Davis R A, Hui T Y
Mammalian Cell and Molecular Biology Laboratory, San Diego State University, San Diego, CA 92182-4614, USA.
Arterioscler Thromb Vasc Biol. 2001 Jun;21(6):887-98. doi: 10.1161/01.atv.21.6.887.
The production of apolipoprotein B (apoB)-containing lipoproteins by the liver is regulated by a complex series of processes involving apoB being cotranslationally translocated across the endoplasmic reticulum and assembled into a lipoprotein particle. The translocation of apoB across the endoplasmic reticulum is facilitated by the intraluminal chaperone, microsomal triglyceride transfer protein (MTP). MTP facilitates the translocation and folding of apoB, as well as the addition of lipid to lipid-binding domains (which consist of amphipathic beta sheets and alpha helices). In the absence of MTP or sufficient lipid, apoB exhibits translocation arrest. Thus, apoB translation, translocation, and assembly with lipids to form a core-containing lipoprotein particle occur as concerted processes. Abrogation of >/=1 of these processes diverts apoB into a degradation pathway that is dependent on conjugation with ubiquitin and proteolysis by the proteasome. The nascent core-containing lipoprotein particle that forms within the lumen of the endoplasmic reticulum can be "enlarged" to form a mature very low density lipoprotein particle. Additional studies show that the assembly and secretion of apoB-containing lipoproteins are linked to the cholesterol/bile acid synthetic pathway controlled by cholesterol 7alpha-hydroxylase. Studies in cultured cells and transgenic mice indicate that the expression of cholesterol 7alpha-hydroxylase indirectly regulates the expression of lipogenic enzymes through changes in the cellular content of mature sterol response element binding proteins. Oxysterols and bile acids may also act via the ligand-activated nuclear receptors LXR and FXR to link the metabolic pathways controlling energy balance and lipid metabolism to nutritional state.
肝脏中含载脂蛋白B（apoB）的脂蛋白的产生受一系列复杂过程的调控，这些过程涉及apoB在内质网中的共翻译转运，并组装成脂蛋白颗粒。内质网腔内伴侣微粒体甘油三酯转运蛋白（MTP）促进了apoB在内质网中的转运。MTP促进apoB的转运和折叠，以及脂质添加到脂质结合结构域（由两亲性β片层和α螺旋组成）。在缺乏MTP或足够脂质的情况下，apoB会出现转运停滞。因此，apoB的翻译、转运以及与脂质组装形成含核心的脂蛋白颗粒是协同进行的过程。这些过程中≥1个过程的废除会使apoB进入依赖于与泛素结合和蛋白酶体蛋白水解的降解途径。在内质网腔内形成的新生含核心脂蛋白颗粒可以“扩大”形成成熟的极低密度脂蛋白颗粒。进一步的研究表明，含apoB脂蛋白的组装和分泌与由胆固醇7α-羟化酶控制的胆固醇/胆汁酸合成途径相关。在培养细胞和转基因小鼠中的研究表明，胆固醇7α-羟化酶的表达通过改变成熟固醇反应元件结合蛋白的细胞含量间接调节脂肪生成酶的表达。氧化固醇和胆汁酸也可能通过配体激活的核受体LXR和FXR起作用，将控制能量平衡和脂质代谢的代谢途径与营养状态联系起来。
