Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice
Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice
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DOI：
10.1194/jlr.m800383-jlr200
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发表时间：
2009-03-01
影响因子：
6.5
通讯作者：
Horton, Jay D.
中科院分区：
文献类型：
--
作者：
Moon, Young-Ah;Hammer, Robert E.;Horton, Jay D.
极长链脂肪酸延长酶（Elongation of Very Long Chain Fatty Acids，缩写为VLVL）5是参与微粒体脂肪酸延长的7种哺乳动物脂肪酸缩合酶之一。为了确定ELOV 15的体内底物和功能，我们产生了Elov 15（-/-）小鼠。使用来自野生型和基因敲除小鼠的肝微粒体蛋白的研究表明，γ-亚麻酸（C18：3，n-6）延伸为二高-γ-亚麻酸（C20：3，n-6）和十八碳四烯酸（C18：4，n-3）延伸为ω 3-花生四烯酸（C20：4，n-3）需要Δ VL 5活性。Elovl 5（-/-）小鼠的组织积累了C18底物，并且下游产物花生四烯酸（C20：4，n-6）和二十二碳六烯酸（DHA，C22：6，n-3）的水平降低。细胞花生四烯酸和DHA浓度降低的结果是固醇调节元件结合蛋白（SREBP）-1c及其参与脂肪酸和甘油三酯合成的靶基因的激活，这最终导致Elov 15（-/-）小鼠发生肝脂肪变性。Elov 15（-/-）小鼠脂肪酸代谢中的分子和代谢变化通过膳食补充花生四烯酸和DHA而逆转。这些研究表明，降低的PUFA VL 5活性导致肝脏脂肪变性，内源性合成的PUFA是小鼠肝脏中SREBP-1c活化和脂肪酸合成的关键调节因子。Moon，Y-A.，R. E. Hammer和J. D.霍顿在小鼠中，SREBP-lc的缺失通过激活SREBP-lc导致脂肪肝。J. Lipid Res. 2009. 50：412-423。
Elongation of very long chain fatty acids (ELOVL) 5 is one of seven mammalian fatty acid condensing enzymes involved in microsomal fatty acid elongation. To determine the in vivo substrates and function of ELOVL5, we generated Elovl5(-/-) mice. Studies using liver microsomal protein from wild-type and knockout mice demonstrated that the elongation of gamma-linolenic (C18:3, n-6) to dihomo-gamma-linolenic (C20:3, n-6) and stearidonic (C18:4, n-3) to omega 3-arachidonic acid (C20:4, n-3) required ELOVL5 activity. Tissues of Elovl5(-/-) mice accumulated the C18 substrates of ELOVL5 and the levels of the downstream products, arachidonic acid (C20: 4, n-6) and docosahexaenoic acid (DHA, C22:6, n-3), were decreased. A consequence of decreased cellular arachidonic acid and DHA concentrations was the activation of sterol regulatory element-binding protein (SREBP)-1c and its target genes involved in fatty acid and triglyceride synthesis, which culminated in the development of hepatic steatosis in Elovl5(-/-) mice. The molecular and metabolic changes in fatty acid metabolism in Elovl5(-/-) mice were reversed by dietary supplementation with arachidonic acid and DHA. These studies demonstrate that reduced ELOVL5 activity leads to hepatic steatosis, and endogenously synthesized PUFAs are key regulators of SREBP-1c activation and fatty acid synthesis in livers of mice.-Moon, Y-A., R. E. Hammer, and J. D. Horton. Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice. J. Lipid Res. 2009. 50: 412-423.