From the Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and Center for Human Nutrition.
J Biol Chem. 2014 Feb 21;289(8):4762-77. doi: 10.1074/jbc.M113.530998. Epub 2014 Jan 14.
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.
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。