Fatty acid remodeling by LPCAT3 enriches arachidonate in phospholipid membranes and regulates triglyceride transport.
Fatty acid remodeling by LPCAT3 enriches arachidonate in phospholipid membranes and regulates triglyceride transport.
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DOI：
10.7554/elife.06328
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发表时间：
2015-04-21
期刊：
影响因子：
7.7
通讯作者：
Shimizu T
中科院分区：
文献类型：
--
作者：
Hashidate-Yoshida T;Harayama T;Hishikawa D;Morimoto R;Hamano F;Tokuoka SM;Eto M;Tamura-Nakano M;Yanobu-Takanashi R;Mukumoto Y;Kiyonari H;Okamura T;Kita Y;Shindou H;Shimizu T
磷脂中的多不饱和脂肪酸(PUFAs)会影响膜的物理性质，但目前还不清楚哪些生物过程受到其调节的影响。例如，膜花生四烯酸不依赖于二十烷类化合物合成的前体作用的功能在很大程度上仍不清楚。在这里，我们表明，溶血磷脂酰胆碱酰基转移酶3(LPCAT3)的缺乏导致膜花生四烯酸水平的急剧下降，LPCAT3缺陷的小鼠由于三酰甘油(TG)在肠道细胞中的广泛积累和功能障碍而在新生儿中是致命的。我们发现，膜中高水平的多不饱和脂肪酸使TGS能够以高密度局部聚集，并且这种聚集促进了有效的TG转移。我们提出了一个由LPCAT3局部浓缩花生四烯酸的模型，以在膜上产生一个独特的TG池，这是肝脏和肠细胞中TG转移和脂蛋白组装的正常方向性所必需的。DOI：由称为脂类的分子组成的http://dx.doi.org/10.7554/eLife.06328.001膜包围着每个活细胞，也在细胞内形成隔间。膜中有成百上千种不同的脂质分子。膜内每种类型的量可能会有所不同，这会影响膜的弹性和其他物理性能。膜中发现的一种类脂被称为花生四烯酸。它参与细胞通讯和其他过程，是幼年动物正常生长发育所必需的。一种名为LPCAT3的酶被认为能将花生四烯酸结合到细胞膜上，但这还没有被证明在活着的动物身上发生。这里，Hashidate-Yoshida，Harayama等人。研究LPCAT3在新生小鼠中的作用。实验表明，该酶在肠道和肝脏中含量较高。缺乏LPCAT3的小鼠与正常小鼠相比，花生四烯酸水平要低得多。这些小鼠还表现出严重的肠道损伤迹象，这是由于它们母亲的乳汁中的脂肪积聚，并在出生后几天内死亡。缺乏LPCAT3的小鼠的肠道和肝脏中有不同数量的另一种脂质-称为三酰甘油。正常情况下，这些脂类会被组装成更大的分子，称为脂蛋白，释放到血液中，用于肌肉和身体其他部位。然而，Hashidate-Yoshida，Harayama等人。研究发现，在缺失LPCAT3的小鼠中，三酰甘油没有组装成脂蛋白，因此它们在肠道和肝脏细胞内积聚。实验还表明，细胞膜中高水平的花生四烯酸和其他类似的脂质使三酰甘油分子聚集在一起，从而增加脂蛋白的产生。S的研究结果表明，LPCAT3将花生四烯酸结合到肠道和肝脏细胞膜上，使三酰甘油能够组装成脂蛋白。下一个挑战将是找出LPCAT3是否对人类脂蛋白的产生也很重要。如果是，那么开发改变这种酶活性的新疗法可能对血液中血脂水平异常(称为血脂异常)的患者有利。DOI：http://dx.doi.org/10.7554/eLife.06328.002
Polyunsaturated fatty acids (PUFAs) in phospholipids affect the physical properties of membranes, but it is unclear which biological processes are influenced by their regulation. For example, the functions of membrane arachidonate that are independent of a precursor role for eicosanoid synthesis remain largely unknown. Here, we show that the lack of lysophosphatidylcholine acyltransferase 3 (LPCAT3) leads to drastic reductions in membrane arachidonate levels, and that LPCAT3-deficient mice are neonatally lethal due to an extensive triacylglycerol (TG) accumulation and dysfunction in enterocytes. We found that high levels of PUFAs in membranes enable TGs to locally cluster in high density, and that this clustering promotes efficient TG transfer. We propose a model of local arachidonate enrichment by LPCAT3 to generate a distinct pool of TG in membranes, which is required for normal directionality of TG transfer and lipoprotein assembly in the liver and enterocytes. DOI: http://dx.doi.org/10.7554/eLife.06328.001 Membranes made of molecules called lipids surround every living cell and also form compartments inside the cell. There are hundreds of different lipid molecules that can be found in membranes. The amount of each type within the membrane can vary, which affects the flexibility and other physical properties of the membrane. One type of lipid found in membranes is called arachidonic acid. It is involved in cell communication and other processes, and is required for young animals to grow and develop properly. An enzyme called LPCAT3 is thought to incorporate arachidonic acid into membranes, but this has not yet been proven to occur in living animals. Here, Hashidate-Yoshida, Harayama et al. studied the role of LPCAT3 in newborn mice. The experiments show that this enzyme is found at high levels in the intestine and liver. Mice that lacked LPCAT3 had much lower levels of arachidonic acid compared with normal mice. These mice also showed signs of severe intestinal damage due to the build up of lipids from their mother's milk, and died within a few days of being born. The mice that lacked LPCAT3 had different amounts of another type of lipid—called triacylglycerols—in their intestine and liver. Normally, these lipids would be assembled into larger molecules called lipoproteins that are released into the blood stream and used in the muscles and other parts of the body. However, Hashidate-Yoshida, Harayama et al. found that in the mice missing LPCAT3, the triacylglycerols did not get assembled into lipoproteins and so they accumulated inside the intestine and liver cells. The experiments also show that high levels of arachidonic acid and other similar lipids in the membrane enable triacylglycerol molecules to cluster together, which increases the production of lipoproteins. Hashidate-Yoshida, Harayama et al.'s findings suggest that LPCAT3 incorporates arachidonic acid into the membrane of intestine and liver cells, which enables triacylglycerols to be assembled into lipoproteins. The next challenge will be to find out if LPCAT3 is also important for the production of lipoproteins in humans. If it is, then developing new therapies that alter the activity of this enzyme might be beneficial for patients with abnormal levels of lipids in the blood (known as dyslipidemia). DOI: http://dx.doi.org/10.7554/eLife.06328.002