Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice
Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice
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DOI：
10.1194/jlr.m039347
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发表时间：
2013-10-01
影响因子：
6.5
通讯作者：
Li, Tiangang
中科院分区：
文献类型：
--
作者：
Bi, Lipeng;Chiang, John Y. L.;Li, Tiangang
肝脏VLDL过度产生是糖尿病的特征性特征，也是糖尿病血脂异常的重要促成因素。肝分拣蛋白1（Sort 1）是一种细胞转运受体，是一种新型的血脂代谢调节因子，通过抑制肝载脂蛋白B的产生来降低血浆胆固醇和甘油三酯。升高的循环游离脂肪酸在肝脏VLDL过度产生和血脂异常的发展中起关键作用。本研究探讨了肝脏Sort 1在肥胖和糖尿病中的调节作用及其在糖尿病血脂异常中的潜在意义。结果显示，在I型和II型糖尿病小鼠模型以及肥胖和肝脏脂肪变性的人类个体中，肝脏Sort 1蛋白显著降低，而增加肝脏Sort 1表达可降低小鼠的血浆胆固醇和甘油三酯。机制研究表明，饱和脂肪酸棕榈酸酯激活细胞外信号调节激酶（ERK）和抑制Sort 1蛋白的机制，涉及Sort 1蛋白的泛素化和降解。一致地，在糖尿病小鼠中肝脏ERK信号被激活，而通过ERK抑制剂阻断ERK信号增加小鼠肝脏Sort 1蛋白。这些结果表明，增加饱和脂肪酸下调肝脏Sort1蛋白，这可能有助于肥胖和糖尿病血脂异常的发展。
Hepatic VLDL overproduction is a characteristic feature of diabetes and an important contributor to diabetic dyslipidemia. Hepatic sortilin 1 (Sort1), a cellular trafficking receptor, is a novel regulator of plasma lipid metabolism and reduces plasma cholesterol and triglycerides by inhibiting hepatic apolipoprotein B production. Elevated circulating free fatty acids play key roles in hepatic VLDL overproduction and the development of dyslipidemia. This study investigated the regulation of hepatic Sort1 in obesity and diabetes and the potential implications in diabetic dyslipidemia. Results showed that hepatic Sort1 protein was markedly decreased in mouse models of type I and type II diabetes and in human individuals with obesity and liver steatosis, whereas increasing hepatic Sort1 expression reduced plasma cholesterol and triglycerides in mice. Mechanistic studies showed that the saturated fatty acid palmitate activated extracellular signal-regulated kinase (ERK) and inhibited Sort1 protein by mechanisms involving Sort1 protein ubiquitination and degradation. Consistently, hepatic ERK signaling was activated in diabetic mice, whereas blocking ERK signaling by an ERK inhibitor increased hepatic Sort1 protein in mice. These results suggest that increased saturated fatty acids downregulate liver Sort1 protein, which may contribute to the development of dyslipidemia in obesity and diabetes.