Targeting FoxO1 for hypertriglyceridemia.
Targeting FoxO1 for hypertriglyceridemia.
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DOI：
10.2174/138945011796150262
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发表时间：
2011-07
影响因子：
3.2
通讯作者：
Dae Hyun Kim;Ting Zhang;S. Ringquist;H. H. Dong-H.
中科院分区：
文献类型：
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作者：
Dae Hyun Kim;Ting Zhang;S. Ringquist;H. H. Dong-H.
高胆固醇血症的特征在于富含胆固醇的脂蛋白（包括极低密度脂蛋白（VLDL）和乳糜微粒）的产生增加和清除减少。由于其促动脉粥样硬化的特征，高甘油三酯血症有助于动脉粥样硬化和冠状动脉疾病的发展。虽然高胆固醇血症的病理生理学仍然知之甚少，但其与肥胖和2型糖尿病的密切关系暗示了高胆固醇血症的发病机制中的胰岛素抵抗。然而，将胰岛素抵抗与高脂血症联系起来的分子基础仍然难以捉摸。临床前研究表明，FoxO 1在控制微粒体甘油三酯转移蛋白（MTP）和载脂蛋白C-III（ApoC-III）的胰岛素依赖性调节中起着关键作用，这两种关键组分催化富含甘油三酯的脂蛋白的产生和清除中的限速步骤。在生理条件下，FoxO 1活性被胰岛素抑制。在胰岛素抵抗状态下，FoxO 1变得失调，导致肝脏中FoxO 1活性不受控制。这种作用导致肝脏过度产生VLDL和受损的富含磷脂酰肌醇的颗粒，解释了高磷脂酰肌醇血症的发病机制。这些数据刺激了这样的假设，即选择性抑制肝脏中FoxO 1活性将改善甘油三酯代谢并改善高甘油三酯血症。在这篇文章中，我们回顾了FoxO 1在胰岛素作用和脂质代谢中的作用，并评估了靶向FoxO 1治疗肥胖和2型糖尿病胰岛素抵抗患者高脂血症的治疗潜力。
Hypertriglyceridemia is characterized by increased production and decreased clearance of triglyceride-rich lipoproteins including very low-density lipoprotein (VLDL) and chylomicron. Due to its proatherogenic profile, hypertriglyceridemia contributes to the development of atherosclerosis and coronary artery disease. While the pathophysiology of hypertriglyceridemia remains poorly understood, its close association with obesity and type 2 diabetes implicates insulin resistance in the pathogenesis of hypertriglyceridemia. However, the molecular basis linking insulin resistance to hypertriglyceridemia remains elusive. Preclinical studies show that FoxO1 plays a pivotal role in controlling insulin-dependent regulation of microsomal triglyceride transfer protein (MTP) and apolipoprotein C-III (ApoC-III), two key components that catalyze the rate-limiting steps in the production and clearance of triglyceride-rich lipoproteins. Under physiological conditions, FoxO1 activity is inhibited by insulin. In insulin resistant states, FoxO1 becomes deregulated, contributing to unbridled FoxO1 activity in the liver. This effect contributes to hepatic overproduction of VLDL and impaired catabolism of triglyceride-rich particles, accounting for the pathogenesis of hypertriglyceridemia. These data spur the hypothesis that selective inhibition of FoxO1 activity in the liver would improve triglyceride metabolism and ameliorate hypertriglyceridemia. In this article, we review the role of FoxO1 in insulin action and lipid metabolism, and evaluate the therapeutic potential of targeting FoxO1 for treating hypertriglyceridemia in insulin resistant subjects with obesity and type 2 diabetes.