Altered cholesterologenic and lipogenic transcriptional profile in livers of aging Snell dwarf (Pit1dw/dwJ) mice
Altered cholesterologenic and lipogenic transcriptional profile in livers of aging Snell dwarf (Pit1dw/dwJ) mice
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DOI：
10.1111/j.1474-9728.2004.00115.x
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发表时间：
2004-10-01
期刊：
影响因子：
7.8
通讯作者：
Papaconstantinou, J
中科院分区：
文献类型：
--
作者：
Boylston, WH;Gerstner, A;Papaconstantinou, J
几种小鼠模型表明，哺乳动物的寿命可以增加单基因突变影响内分泌信号，特别是通过GH/IGF-1轴。在这项研究中，我们确定了长寿的Snell（Pit 1（dw/dwJ））侏儒小鼠的肝脏基因表达特征的年龄无关模式。对年轻和老年雄性小鼠肝脏进行比较微阵列分析，以发现Pit 1（dw/dwJ）和对照小鼠之间差异表达的特定基因。通过实时RT-PCR的进一步检查证实，编码HMG-CoA合酶-1、HMG-CoA还原酶、法呢基二磷酸合酶、异戊烯焦磷酸异构酶、甲羟戊酸脱羧酶、角鲨烯环氧酶、羊毛甾醇脱甲基酶、苹果酸酶和载脂蛋白A-IV的转录物在3-5月龄和24-28月龄的雄性和雌性Pit 1（dw/dwJ）肝脏中均显著降低。相比之下，编码β 3肾上腺素能受体、脂蛋白脂酶、PPARgamma和极低密度脂蛋白受体同源物的转录物在侏儒肝脏中相对于年龄匹配的对照组显著增加。这些研究揭示了持久的转录变化特征的Pit 1（dw/dwJ）侏儒小鼠，涉及基因调节胆固醇生物合成，脂肪酸代谢和脂蛋白稳态。与整体能量代谢有关，肝脏基因表达的这种稳定转变可能通过影响通常在线粒体和过氧化物酶体内划分的特定代谢功能而有助于长寿决定;此外，这种代谢转变也可能与热量限制诱导的许多转录变化平行。
Several murine models demonstrate that mammalian longevity can be increased by single gene mutations affecting endocrine signalling, particularly via the GH/IGF-1 axis. In this study, we identify age-independent patterns of hepatic gene expression characteristic of long-lived Snell (Pit1(dw/dwJ))dwarf mice. Comparative microarray analysis of young and aged male livers was performed to discover specific genes differentially expressed between Pit1(dw/dwJ) and control mice. Further examination by real-time RT-PCR confirmed that transcripts encoding HMG-CoA synthase-1, HMG-CoA reductase, farnesyl diphosphate synthase, isopentenyl pyrophosphate isomerase, mevalonate decarboxylase, squalene epoxidase, lanosterol demethylase, malic enzyme and apolipoprotein A-IV were significantly decreased in both male and female Pit1(dw/dwJ) livers at 3-5 and 24-28 months of age. In contrast, transcripts encoding the beta(3)-adrenergic receptor, lipoprotein lipase, PPARgamma and a very low-density lipoprotein receptor homologue were increased significantly in dwarf livers relative to age-matched controls. These studies reveal enduring transcriptional changes characteristic of Pit1(dw/dwJ) dwarf mice that involve genes regulating cholesterol biosynthesis, fatty acid metabolism and lipoprotein homeostasis. Linked to global energy metabolism, this stable shift in hepatic gene expression may contribute to longevity determination by influencing particular metabolic functions often compartmentalized within the mitochondrion and peroxisome; further this metabolic shift may also parallel many transcriptional changes induced by caloric restriction.