Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance
Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance
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DOI：
10.1172/jci26991
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发表时间：
2006-06-01
影响因子：
15.9
通讯作者：
Rossetti, Luciano
中科院分区：
文献类型：
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作者：
Gutierrez-Juarez, Roger;Pocai, Alessandro;Rossetti, Luciano
硬脂酰辅酶A去饱和酶-1（SCD 1）催化饱和脂肪酸合成单不饱和脂肪酸。Scd 1基因位点靶向破坏的小鼠是瘦的，并显示出增加的胰岛素敏感性。为了研究饮食诱导的肝脏胰岛素抵抗是否需要Scd 1活性，我们使用了序列特异性反义寡核苷酸（阿索）来降低饮食诱导的胰岛素抵抗大鼠和小鼠肝脏Scd 1表达。与用乱序阿索（对照）处理的大鼠相比，用Scd 1阿索处理的大鼠显著降低肝脏Scd 1表达（类似于80%）和总Scd活性（类似于50%）。胰岛素钳夹研究显示，在高脂喂养的大鼠和小鼠中存在严重的肝脏胰岛素抵抗，经Scd 1阿索治疗5天后完全逆转。后一种处理降低了葡萄糖的产生（类似于75%），糖原异生和糖原分解。Scd 1的下调也导致Akt磷酸化增加，葡萄糖-6-磷酸酶（Glc-6-ATPase）和磷酸烯醇式丙酮酸羧激酶（PEPCK）的表达显著降低。因此，Scd 1是饮食诱导的肝胰岛素抵抗发作所必需的。
Stearoyl-CoA desaturase-1(SCD1) catalyzes the synthesis of monounsaturated fatty acids from saturated fatty acids. Mice with a targeted disruption of Scd1 gene locus are lean and display increased insulin sensitivity. To examine whether Scd1 activity is required for the development of diet-induced hepatic insulin resistance, we used a sequence-specific antisense oligodeoxynucleotide (ASO) to lower hepatic Scd1 expression in rats and mice with diet-induced insulin resistance. Treatment of rats with Scd1 ASO markedly decreased liver Scd1 expression (similar to 80%) and total Scd activity (similar to 50%) compared with that in rats treated with scrambled ASO (control). Insulin clamp studies revealed severe hepatic insulin resistance in high-fat-fed rats and mice that was completely reversed by 5 days of treatment with Scd1 ASO. The latter treatment decreased glucose production (by similar to 75%), gluconeogenesis, and glycogenolysis. Downregulation of Scd1 also led to increased Akt phosphorylation and marked decreases in the expression of glucose-6-phosphatase (Glc-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Thus, Scd1 is required for the onset of diet-induced hepatic insulin resistance.