Comparison of dose-response relationships for induction of lipid metabolizing and growth regulatory genes by peroxisome proliferators in rat liver.
Comparison of dose-response relationships for induction of lipid metabolizing and growth regulatory genes by peroxisome proliferators in rat liver.
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大鼠肝脏中过氧化物酶体增殖剂诱导脂质代谢和生长调节基因的剂量-反应关系的比较。
DOI：
10.1006/taap.1998.8443
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发表时间：
1998
影响因子：
3.8
通讯作者：
VandenHeuvel,JP
中科院分区：
文献类型：
--
作者：
Belury,MA;Moya-Camarena,SY;Sun,H;Snyder,E;Davis,JW;Cunningham,ML;VandenHeuvel,JP
过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor，PPAR）对基因表达的调控在过氧化物酶体增殖物对脂质代谢的影响中起着关键作用，并可能参与肝癌的发生。现已清楚地证明，PPAR参与过氧化物酶体增殖物介导的脂肪酸代谢基因（例如酰基辅酶A氧化酶（ACO）、脂肪酸结合蛋白（FABP）和细胞色素P450 IVA 1（CYP 4A 1））的诱导。然而，过氧化物酶体增殖物的重要的生长调节基因，如c-mychas的诱导没有得到广泛的研究。在这些研究中，我们检测了诱导PPAR调节和脂质代谢基因ACO、FABP和CYP 4A 1 mRNA的剂量-反应关系，并将其与即刻早期基因myc进行比较。亚慢性给予Wy 14，643可诱导脂质代谢和生长调节基因，但诱导程度不同，敏感性也不同。导致ACO和FABP表达显著变化的最低剂量为10 ppm。在检查的最低剂量（5 ppm）下，CYP 4A 1和c-myc的mRNA受到显著影响。此外，相对于溶剂处理动物，最大诱导范围为105倍（CYP 4A 1）至不到10倍（FABP）。ACO、FABP和CYP 4A 1（而非c-myc）的mRNA蓄积显示出典型的受体介导的剂量-反应关系。将对基因表达的影响与肝细胞增殖率（肿瘤促进和肝癌发生的相关标志物）进行比较。令人惊讶的是，ACO mRNA表现出良好的相关性（r2= 0.9），而c-myc mRNA表现出较差的相关性（r2= 0.3）与大鼠肝脏细胞增殖。虽然ACO和c-myc mRNA积累的剂量-反应关系之间的差异可能表明即刻早期基因不受PPAR控制，但来自PPARα敲除小鼠的证据支持脂质代谢和生长调节基因中的该受体。这项研究显示了过氧化物酶体增殖物介导的反应的复杂性，ACO是PPAR介导的事件以及细胞增殖的良好标志物，而c-myc，一种已知的生长调节基因，部分通过PPAR被Wy 14，643诱导，但与细胞增殖没有很好的相关性。
The regulation of gene expression via the peroxisome proliferator-activated receptor (PPAR) is believed to be critical in the effects of peroxisome proliferators on lipid metabolism and possibly in hepatocarcinogenesis. The involvement of PPAR in the peroxisome proliferator-mediated induction of fatty acid metabolizing genes such as acyl-CoA oxidase (ACO), fatty acid-binding protein (FABP), and cytochrome P450IVA1 (CYP4A1) has been clearly demonstrated. However, the induction by peroxisome proliferators of important growth regulatory genes such asc-mychas not been investigated extensively. In these studies we examined the dose–response relationships for the induction of mRNA for the PPAR-regulated and lipid metabolizing genesACO, FABP,andCYP4A1and compared them to the immediate early genec-myc.Liver mRNA from rats fed various amounts of the peroxisome proliferator Wy14,643 for 13 weeks was utilized. The lipid metabolism and growth regulatory genes were induced by subchronic administration of Wy14,643 but to varying degrees and with different sensitivities. The lowest dose that resulted in a significant change in ACO and FABP expression was 10 ppm. The mRNA for CYP4A1 and c-myc was significantly affected at the lowest dose examined (5 ppm). Also, the maximal induction ranged from 105-fold (CYP4A1) to less than 10-fold (FABP) relative to vehicle-treated animals. The accumulation of mRNA for ACO, FABP, and CYP4A1, but not c-myc, showed typical receptor-mediated dose–response relationships. The effects on gene expression were compared to rates of hepatic cell proliferation, a pertinent marker of tumor promotion and hepatocarcinogenesis. Surprisingly, ACO mRNA showed an excellent correlation (r2= 0.9) while c-myc mRNA exhibited a poor correlation (r2= 0.3) with cell proliferation in rat liver. Although the differences between the dose–response relationships of ACO and c-myc mRNA accumulation may suggest immediate early genes are not controlled by PPAR, evidence from PPARα null mice support this receptor in both lipid metabolism and growth regulatory genes. This study shows the complexity of responses mediated by peroxisome proliferators, with ACO being a good marker of PPAR-mediated events as well as cell proliferation, while c-myc, a known growth regulatory gene, was induced by Wy14,643 partially via PPAR but did not correlate well with cell proliferation.
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诱导基因转录：对生物标志物的影响。
影响因子：
9.3
作者：
Charles H. Sewall;Douglas A. Bell;George C. Clark;Angelika M Tritscher;Douglas B Tully;Jack Vanden Heuvel;G. Lucier
通讯作者：
G. Lucier
影响因子：
3.9
作者：
ISSEMANN, I;PRINCE, R;GREEN, S
通讯作者：
GREEN, S
用过氧化物酶体增殖剂处理的大鼠的差异原癌基因 mRNA 诱导。
DOI：
--
发表时间：
1990
期刊：
Biochemical and Biophysical Research Communications - BBRC
影响因子：
--
作者：
M. Cherkaoui Malki;Y. Lone;M. Corral;N. Latruffe
通讯作者：
N. Latruffe
影响因子：
10.4
作者：
Dickerson RL;Hooper MJ;Gard NW;Cobb GP;Kendall RJ
通讯作者：
Kendall RJ
通过过氧化物酶体增殖剂协调诱导酰基辅酶A结合蛋白、脂肪酸结合蛋白和过氧化物酶体β-氧化。
DOI：
10.1016/0167-4889(93)90039-r
发表时间：
1993
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
VandenHeuvel,JP;Sterchele,PF;Nesbit,DJ;Peterson,RE
通讯作者：
Peterson,RE