Suppr超能文献

肝糖异生被磷酸脂酸增强,而在脂肪营养不良的 Agpat2-/- 小鼠中,磷酸脂酸不受胰岛素抑制。

Hepatic gluconeogenesis is enhanced by phosphatidic acid which remains uninhibited by insulin in lipodystrophic Agpat2-/- mice.

机构信息

From the Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and Center for Human Nutrition.

出版信息

J Biol Chem. 2014 Feb 21;289(8):4762-77. doi: 10.1074/jbc.M113.530998. Epub 2014 Jan 14.

Abstract

In this study we examined the role of phosphatidic acid (PA) in hepatic glucose production (HGP) and development of hepatic insulin resistance in mice that lack 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2). Liver lysophosphatidic acid and PA levels were increased ∼2- and ∼5-fold, respectively, in male Agpat2(-/-) mice compared with wild type mice. In the absence of AGPAT2, the liver can synthesize PAs by activating diacylglycerol kinase or phospholipase D, both of which were elevated in the livers of Agpat2(-/-) mice. We found that PAs C16:0/18:1 and C18:1/20:4 enhanced HGP in primary WT hepatocytes, an effect that was further enhanced in primary hepatocytes from Agpat2(-/-) mice. Lysophosphatidic acids C16:0 and C18:1 failed to increase HGP in primary hepatocytes. The activation of HGP was accompanied by an up-regulation of the key gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. This activation was suppressed by insulin in the WT primary hepatocytes but not in the Agpat2(-/-) primary hepatocytes. Thus, the lack of normal insulin signaling in Agpat2(-/-) livers allows unrestricted PA-induced gluconeogenesis significantly contributing to the development of hyperglycemia in these mice.

摘要

在这项研究中,我们研究了磷脂酸(PA)在缺乏 1-酰基甘油-3-磷酸 O-酰基转移酶 2(AGPAT2)的小鼠肝葡萄糖产生(HGP)和肝胰岛素抵抗中的作用。与野生型小鼠相比,雄性 Agpat2(-/-)小鼠的肝溶血磷脂酸和 PA 水平分别增加了约 2 倍和 5 倍。在缺乏 AGPAT2 的情况下,肝脏可以通过激活二酰基甘油激酶或磷脂酶 D 来合成 PA,这两种酶在 Agpat2(-/-)小鼠的肝脏中均升高。我们发现,PA C16:0/18:1 和 C18:1/20:4 增强了 WT 原代肝细胞中的 HGP,而在 Agpat2(-/-)原代肝细胞中,这种作用进一步增强。溶血磷脂酸 C16:0 和 C18:1 不能增加原代肝细胞中的 HGP。HGP 的激活伴随着关键的糖异生酶葡萄糖-6-磷酸酶和磷酸烯醇丙酮酸羧激酶的上调。这种激活在 WT 原代肝细胞中被胰岛素抑制,但在 Agpat2(-/-)原代肝细胞中不受抑制。因此,Agpat2(-/-)肝脏中正常胰岛素信号的缺失允许不受限制的 PA 诱导的糖异生显著促进这些小鼠的高血糖发展。

相似文献

1
Hepatic gluconeogenesis is enhanced by phosphatidic acid which remains uninhibited by insulin in lipodystrophic Agpat2-/- mice.
J Biol Chem. 2014 Feb 21;289(8):4762-77. doi: 10.1074/jbc.M113.530998. Epub 2014 Jan 14.
5
Activation of Sphingolipid Pathway in the Livers of Lipodystrophic Mice.
J Endocr Soc. 2017 May 18;1(7):980-993. doi: 10.1210/js.2017-00157. eCollection 2017 Jul 1.
7
A regulatory role for 1-acylglycerol-3-phosphate-O-acyltransferase 2 in adipocyte differentiation.
J Biol Chem. 2006 Apr 21;281(16):11082-9. doi: 10.1074/jbc.M509612200. Epub 2006 Feb 22.
10
Inhibited insulin signaling in mouse hepatocytes is associated with increased phosphatidic acid but not diacylglycerol.
J Biol Chem. 2015 Feb 6;290(6):3519-28. doi: 10.1074/jbc.M114.602789. Epub 2014 Dec 15.

引用本文的文献

2
Involvement of a battery of investigated genes in lipid droplet pathophysiology and associated comorbidities.
Adipocyte. 2024 Dec;13(1):2403380. doi: 10.1080/21623945.2024.2403380. Epub 2024 Sep 27.
5
Regulated adipose tissue-specific expression of human in lipodystrophic -null mice results in regeneration of adipose tissue.
iScience. 2023 Sep 1;26(10):107806. doi: 10.1016/j.isci.2023.107806. eCollection 2023 Oct 20.
7
Activation of Sphingolipid Pathway in the Livers of Lipodystrophic Mice.
J Endocr Soc. 2017 May 18;1(7):980-993. doi: 10.1210/js.2017-00157. eCollection 2017 Jul 1.
8
Lysophosphatidic acid counteracts glucagon-induced hepatocyte glucose production via STAT3.
Sci Rep. 2017 Mar 9;7(1):127. doi: 10.1038/s41598-017-00210-y.

本文引用的文献

1
2
SnapShot: cancer metabolism pathways.
Cell Metab. 2013 Mar 5;17(3):466-466.e2. doi: 10.1016/j.cmet.2013.02.016.
3
Lysophospholipid acyltransferases: 1-acylglycerol-3-phosphate O-acyltransferases. From discovery to disease.
Curr Opin Lipidol. 2012 Aug;23(4):290-302. doi: 10.1097/MOL.0b013e328354fcf4.
4
How to diagnose a lipodystrophy syndrome.
Ann Endocrinol (Paris). 2012 Jun;73(3):170-89. doi: 10.1016/j.ando.2012.04.010. Epub 2012 Jun 28.
7
NOX4 pathway as a source of selective insulin resistance and responsiveness.
Arterioscler Thromb Vasc Biol. 2012 May;32(5):1236-45. doi: 10.1161/ATVBAHA.111.244525. Epub 2012 Feb 9.
8
Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling.
Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1667-72. doi: 10.1073/pnas.1110730109. Epub 2012 Jan 17.
9
Putting the pH into phosphatidic acid signaling.
BMC Biol. 2011 Dec 2;9:85. doi: 10.1186/1741-7007-9-85.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验