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过氧化物酶体增殖物激活受体α（PPARα）依赖性 Insig2a 过表达可抑制禁食期间 SREBP-1c 的加工。

PPARα-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting.

机构信息

Department of Physiology, Keimyung University School of Medicine, Daegu, 42601, South Korea.

Department of Molecular Medicine, Inha University School of Medicine, Incheon, 22212, South Korea.

出版信息

Sci Rep. 2017 Aug 30;7(1):9958. doi: 10.1038/s41598-017-10523-7.

DOI:10.1038/s41598-017-10523-7
PMID:28855656
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5577246/
Abstract

Peroxisome-proliferator-activated receptor alpha (PPARα) and sterol regulatory element-binding protein (SREBP) play a role in regulating cellular fatty acid and cholesterol homeostasis via fatty acid oxidation and lipogenesis. The control of SREBP processing is regulated by the insulin induced gene (INSIG)2a protein, which binds SREBP to prevent SREBP translocation to the Golgi apparatus during nutrient starvation in the liver. However, the regulation of SREBP-1c processing by INSIGs during fasting and the regulatory mechanisms of the mouse Insig2a gene expression have not been clearly addressed. In the present study, we found that Insig2a was upregulated by PPARα in mouse livers and primary hepatocytes during fasting, whereas Insig2a mRNA expression was decreased in the livers of refed mice. A PPAR-responsive element between -126 bp and -114 bp in the Insig2a promoter was identified by a transient transfection assay and a chromatin immunoprecipitation assay; its role in regulation by PPARα was characterised using Pparα-null mice. These results suggest that PPARα is a trans-acting factor that enhances Insig2a gene expression, thereby suppressing SREBP-1c processing during fasting.

摘要

过氧化物酶体增殖物激活受体α（PPARα）和固醇调节元件结合蛋白（SREBP）通过脂肪酸氧化和脂肪生成在调节细胞脂肪酸和胆固醇稳态方面发挥作用。SREBP 加工的控制受胰岛素诱导基因（INSIG）2a 蛋白调节，该蛋白将 SREBP 结合以防止营养饥饿期间 SREBP 向高尔基体的易位在肝脏中。然而，在禁食期间 INSIG 对 SREBP-1c 加工的调节以及小鼠 Insig2a 基因表达的调节机制尚未得到明确解决。在本研究中，我们发现 Insig2a 在禁食期间在小鼠肝脏和原代肝细胞中由 PPARα 上调，而在重新喂养的小鼠肝脏中 Insig2a mRNA 表达降低。通过瞬时转染测定和染色质免疫沉淀测定鉴定了 Insig2a 启动子中-126bp 至-114bp 之间的 PPAR 反应元件；使用 Pparα-/- 小鼠对其在 PPARα 调节中的作用进行了表征。这些结果表明，PPARα 是一种反式作用因子，可增强 Insig2a 基因表达，从而在禁食期间抑制 SREBP-1c 加工。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/03a55900297e/41598_2017_10523_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/381d46b23810/41598_2017_10523_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/7157fe5bbf51/41598_2017_10523_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/335989e8f12d/41598_2017_10523_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/3639b7959bcd/41598_2017_10523_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/b20d0c18033e/41598_2017_10523_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/316cda7169c8/41598_2017_10523_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/e81bf524ccde/41598_2017_10523_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/03a55900297e/41598_2017_10523_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/381d46b23810/41598_2017_10523_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/7157fe5bbf51/41598_2017_10523_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/335989e8f12d/41598_2017_10523_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/3639b7959bcd/41598_2017_10523_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/b20d0c18033e/41598_2017_10523_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/316cda7169c8/41598_2017_10523_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/e81bf524ccde/41598_2017_10523_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/00b0/5577246/03a55900297e/41598_2017_10523_Fig8_HTML.jpg

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