ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content.
ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content.
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DOI：
10.1194/jlr.m054080
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发表时间：
2015-03
影响因子：
6.5
通讯作者：
Shulman GI
中科院分区：
文献类型：
--
作者：
Camporez JPG;Kanda S;Petersen MC;Jornayvaz FR;Samuel VT;Bhanot S;Petersen KF;Jurczak MJ;Shulman GI
ApoA 5在调节血浆TG浓度方面发挥关键作用。为了确定ApoA 5是否也影响肝脏和骨骼肌中的异位脂质沉积以及组织胰岛素敏感性，我们用反义寡核苷酸（阿索）处理小鼠以降低ApoA 5的肝脏表达。阿索处理使肝脏中的ApoA 5蛋白表达降低60- 70%。ApoA 5 ASO处理的小鼠显示出约3倍的血浆TG浓度，这与血浆TG清除率降低相关。此外，ApoA 5 ASO处理的小鼠喂食高脂饮食（HFD）表现出降低的肝脏和骨骼肌TG摄取和降低的肝脏和肌肉TG和甘油二酯（DAG）含量。HFD喂养的ApoA 5 ASO处理的小鼠被保护免于HFD诱导的胰岛素抵抗，如通过高胰岛素-正常血糖钳夹评估的。这种保护作用可能归因于肝脏和外周胰岛素反应性的增加，与肝脏和肌肉中蛋白激酶C（PKC）-ε和PKCθ的DAG活化分别降低相关，以及这些组织中胰岛素刺激的AKT 2磷酸化增加。总之，这些研究证明了ApoA 5通过调节肝脏和骨骼肌中的异位脂质蓄积作为对饮食诱导的肝脏和肌肉胰岛素抵抗的易感性的调节剂的新作用。
ApoA5 has a critical role in the regulation of plasma TG concentrations. In order to determine whether ApoA5 also impacts ectopic lipid deposition in liver and skeletal muscle, as well as tissue insulin sensitivity, we treated mice with an antisense oligonucleotide (ASO) to decrease hepatic expression of ApoA5. ASO treatment reduced ApoA5 protein expression in liver by 60–70%. ApoA5 ASO-treated mice displayed approximately 3-fold higher plasma TG concentrations, which were associated with decreased plasma TG clearance. Furthermore, ApoA5 ASO-treated mice fed a high-fat diet (HFD) exhibited reduced liver and skeletal muscle TG uptake and reduced liver and muscle TG and diacylglycerol (DAG) content. HFD-fed ApoA5 ASO-treated mice were protected from HFD-induced insulin resistance, as assessed by hyperinsulinemic-euglycemic clamps. This protection could be attributed to increases in both hepatic and peripheral insulin responsiveness associated with decreased DAG activation of protein kinase C (PKC)-ε and PKCθ in liver and muscle, respectively, and increased insulin-stimulated AKT2 phosphorylation in these tissues. In summary, these studies demonstrate a novel role for ApoA5 as a modulator of susceptibility to diet-induced liver and muscle insulin resistance through regulation of ectopic lipid accumulation in liver and skeletal muscle.