Activation of peroxisome proliferator-activated receptor α increases the expression and activity of microsomal triglyceride transfer protein in the liver
Activation of peroxisome proliferator-activated receptor α increases the expression and activity of microsomal triglyceride transfer protein in the liver
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DOI：
10.1074/jbc.m412107200
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发表时间：
2005-01-14
影响因子：
4.8
通讯作者：
Oscarsson, J
中科院分区：
文献类型：
--
作者：
Améen, C;Edvardsson, U;Oscarsson, J
微粒体甘油三酯转移蛋白(MTP)是含有载脂蛋白B(Apo B)的脂蛋白的组装和分泌的限速因子。此前，我们证明了过氧化物酶体增殖物激活受体(PPAR)α激动剂Wy 14,643(Wy)在减少甘油三酯合成的情况下增加apoB-100的分泌。在这项研究中，我们试图确定PPARpha激活是否增加了MTP的表达和活性。WY可增加大鼠和小鼠肝脏MTP的表达和活性，增加原代培养的大鼠和小鼠肝细胞MTP的表达。加入放线菌素D可阻断这种增加，并且含有保守的DR1元件的MTP启动子(-136到+67)被Wy激活，表明PPARpha激活了该基因的转录。WY不影响PPARα缺失小鼠肠道或培养的肝细胞中MTP的表达。维甲酸X受体激动剂(9-顺式维甲酸)，而不是PPARγ激动剂(罗格列酮)，可增加野生型和PPARα缺失小鼠培养的肝细胞MTP mRNA的表达。在WY孵育的大鼠肝细胞中，MTP mRNA水平在6~24 h升高，MTP蛋白表达和apoB-100分泌在24~72 h升高。这种作用与apoB-100分泌的变化是平行的，表明WY对apoB-100分泌的影响是通过增加MTP的表达来实现的。
Microsomal triglyceride transfer protein (MTP) is rate-limiting in the assembly and secretion of lipoproteins containing apolipoprotein (apo) B. Previously we demonstrated that Wy 14,643 (Wy), a peroxisome proliferator-activated receptor (PPAR) alpha agonist, increases apoB-100 secretion despite decreased triglyceride synthesis. In this study, we sought to determine whether PPARalpha activation increases MTP expression and activity. Treatment with Wy increased hepatic MTP expression and activity in rats and mice and increased MTP expression in primary cultures of rat and mouse hepatocytes. Addition of actinomycin D blocked this increase and the MTP promoter (-136 to +67) containing a conserved DR1 element was activated by Wy, showing that PPARalpha activates transcription of the gene. Wy did not affect MTP expression in the intestine or in cultured hepatocytes from PPARalpha-null mice. A retinoid X receptor agonist (9-cis-retinoic acid), but not a PPARgamma agonist (rosiglitazone), increased MTP mRNA expression in cultured hepatocytes from both wild type and PPAR alpha-null mice. In rat hepatocytes incubated with Wy, MTP mRNA levels increased between 6 and 24 h, and MTP protein expression and apoB-100 secretion increased between 24 and 72 h. In conclusion, PPARalpha activation stimulates hepatic MTP expression via increased transcription of the Mtp gene. This effect is paralleled by a change in apoB-100 secretion, indicating that the effect of Wy on apoB-100 secretion is mediated by increased expression of MTP.