FoxO1 integrates insulin signaling to VLDL production.
FoxO1 integrates insulin signaling to VLDL production.
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DOI：
10.4161/cc.7.20.6882
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Dong HH
中科院分区：
文献类型：
--
作者：
Kamagate A;Dong HH
极低密度脂蛋白（VLDL）是富含磷脂酰胆碱的颗粒。VLDL在肝细胞中合成，并通过胰岛素严格调节的途径从肝脏分泌。肝脏VLDL的产生响应于胰岛素作用的减少而被刺激，导致在空腹条件下VLDL向血液中的释放增加。循环VLDL充当将脂质转运至外周组织以实现能量稳态的载体。相反，餐后胰岛素释放增加会抑制肝脏VLDL的产生。这种作用对于防止正常个体餐后血脂谱的长期波动至关重要。在患有肥胖症和2型糖尿病的受试者中，由于肝脏中的胰岛素抵抗，胰岛素调节VLDL产生的能力受损，导致VLDL分泌过量和富含磷脂酰肌醇的颗粒在血液中积聚。这种脂质代谢异常是高脂血症发病机制的特征，并导致肥胖和2型糖尿病患者冠状动脉疾病风险增加。然而，胰岛素抵抗与VLDL过量产生之间的分子基础仍然知之甚少。我们最近的研究表明，叉头转录因子FoxO1在肝脏中起作用，将肝脏胰岛素作用整合到VLDL的产生中。胰岛素抵抗肝脏中FoxO1活性增强促进肝脏VLDL过度产生，并易导致高胆固醇血症的发生。这些新发现提出了一个重要的问题：FoxO1是改善高脂血症的治疗靶点吗？在这里，我们讨论这个问题的背景下，我们对高胆固醇血症的病理生理学的理解的最新进展。
Very low-density lipoproteins (VLDL) are triglyceride-rich particles. VLDL is synthesized in hepatocytes and secreted from the liver in a pathway that is tightly regulated by insulin. Hepatic VLDL production is stimulated in response to reduced insulin action, resulting in increased release of VLDL into the blood under fasting conditions. Circulating VLDL serves as a vehicle for transporting lipids to peripheral tissues for energy homeostasis. Conversely, hepatic VLDL production is suppressed in response to increased insulin release after meals. This effect is critical for preventing prolonged excursion of postprandial plasma lipid profiles in normal individuals. In subjects with obesity and type 2 diabetes, the ability of insulin to regulate VLDL production becomes impaired due to insulin resistance in the liver, resulting in excessive VLDL secretion and accumulation of triglyceride-rich particles in the blood. Such abnormality in lipid metabolism characterizes the pathogenesis of hypertriglyceridemia and accounts for increased risk of coronary artery disease in obesity and type 2 diabetes. Nevertheless, the molecular basis that links insulin resistance to VLDL overproduction remains poorly understood. Our recent studies illustrate that the forkhead transcription factor FoxO1 acts in the liver to integrate hepatic insulin action to VLDL production. Augmented FoxO1 activity in insulin resistant livers promotes hepatic VLDL overproduction and predisposes to the development of hypertriglyceridemia. These new findings raise an important question: Is FoxO1 a therapeutic target for ameliorating hypertriglyceridemia? Here we discuss this question in the context of recent advances toward our understanding of the pathophysiology of hypertriglyceridemia.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
4.8
作者：
Améen, C;Edvardsson, U;Oscarsson, J
通讯作者：
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影响因子：
8.2
作者：
Bernard, S;Touzet, S;Moulin, P
通讯作者：
Moulin, P
DOI：
10.1161/atvbaha.107.148817
发表时间：
2008-01-01
影响因子：
8.7
作者：
Barter, Philip J.;Rye, Kerry-Anne
通讯作者：
Rye, Kerry-Anne
影响因子：
8.2
作者：
Adiels, M.;Westerbacka, J.;Boren, J.
通讯作者：
Boren, J.