Hepatic insig-1 or-2 overexpression reduces lipogenesis in obese Zucker diabetic fatty rats and in fasted/refed normal rats
Hepatic insig-1 or-2 overexpression reduces lipogenesis in obese Zucker diabetic fatty rats and in fasted/refed normal rats
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DOI：
10.1073/pnas.0401715101
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发表时间：
2004-05-04
影响因子：
11.1
通讯作者：
Unger, RH
中科院分区：
文献类型：
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作者：
Takaishi, K;Duplomb, L;Unger, RH
为了确定胰岛素诱导基因1（insig-1）在培养的前脂肪细胞中表现出的抗脂肪生成作用是否也发生在体内，我们用含有insig-1或-2 cDNA的重组腺病毒感染Zucker糖尿病脂肪（ZDF）（fa/fa）大鼠。这两种蛋白质的增加出现在他们的肝脏。在对照ZDF（fa/fa）大鼠感染腺病毒含有β-半乳糖苷酶（P-gal）cDNA，三酰甘油在肝脏和血浆急剧上升，而insig感染大鼠表现出显着衰减的肝脂肪变性和高脂血症的增加。Insig过表达与核固醇调节元件结合蛋白（SREBP）-1c（转录因子的活化形式）水平的显著降低有关。SREBP-1c脂肪生成靶酶的mRNA也下降。与对照组相比，在未经治疗的肥胖ZDF（fa/fa）大鼠脂肪肝中，内源性insig-1（而非-2a和-2b）的mRNA水平较高，但这种升高不足以阻止SREBP-1c表达和活性增加约3倍。在正常动物中，腺病毒诱导的insigs过表达减少了再喂养引起的SREBP-1c mRNA及其靶酶的增加。研究结果表明，当在肝脏中转基因过表达时，两种insigs都具有抗脂肪生成作用，SREBP-1c介导的脂肪生成增加。然而，与增加的脂肪生成相关的内源性insig-1表达的增加可能会限制它，但不足以阻止它。
To determine whether the antilipogenic actions of insulin-induced gene 1 (insig-1) demonstrated in cultured preadipocytes also occur in vivo, we infected Zucker diabetic fatty (ZDF) (fa/fa) rats, with recombinant adenovirus containing insig-1 or -2 cDNA. An increase of both proteins appeared in their livers. In control ZDF (fa/fa) rats infected with adenovirus containing the beta-galactosidase (P-gal) cDNA, triacylglycerols in the liver and plasma rose steeply whereas the insig-infected rats exhibited substantial attenuation of the increase in hepatic steatosis and hyperlipidemia. Insig overexpres-sion was associated with a striking reduction in the elevated level of nuclear sterol regulatory element-binding protein (SREBP)-1c, the activated form of the transcription factor. The mRNA of SREBP-1c lipogenic target enzymes also fell. The mRNA of endog-enous insig-1, but not -2a and -2b, was higher in the fatty livers of untreated obese ZDF (fa/fa) rats compared with controls, but the elevation was not sufficient to block the approximate to3-fold increase in SREBP-1c expression and activity. In normal animals, adenovirus-induced overexpression of the insigs reduced the increase in SREBP-1c mRNA and its target enzymes caused by refeeding. The findings demonstrated that both insigs have antilipogenic action when transgenically overexpressed in livers with increased SREBP-1c-mediated lipogenesis. However, the increase in endogenous insig-1 expression associated with augmented lipogenesis may limit it, but is insufficient to prevent it.