Kang S, Davis R A
Mammalian Cell and Molecular Biology Lab, Department of Biology, The Molecular Biology Institute, San Diego State University, San Diego, California 92182-0057, USA.
Biochim Biophys Acta. 2000 Dec 15;1529(1-3):223-30. doi: 10.1016/s1388-1981(00)00151-7.
The assembly and secretion of apo B100 containing lipoproteins (i.e., VLDL) by the liver and cholesterol metabolism are interrelated on several different levels and for several different physiologic reasons. Firstly, hepatic VLDL is the major precursor for LDL, which in the human is the major vehicle responsible for transporting cholesterol to peripheral tissues. Secondly, cholesterol is supplied to many tissues by a specific uptake of LDL via LDL receptor, which is expressed in a regulated manner by most mammalian tissues. Thirdly, the rate of hepatic cholesterol biosynthesis and metabolism to bile acids correlates with production of VLDL. This apparent coordinate expression of cholesterol biosynthetic/catabolic enzymes and hepatic VLDL assembly/secretion are mediated at least in part through the sterol response element binding protein (SREBP) transcription factor family. Their gene targets include a plethora of enzymes that regulate glycolysis, energy production, lipogenesis and cholesterol catabolism. Studies of hepatoma cells overexpressing CYP7A1, the rate-limiting enzyme controlling bile acid synthesis, show that as a result of increased mature SREBP1, there is a coordinate induction of lipogenesis and the assembly and secretion of VLDL. These and additional studies show that the bile acid synthetic pathway and the VLDL assembly/secretion pathway are coordinately linked through SREBP-dependent transcription. Based on studies showing that within the liver acinus, the expression of CYP7A1 is mainly in the pericentral region while HMG-CoA reductase is mainly periportal, we propose that a 'metabolic zonal segregation' plays an important role in coordinate regulation of cholesterol and VLDL metabolism. This putative 'metabolic zonal segregation' may provide segregation of metabolic functions which may be mutually antagonistic. For example, there may be physiologic states in which the bile acid synthetic pathway may compete with the VLDL assembly/secretion pathway for a limited amount of cholesterol. Metabolic antagonism (e.g., competition for cholesterol) may be avoided via inducing SREBP-mediated transcription. Adaptation of catabolic hepatocytes to accommodate the expression of VLDL assembly/secretion may occur in response to activation of SREBP-mediated transcription. Support for these is discussed.
肝脏中含载脂蛋白B100的脂蛋白（即极低密度脂蛋白，VLDL）的组装与分泌以及胆固醇代谢在几个不同层面上相互关联，且存在多种不同的生理原因。首先，肝脏极低密度脂蛋白是低密度脂蛋白（LDL）的主要前体，在人类中，低密度脂蛋白是负责将胆固醇转运至外周组织的主要载体。其次，胆固醇通过大多数哺乳动物组织以受调控方式表达的低密度脂蛋白受体对低密度脂蛋白的特异性摄取，被供应至许多组织。第三，肝脏胆固醇生物合成及向胆汁酸代谢的速率与极低密度脂蛋白的产生相关。胆固醇生物合成/分解代谢酶与肝脏极低密度脂蛋白组装/分泌的这种明显的协同表达至少部分是通过固醇调节元件结合蛋白（SREBP）转录因子家族介导的。它们的基因靶点包括大量调节糖酵解、能量产生、脂肪生成和胆固醇分解代谢的酶。对过表达细胞色素P450 7A1（CYP7A1，控制胆汁酸合成的限速酶）的肝癌细胞的研究表明，由于成熟的固醇调节元件结合蛋白1（SREBP1）增加，脂肪生成以及极低密度脂蛋白的组装与分泌会协同诱导。这些研究及其他研究表明，胆汁酸合成途径与极低密度脂蛋白组装/分泌途径通过SREBP依赖的转录协同相连。基于显示在肝腺泡内，细胞色素P450 7A1的表达主要在中央周围区域，而3-羟基-3-甲基戊二酰辅酶A还原酶主要在门静脉周围区域的研究，我们提出“代谢区带分离”在胆固醇和极低密度脂蛋白代谢的协同调节中起重要作用。这种假定的“代谢区带分离”可能提供可能相互拮抗的代谢功能的分离。例如，可能存在胆汁酸合成途径与极低密度脂蛋白组装/分泌途径争夺有限量胆固醇的生理状态。可通过诱导SREBP介导的转录来避免代谢拮抗（如对胆固醇的竞争）。分解代谢肝细胞对极低密度脂蛋白组装/分泌表达的适应可能会因SREBP介导的转录激活而发生。文中对这些内容进行了讨论。
