• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

半胱天冬酶-2 和 p75 神经营养因子受体 (p75NTR) 参与肝细胞中 SREBP 和脂质基因的调控。

Caspase-2 and p75 neurotrophin receptor (p75NTR) are involved in the regulation of SREBP and lipid genes in hepatocyte cells.

机构信息

Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, POB 63, FI-00014, Helsinki, Finland.

Minerva Foundation Institute for Medical Research, Biomedicum 2, Tukholmankatu 8, FI-00290, Helsinki, Finland.

出版信息

Cell Death Dis. 2019 Jul 11;10(7):537. doi: 10.1038/s41419-019-1758-z.

DOI:10.1038/s41419-019-1758-z
PMID:31296846
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6624261/
Abstract

Lipid-induced toxicity is part of several human diseases, but the mechanisms involved are not fully understood. Fatty liver is characterized by the expression of different growth and tissue factors. The neurotrophin, nerve growth factor (NGF) and its pro-form, pro-NGF, are present in fatty liver together with p75 neurotrophin receptor (p75NTR). Stimulation of human Huh7 hepatocyte cells with NGF and pro-NGF induced Sterol-regulator-element-binding protein-2 (SREBP2) activation and increased Low-Density Lipoprotein Receptor (LDLR) expression. We observed that phosphorylation of caspase-2 by p38 MAPK was essential for this regulation involving a caspase-3-mediated cleavage of SREBP2. RNA sequencing showed that several genes involved in lipid metabolism were altered in p75NTR-deficient mouse liver. The same lipogenic genes were downregulated in p75NTR gene-engineered human Huh7 cells and reciprocally upregulated by stimulation of p75NTRs. In the knock-out mice the serum cholesterol and triglyceride levels were reduced, suggesting a physiological role of p75NTRs in whole-body lipid metabolism. Taken together, this study shows that p75NTR signaling influences a network of genes involved in lipid metabolism in liver and hepatocyte cells. Modulation of p75NTR signaling may be a target to consider in various metabolic disorders accompanied by increased lipid accumulation.

摘要

脂质诱导的毒性是几种人类疾病的一部分，但涉及的机制尚未完全阐明。脂肪肝的特征是不同生长和组织因子的表达。神经生长因子（NGF）及其前体形式，前神经生长因子（pro-NGF）与 p75 神经生长因子受体（p75NTR）一起存在于脂肪肝中。用 NGF 和 pro-NGF 刺激人 Huh7 肝细胞可诱导固醇调节元件结合蛋白-2（SREBP2）激活和增加低密度脂蛋白受体（LDLR）表达。我们观察到 p38 MAPK 对 caspase-2 的磷酸化对于这种调节是必不可少的，涉及 caspase-3 介导的 SREBP2 切割。RNA 测序显示，p75NTR 缺失的小鼠肝脏中几种参与脂质代谢的基因发生了改变。在 p75NTR 基因工程化的人 Huh7 细胞中，相同的生脂基因下调，而 p75NTRs 的刺激则上调。在敲除小鼠中，血清胆固醇和甘油三酯水平降低，提示 p75NTR 在全身脂质代谢中具有生理作用。总之，这项研究表明，p75NTR 信号影响了肝脏和肝细胞中参与脂质代谢的基因网络。调节 p75NTR 信号可能是各种伴有脂质积累增加的代谢紊乱的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/360b7da9eab0/41419_2019_1758_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/937dc9517e0a/41419_2019_1758_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/6a828d5e31ae/41419_2019_1758_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/fed30bf61d62/41419_2019_1758_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/2a68c64f00a8/41419_2019_1758_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/bbdfb057f8f1/41419_2019_1758_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/26f5ef5b5f34/41419_2019_1758_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/360b7da9eab0/41419_2019_1758_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/937dc9517e0a/41419_2019_1758_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/6a828d5e31ae/41419_2019_1758_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/fed30bf61d62/41419_2019_1758_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/2a68c64f00a8/41419_2019_1758_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/bbdfb057f8f1/41419_2019_1758_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/26f5ef5b5f34/41419_2019_1758_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869d/6624261/360b7da9eab0/41419_2019_1758_Fig7_HTML.jpg

相似文献

1
Caspase-2 and p75 neurotrophin receptor (p75NTR) are involved in the regulation of SREBP and lipid genes in hepatocyte cells.半胱天冬酶-2 和 p75 神经营养因子受体 (p75NTR) 参与肝细胞中 SREBP 和脂质基因的调控。
Cell Death Dis. 2019 Jul 11;10(7):537. doi: 10.1038/s41419-019-1758-z.
2
p75 Neurotrophin Receptor Signaling Activates Sterol Regulatory Element-binding Protein-2 in Hepatocyte Cells via p38 Mitogen-activated Protein Kinase and Caspase-3.p75神经营养因子受体信号通过p38丝裂原活化蛋白激酶和半胱天冬酶-3激活肝细胞中的固醇调节元件结合蛋白-2 。
J Biol Chem. 2016 May 13;291(20):10747-58. doi: 10.1074/jbc.M116.722272. Epub 2016 Mar 16.
3
Nerve growth factor survival signaling in cultured hippocampal neurons is mediated through TrkA and requires the common neurotrophin receptor P75.培养的海马神经元中神经生长因子的存活信号是通过TrkA介导的，并且需要共同的神经营养因子受体P75。
Neuroscience. 2002;115(4):1089-108. doi: 10.1016/s0306-4522(02)00539-0.
4
Nerve growth factor (NGF) and pro-NGF increase low-density lipoprotein (LDL) receptors in neuronal cells partly by different mechanisms: role of LDL in neurite outgrowth.神经生长因子（NGF）和前体神经生长因子（pro-NGF）通过部分不同机制增加神经元细胞中的低密度脂蛋白（LDL）受体：LDL在神经突生长中的作用
J Neurochem. 2016 Jan;136(2):306-15. doi: 10.1111/jnc.13397. Epub 2015 Nov 19.
5
Type I interferons up-regulate the expression and signalling of p75 NTR/TrkA receptor complex in differentiated human SH-SY5Y neuroblastoma cells.I型干扰素上调分化的人SH-SY5Y神经母细胞瘤细胞中p75神经营养因子受体/酪氨酸激酶A（p75 NTR/TrkA）受体复合物的表达和信号传导。
Neuropharmacology. 2014 Apr;79:321-34. doi: 10.1016/j.neuropharm.2013.12.002. Epub 2013 Dec 11.
6
Osthol ameliorates fat milk-induced fatty liver in mice by regulation of hepatic sterol regulatory element-binding protein-1c/2-mediated target gene expression.蛇床子素通过调节肝固醇调节元件结合蛋白-1c/2 介导的靶基因表达改善脂肪乳诱导的小鼠脂肪肝。
Eur J Pharmacol. 2011 Sep;666(1-3):183-8. doi: 10.1016/j.ejphar.2011.05.014. Epub 2011 May 20.
7
Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice.炎症应激会加剧载脂蛋白E基因敲除小鼠肝细胞和脂肪肝中的脂质积累。
Hepatology. 2008 Sep;48(3):770-81. doi: 10.1002/hep.22423.
8
Activated hepatic stellate cells overexpress p75NTR after partial hepatectomy and undergo apoptosis on nerve growth factor stimulation.部分肝切除术后，活化的肝星状细胞过度表达p75神经营养因子受体，并在神经生长因子刺激下发生凋亡。
Liver Int. 2006 Jun;26(5):595-603. doi: 10.1111/j.1478-3231.2006.01267.x.
9
The p75-mediated effect of nerve growth factor in L6C5 myogenic cells.神经生长因子在L6C5成肌细胞中由p75介导的效应。
BMC Res Notes. 2017 Dec 4;10(1):686. doi: 10.1186/s13104-017-2994-x.
10
Enhanced Liver Regeneration After Partial Hepatectomy in Sterol Regulatory Element-Binding Protein (SREBP)-1c-Null Mice is Associated with Increased Hepatocellular Cholesterol Availability.甾醇调节元件结合蛋白（SREBP）-1c基因缺失小鼠部分肝切除术后肝脏再生增强与肝细胞胆固醇可利用性增加有关。
Cell Physiol Biochem. 2018;47(2):784-799. doi: 10.1159/000490030. Epub 2018 May 22.

引用本文的文献

1
USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cells.USP14对人类SH-SY5Y多巴胺能细胞中的蛋白质稳态调节和α-突触核蛋白降解至关重要。
Heliyon. 2025 Jan 23;11(3):e42031. doi: 10.1016/j.heliyon.2025.e42031. eCollection 2025 Feb 15.
2
Cholinergic neurodegeneration and cholesterol metabolism dysregulation by constitutive p75 signaling in the p75-KO mice.在p75基因敲除小鼠中，组成型p75信号通路导致胆碱能神经变性和胆固醇代谢失调。
Front Mol Neurosci. 2023 Oct 13;16:1237458. doi: 10.3389/fnmol.2023.1237458. eCollection 2023.
3
NGF Modulates Cholesterol Metabolism and Stimulates ApoE Secretion in Glial Cells Conferring Neuroprotection against Oxidative Stress.

本文引用的文献

1
ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P.内质网应激通过 caspase-2 激活 S1P 驱动脂肪生成和脂肪性肝炎。
Cell. 2018 Sep 20;175(1):133-145.e15. doi: 10.1016/j.cell.2018.08.020. Epub 2018 Sep 13.
2
Caspase-2 deficiency enhances whole-body carbohydrate utilisation and prevents high-fat diet-induced obesity.半胱天冬酶-2 缺乏增强全身碳水化合物利用并预防高脂肪饮食诱导的肥胖。
Cell Death Dis. 2017 Oct 26;8(10):e3136. doi: 10.1038/cddis.2017.518.
3
The MBOAT7 variant rs641738 alters hepatic phosphatidylinositols and increases severity of non-alcoholic fatty liver disease in humans.
NGF 调节胆固醇代谢并刺激神经胶质细胞分泌载脂蛋白 E，从而提供神经保护作用以对抗氧化应激。
Int J Mol Sci. 2022 Apr 27;23(9):4842. doi: 10.3390/ijms23094842.
4
MDM2 Binding Protein Induces the Resistance of Hepatocellular Carcinoma Cells to Molecular Targeting Agents Enhancing the Transcription Factor Activity of the Pregnane X Receptor.MDM2结合蛋白诱导肝癌细胞对分子靶向药物产生抗性，增强孕烷X受体的转录因子活性。
Front Oncol. 2021 Jun 24;11:715193. doi: 10.3389/fonc.2021.715193. eCollection 2021.
5
Neurotrophins as Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis.神经营养因子作为细胞代谢的关键调节因子：对胆固醇稳态的影响
Int J Mol Sci. 2021 May 26;22(11):5692. doi: 10.3390/ijms22115692.
6
Acceleration of TAA-Induced Liver Fibrosis by Stress Exposure Is Associated with Upregulation of Nerve Growth Factor and Glycopattern Deviations.应激暴露加速 TAA 诱导的肝纤维化与神经生长因子上调和糖基化模式改变有关。
Int J Mol Sci. 2021 May 11;22(10):5055. doi: 10.3390/ijms22105055.
7
The p53-caspase-2 axis in the cell cycle and DNA damage response.p53-caspase-2 轴在细胞周期和 DNA 损伤反应中的作用。
Exp Mol Med. 2021 Apr;53(4):517-527. doi: 10.1038/s12276-021-00590-2. Epub 2021 Apr 14.
8
Neuronal apoptosis induced by morphine withdrawal is mediated by the p75 neurotrophin receptor.吗啡戒断诱导的神经元凋亡是由 p75 神经营养因子受体介导的。
J Neurochem. 2021 Jul;158(2):169-181. doi: 10.1111/jnc.15355. Epub 2021 Apr 12.
9
PGC-1α Signaling Increases GABA(A) Receptor Subunit α2 Expression, GABAergic Neurotransmission and Anxiety-Like Behavior in Mice.PGC-1α信号通路增加小鼠体内GABA(A)受体亚基α2的表达、γ-氨基丁酸能神经传递及类似焦虑的行为。
Front Mol Neurosci. 2021 Feb 1;14:588230. doi: 10.3389/fnmol.2021.588230. eCollection 2021.
10
Protective Role of Low Ethanol Administration Following Ischemic Stroke via Recovery of KCC2 and p75 Expression.低乙醇给药通过恢复 KCC2 和 p75 表达对缺血性脑卒中的保护作用。
Mol Neurobiol. 2021 Mar;58(3):1145-1161. doi: 10.1007/s12035-020-02176-x. Epub 2020 Oct 24.
MBOAT7基因变异体rs641738改变肝脏磷脂酰肌醇并增加人类非酒精性脂肪性肝病的严重程度。
J Hepatol. 2016 Dec;65(6):1263-1265. doi: 10.1016/j.jhep.2016.07.045. Epub 2016 Aug 9.
4
Recent advances in the pharmacological management of hypercholesterolaemia.近期高胆固醇血症药理学治疗的进展。
Lancet Diabetes Endocrinol. 2016 May;4(5):436-46. doi: 10.1016/S2213-8587(16)00074-7. Epub 2016 Mar 21.
5
p75 Neurotrophin Receptor Signaling Activates Sterol Regulatory Element-binding Protein-2 in Hepatocyte Cells via p38 Mitogen-activated Protein Kinase and Caspase-3.p75神经营养因子受体信号通过p38丝裂原活化蛋白激酶和半胱天冬酶-3激活肝细胞中的固醇调节元件结合蛋白-2 。
J Biol Chem. 2016 May 13;291(20):10747-58. doi: 10.1074/jbc.M116.722272. Epub 2016 Mar 16.
6
Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease.半胱天冬酶-2会引发肥胖、代谢综合征和非酒精性脂肪性肝病。
Cell Death Dis. 2016 Feb 18;7(2):e2096. doi: 10.1038/cddis.2016.19.
7
p75 Neurotrophin Receptor Regulates Energy Balance in Obesity.p75 神经生长因子受体调节肥胖中的能量平衡。
Cell Rep. 2016 Jan 12;14(2):255-68. doi: 10.1016/j.celrep.2015.12.028. Epub 2015 Dec 31.
8
Peroxisome proliferator-activated receptor-γ (PPARγ) agonist is neuroprotective and stimulates PGC-1α expression and CREB phosphorylation in human dopaminergic neurons.过氧化物酶体增殖物激活受体γ（PPARγ）激动剂具有神经保护作用，并能刺激人多巴胺能神经元中PGC-1α的表达和CREB的磷酸化。
Neuropharmacology. 2016 Mar;102:266-75. doi: 10.1016/j.neuropharm.2015.11.020. Epub 2015 Nov 26.
9
Nerve growth factor (NGF) and pro-NGF increase low-density lipoprotein (LDL) receptors in neuronal cells partly by different mechanisms: role of LDL in neurite outgrowth.神经生长因子（NGF）和前体神经生长因子（pro-NGF）通过部分不同机制增加神经元细胞中的低密度脂蛋白（LDL）受体：LDL在神经突生长中的作用
J Neurochem. 2016 Jan;136(2):306-15. doi: 10.1111/jnc.13397. Epub 2015 Nov 19.
10
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.使用DESeq2对RNA测序数据的倍数变化和离散度进行适度估计。
Genome Biol. 2014;15(12):550. doi: 10.1186/s13059-014-0550-8.