Germany.
Enzyme. 1992;46(1-3):72-93. doi: 10.1159/000468779.
With respect to hepatocyte heterogeneity in ammonia and amino acid metabolism, two different patterns of sublobular gene expression are distinguished: 'gradient-type' and 'strict- or compartment-type' zonation. An example for strict-type zonation is the reciprocal distribution of carbamoylphosphate synthase and glutamine synthase in the liver lobule. The mechanisms underlying the different sublobular gene expressions are not yet settled but may involve the development of hepatic architecture, innervation, blood-borne hormonal and metabolic factors. The periportal zone is characterized by a high capacity for uptake and catabolism of amino acids (except glutamate and aspartate) as well as for urea synthesis and gluconeogenesis. On the other hand, glutamine synthesis, ornithine transamination and the uptake of vascular glutamate, aspartate, malate and alpha-ketoglutarate are restricted to a small perivenous hepatocyte population. Accordingly, in the intact liver lobule the major pathways for ammonia detoxication, urea and glutamine synthesis, are anatomically switched behind each other and represent in functional terms the sequence of the periportal low affinity system (urea synthesis) and a previous high affinity system (glutamine synthesis) for ammonia detoxication. Perivenous glutamine synthase-containing hepatocytes ('scavenger cells') act as a high affinity scavenger for the ammonia, which escapes the more upstream urea-synthesizing compartment. Periportal glutaminase acts as a pH- and hormone-modulated ammonia-amplifying system in the mitochondria of periportal hepatocytes. The activity of this amplifying system is one crucial determinant for flux through the urea cycle in view of the high Km (ammonia) of carbamoylphosphate synthase, the rate-controlling enzyme of the urea cycle. The structural and functional organization of glutamine and ammonia-metabolizing pathways in the liver lobule provides one basis for the understanding of a hepatic role in systemic acid base homeostasis. Urea synthesis is a major pathway for irreversible removal of metabolically generated bicarbonate. The lobular organization enables the adjustment of the urea cycle flux and accordingly the rate of irreversible hepatic bicarbonate elimination to the needs of the systemic acid base situation, without the threat of hyperammonemia.
关于肝细胞在氨和氨基酸代谢方面的异质性，可区分出两种不同的小叶下基因表达模式：“梯度型”和“严格或分隔型”分区。严格型分区的一个例子是氨甲酰磷酸合成酶和谷氨酰胺合成酶在肝小叶中的相互分布。不同小叶下基因表达的潜在机制尚未确定，但可能涉及肝脏结构的发育、神经支配、血源性激素和代谢因子。门周区的特点是对氨基酸（谷氨酸和天冬氨酸除外）的摄取和分解代谢以及尿素合成和糖异生能力较强。另一方面，谷氨酰胺合成、鸟氨酸转氨作用以及血管内谷氨酸、天冬氨酸、苹果酸和α-酮戊二酸的摄取仅限于一小部分肝静脉周围的肝细胞群体。因此，在完整的肝小叶中，氨解毒、尿素和谷氨酰胺合成的主要途径在解剖学上相互交错，在功能上代表了门周低亲和力系统（尿素合成）和先前的高亲和力系统（谷氨酰胺合成）对氨解毒的顺序。含谷氨酰胺合成酶的肝静脉周围肝细胞（“清除细胞”）作为氨的高亲和力清除剂，可清除上游更多的尿素合成隔室中逸出的氨。门周谷氨酰胺酶在门周肝细胞的线粒体中作为pH和激素调节的氨放大系统发挥作用。鉴于尿素循环的限速酶氨甲酰磷酸合成酶的高Km（氨），该放大系统的活性是尿素循环通量的一个关键决定因素。肝小叶中谷氨酰胺和氨代谢途径的结构和功能组织为理解肝脏在全身酸碱平衡中的作用提供了一个基础。尿素合成是代谢产生的碳酸氢盐不可逆清除的主要途径。小叶组织能够根据全身酸碱状况的需要调整尿素循环通量，从而调整肝脏不可逆碳酸氢盐清除率，而不会有高氨血症的风险。
