Alterations in hepatic metabolism in fld mice reveal a role for lipin 1 in regulating VLDL-triacylglyceride secretion.
Alterations in hepatic metabolism in fld mice reveal a role for lipin 1 in regulating VLDL-triacylglyceride secretion.
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DOI：
10.1161/atvbaha.108.171538
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Finck BN
中科院分区：
文献类型：
--
作者：
Chen Z;Gropler MC;Norris J;Lawrence JC Jr;Harris TE;Finck BN
Lipin 1作为转录调节因子控制细胞核中的脂肪酸代谢，并作为催化磷酸甘油三酰甘油酯（TAG）合成中倒数第二步的酶控制细胞质中的脂肪酸代谢。我们试图通过功能获得和功能丧失的方法来评估脂蛋白1对肝脏TAG合成和分泌的影响。TAG合成率在从成年lipin 1缺陷（fld）小鼠分离的肝细胞中没有受损，实际上在14日龄fld小鼠中增加。此外，与同窝对照组相比，两个年龄段的fld小鼠中VLDL-TAG分泌速率显著增加。Lipin 1过表达不改变TAG合成速率，但显著抑制VLDL-TAG分泌。Lipin 1介导的VLDL-TAG分泌抑制与介导其转录调节作用的肽基序有关。然而，表达的候选基因所需的极低密度脂蛋白的组装和分泌是不变的脂蛋白1激活或缺陷。最后，脂蛋白1在肥胖胰岛素抵抗小鼠中的肝脏表达减少，而这些小鼠肝脏中腺病毒介导的脂蛋白1过表达抑制VLDL-TAG分泌并改善肝脏胰岛素信号传导。总的来说，这些研究揭示了Lipin 1对肝脏TAG代谢和肥胖相关的肝脏胰岛素抵抗的新的和意想不到的作用。
Lipin 1 controls fatty acid metabolism in the nucleus as a transcriptional regulator and in the cytosol as an enzyme catalyzing the penultimate step in phosphoglycerol triacylglyceride (TAG) synthesis. We sought to evaluate the effects of lipin 1 on hepatic TAG synthesis and secretion by gain-of-function and loss-of-function approaches. Rates of TAG synthesis were not impaired in hepatocytes isolated from adult lipin 1—deficient (fld) mice and were actually increased in 14-day-old fld mice. Additionally, compared to littermate controls, VLDL-TAG secretion rates were markedly increased in fld mice of both ages. Lipin 1 overexpression did not alter TAG synthesis rates but significantly suppressed VLDL-TAG secretion. The lipin 1-mediated suppression of VLDL-TAG secretion was linked to the peptide motif mediating its transcriptional-regulatory effects. However, the expression of candidate genes required for VLDL assembly and secretion was unaltered by lipin 1 activation or deficiency. Finally, the hepatic expression of lipin 1 was diminished in obese insulin-resistant mice, whereas adenoviral-mediated overexpression of lipin 1 in liver of these mice inhibits VLDL-TAG secretion and improves hepatic insulin signaling. Collectively, these studies reveal new and unexpected effects of lipin 1 on hepatic TAG metabolism and obesity-related hepatic insulin resistance.