Castro Cabezas M
Department of Vascular Medicine F02.126, University Medical Center Utrecht, P.O Box 85500, 3508 GA Utrecht, The Netherlands.
Biochem Soc Trans. 2003 Oct;31(Pt 5):1090-3. doi: 10.1042/bst0311090.
FCHL (familial combined hyperlipidaemia) is the most frequent inherited disorder of lipid metabolism leading to premature atherosclerosis. The usual phenotype in FCHL is elevated fasting plasma triacylglycerols, low HDL (high-density lipoprotein)-cholesterol concentrations and elevated plasma apolipoprotein B concentrations. The metabolic basis for this phenotype is hepatic overproduction of VLDL (very-low-density lipoprotein), which is only partly linked to the insulin resistance associated with FCHL. At this stage the molecular basis for this VLDL overproduction is not known, but emerging evidence points to a disturbed trapping of peripheral fatty acids, resulting in enhanced hepatic flux of NEFA [non-esterified ('free') fatty acids]. Postprandial hyperlipidaemia with accumulation of lipoprotein remnants and NEFA have been implicated in the development of atherosclerosis in this disorder. It has been proposed that, by VLDL overproduction, fasting hypertriglyceridaemia may lead to 'overflow' of the catabolic cascade for triacylglycerol-rich particles, thereby explaining the delayed catabolism of remnants in FCHL. Delayed clearance of remnants of VLDL and chylomicrons leads to enhanced interaction of these highly atherogenic particles with the endothelium, and enhanced trans-endothelial migration of the particles, resulting in a chronic inflammatory response that is the initiation of the atherosclerotic lesion. In this process, activated leucocytes (either directly by the remnants or indirectly by released NEFA) play an important role by adherence to the endothelium and migration into the subendothelial space, where the uptake of atherogenic remnants results in a vicious cycle of activation of endothelium, leucocytes and production of cytokines.
家族性混合型高脂血症（FCHL）是导致早发性动脉粥样硬化的最常见的遗传性脂质代谢紊乱疾病。FCHL的常见表型为空腹血浆甘油三酯升高、高密度脂蛋白（HDL）胆固醇浓度降低以及血浆载脂蛋白B浓度升高。这种表型的代谢基础是肝脏极低密度脂蛋白（VLDL）产生过多，这仅部分与FCHL相关的胰岛素抵抗有关。目前尚不清楚这种VLDL产生过多的分子基础，但新出现的证据表明外周脂肪酸捕获受到干扰，导致肝脏非酯化（“游离”）脂肪酸（NEFA）通量增加。餐后高脂血症伴脂蛋白残粒和NEFA蓄积与该疾病的动脉粥样硬化发展有关。有人提出，通过VLDL产生过多，空腹高甘油三酯血症可能导致富含甘油三酯颗粒的分解代谢级联“溢出”，从而解释了FCHL中残粒分解代谢延迟的原因。VLDL和乳糜微粒残粒的清除延迟导致这些高度致动脉粥样硬化的颗粒与内皮细胞的相互作用增强，以及颗粒跨内皮迁移增强，从而引发慢性炎症反应，这是动脉粥样硬化病变的起始。在这个过程中，活化的白细胞（直接通过残粒或间接通过释放的NEFA）通过黏附于内皮细胞并迁移到内皮下间隙发挥重要作用，在内皮下间隙中，致动脉粥样硬化残粒的摄取导致内皮细胞、白细胞活化和细胞因子产生的恶性循环。
