Division of Immunogenetics, Rangos Research Center, Children's Hospital of Pittsburgh of UPMC, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Curr Drug Targets. 2011 Aug;12(9):1245-55. doi: 10.2174/138945011796150262.
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.
高甘油三酯血症的特征是富含甘油三酯的脂蛋白（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，高甘油三酯血症导致动脉粥样硬化和冠心病的发展。虽然高甘油三酯血症的病理生理学仍知之甚少，但它与肥胖和 2 型糖尿病密切相关，表明胰岛素抵抗在高甘油三酯血症的发病机制中起作用。然而，将胰岛素抵抗与高甘油三酯血症联系起来的分子基础仍然难以捉摸。临床前研究表明，FoxO1 在控制胰岛素依赖性调节微粒体甘油三酯转移蛋白（MTP）和载脂蛋白 C-III（ApoC-III）方面发挥着关键作用，这两种关键成分催化富含甘油三酯的脂蛋白的产生和清除的限速步骤。在生理条件下，FoxO1 的活性受胰岛素抑制。在胰岛素抵抗状态下，FoxO1 变得失调，导致肝脏中 FoxO1 活动不受控制。这种作用导致 VLDL 的肝脏过度产生和富含甘油三酯颗粒的代谢受损，导致高甘油三酯血症的发病机制。这些数据促使人们假设选择性抑制肝脏中的 FoxO1 活性将改善甘油三酯代谢并改善高甘油三酯血症。在本文中，我们综述了 FoxO1 在胰岛素作用和脂质代谢中的作用，并评估了针对 FoxO1 治疗肥胖和 2 型糖尿病伴胰岛素抵抗患者高甘油三酯血症的治疗潜力。
