Peroxisome proliferator-activated receptor-δ induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice
Peroxisome proliferator-activated receptor-δ induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice
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DOI：
10.1002/hep.22334
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发表时间：
2008-08-01
期刊：
影响因子：
13.5
通讯作者：
Wang, Nanping
中科院分区：
文献类型：
--
作者：
Qin, Xiaomei;Xie, Xuefen;Wang, Nanping
原发性非酒精性脂肪肝是慢性肝病最常见的形式之一，与胰岛素抵抗状态如糖尿病和肥胖有关。最近的工作揭示了过氧化物酶体增殖物激活受体-δ（PPAR δ）在脂质稳态和胰岛素抵抗中的潜在意义。在这项研究中，我们研究了PPAR δ对固醇调节元件结合蛋白-1（SREBP-1）的影响，SREBP-1是一种控制肝细胞脂肪生成的关键转录因子。用GW 0742（PPARDelta激动剂）或PPARDelta过表达处理显着减少细胞内脂质积聚。肝细胞中GW 0742和PPAR δ过表达诱导胰岛素诱导基因-1（Insig-1）的表达，Insig-1是一种内质网蛋白，在mRNA和蛋白水平上抑制SREBP活化。PPARdelta抑制SREBP-1蛋白水解加工成成熟的活性形式，从而抑制脂肪酸合成酶、硬脂酰辅酶A去饱和酶-1和乙酰辅酶A羧化酶等脂肪生成基因的表达。我们的研究结果揭示了一个直接绑定的过氧化物酶体增殖物的非经典响应元件基序上游的转录起始位点的人Insig-1的过氧化物酶体δ。该位点的破坏减少了Insig-1的诱导，这表明Insig-1是肝细胞中的直接PPAR δ靶基因。内源性Insig-1的敲低减弱了GW 0742对SREBP-1及其靶基因的抑制作用，表明PPAR δ通过诱导Insig-1抑制SREBP-1活化。此外，通过静脉内感染PPARdelta腺病毒过表达PPARdelta诱导Insig-1的表达，抑制SREBP-1的激活，从而改善肥胖db/db小鼠的肝脏脂肪变性。结论：我们的研究揭示了一种新的机制，通过这种机制，PPARdelta调节脂肪生成，这表明PPARdelta调节剂在肥胖和2型糖尿病以及相关脂肪性肝病中的潜在治疗应用。
Primary nonalcoholic fatty liver disease is one of the most common forms of chronic liver diseases and is associated with insulin-resistant states such as diabetes and obesity. Recent work has revealed potential implications of peroxisome proliferator-activated receptor-delta (PPAR delta) in lipid homeostasis and insulin resistance. In this study, we examined the effect of PPAR delta on sterol regulatory element-binding protein-1 (SREBP-1), a pivotal transcription factor controlling lipogenesis in hepatocytes. Treatment with GW0742, the PPAR delta agonist, or overexpression of PPAR delta markedly reduced intracellular lipid accumulation. GW0742 and PPAR delta overexpression in hepatocytes induced the expression of insulin-induced gene-1 (Insig-1), an endoplasmic reticulum protein braking SREBP activation, at both the mRNA and the protein levels. PPAR delta inhibited the proteolytic processing of SREBP-1 into the mature active form, thereby suppressing the expression of the lipogenic genes fatty acid synthase, stearyl CoA desaturase-1, and acetyl coenzyme A carboxylase. Our results revealed a direct binding of PPAR delta to a noncanonical peroxisome proliferator responsive element motif upstream of the transcription initiation site of human Insig-1. The disruption of this site diminished the induction of Insig-1, which suggested that Insig-1 is a direct PPAR delta target gene in hepatocytes. Knockdown of endogenous Insig-1 attenuated the suppressive effect of GW0742 on SREBP-1 and its target genes, indicating PPAR delta inhibited SREBP-1 activation via induction of Insig-1. Furthermore, overexpression of PPAR delta by intravenous infection with the PPAR delta adenovirus induced the expression of Insig-1, suppressed SREBP-1 activation, and, consequently, ameliorated hepatic steatosis in obese db/db mice. Conclusion: Our study reveals a novel mechanism by which PPAR delta regulates lipogenesis, suggesting potential therapeutic applications of PPAR delta modulators in obesity and type 2 diabetes, as well as related steatotic liver diseases.