Qin Xiaomei, Xie Xuefen, Fan Yanbo, Tian Jianwei, Guan Youfei, Wang Xian, Zhu Yi, Wang Nanping
Institute of Cardiovascular Science and Key Laboratory of Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing, China.
Hepatology. 2008 Aug;48(2):432-41. doi: 10.1002/hep.22334.
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 (PPARdelta) in lipid homeostasis and insulin resistance. In this study, we examined the effect of PPARdelta on sterol regulatory element-binding protein-1 (SREBP-1), a pivotal transcription factor controlling lipogenesis in hepatocytes. Treatment with GW0742, the PPARdelta agonist, or overexpression of PPARdelta markedly reduced intracellular lipid accumulation. GW0742 and PPARdelta 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. PPARdelta 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 PPARdelta 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 PPARdelta target gene in hepatocytes. Knockdown of endogenous Insig-1 attenuated the suppressive effect of GW0742 on SREBP-1 and its target genes, indicating PPARdelta inhibited SREBP-1 activation via induction of Insig-1. Furthermore, overexpression of PPARdelta by intravenous infection with the PPARdelta adenovirus induced the expression of Insig-1, suppressed SREBP-1 activation, and, consequently, ameliorated hepatic steatosis in obese db/db mice.
Our study reveals a novel mechanism by which PPARdelta regulates lipogenesis, suggesting potential therapeutic applications of PPARdelta modulators in obesity and type 2 diabetes, as well as related steatotic liver diseases.
原发性非酒精性脂肪性肝病是最常见的慢性肝病形式之一，与糖尿病和肥胖等胰岛素抵抗状态相关。最近的研究揭示了过氧化物酶体增殖物激活受体δ（PPARδ）在脂质稳态和胰岛素抵抗中的潜在作用。在本研究中，我们研究了PPARδ对甾醇调节元件结合蛋白-1（SREBP-1）的影响，SREBP-1是控制肝细胞脂质生成的关键转录因子。用PPARδ激动剂GW0742处理或PPARδ过表达显著减少细胞内脂质积累。GW0742和PPARδ在肝细胞中的过表达在mRNA和蛋白质水平上均诱导了胰岛素诱导基因-1（Insig-1）的表达，Insig-1是一种在内质网中抑制SREBP激活的蛋白质。PPARδ抑制SREBP-1蛋白水解加工成成熟的活性形式，从而抑制脂质生成基因脂肪酸合酶、硬脂酰辅酶A去饱和酶-1和乙酰辅酶A羧化酶的表达。我们的结果揭示了PPARδ与人Insig-1转录起始位点上游的非经典过氧化物酶体增殖物反应元件基序直接结合。该位点的破坏减弱了Insig-1的诱导，这表明Insig-1是肝细胞中PPARδ的直接靶基因。内源性Insig-1的敲低减弱了GW0742对SREBP-1及其靶基因的抑制作用，表明PPARδ通过诱导Insig-1抑制SREBP-1激活。此外，通过静脉注射PPARδ腺病毒过表达PPARδ可诱导Insig-1表达，抑制SREBP-1激活，从而改善肥胖db/db小鼠的肝脂肪变性。
我们的研究揭示了PPARδ调节脂质生成的新机制，提示PPARδ调节剂在肥胖和2型糖尿病以及相关脂肪性肝病中具有潜在的治疗应用。
