Differential response to trichloroethylene-induced hepatosteatosis in wild-type and PPARalpha-humanized mice.
Differential response to trichloroethylene-induced hepatosteatosis in wild-type and PPARalpha-humanized mice.
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DOI：
10.1289/ehp.1001928
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发表时间：
2010-11
影响因子：
10.4
通讯作者：
Nakajima T
中科院分区：
文献类型：
--
作者：
Ramdhan DH;Kamijima M;Wang D;Ito Y;Naito H;Yanagiba Y;Hayashi Y;Tanaka N;Aoyama T;Gonzalez FJ;Nakajima T
三氯乙酸是三氯乙烯（TRI）的氧化代谢产物，是过氧化物酶体增殖物激活受体α（PPAR）α的配体，参与脂质稳态和抗炎作用。我们研究了小鼠和人PPARα在TRI-induced肝脂肪变性和毒性中的作用。将Sv/129背景下的雄性野生型（mPPARα）、Pparα-null和人源化PPARα（hPPARα）小鼠通过吸入暴露于0、1，000和2，000 ppm TRI，每天8小时，持续7天。我们通过生化和组织病理学测量评估了TRI-induced脂肪变性或肝损伤。暴露于1，000和2，000 ppm TRI后，所有小鼠品系的血浆丙氨酸氨基转移酶和天冬氨酸氨基转移酶活性均升高。在所有小鼠品系中，暴露均诱导肝细胞坏死和炎性细胞，但仅在Pparα-null和hPPARα小鼠中观察到肝脏脂质蓄积。除了mPPARα和hPPARα小鼠之间的少数基因不同外，未观察到TRI-mediated诱导肝脏PPARα靶基因的差异。然而，TRI显著增加了Pparα-null和hPPARα小鼠中甘油三酯（TG）合成酶、二酰基甘油酰基转移酶和PPARγ的表达，这可能是其肝脏中TG升高的原因。TRI暴露升高了所有小鼠的核因子-κ B（NFκB）p52 mRNA和蛋白，与PPARα基因型无关。NFκB-p52是TRI引起的炎症反应的候选分子标志物，而PPARα可能参与了TRI诱导的脂肪肝。然而，与小鼠PPARα相比，人PPARα对TRI-mediated效应的保护作用可能较弱。
Trichloroacetic acid, an oxidative metabolite of trichloroethylene (TRI), is a ligand of the peroxisome proliferator-activated receptor α (PPAR) α, which is involved in lipid homeostasis and anti-inflammation. We examined the role of mouse and human PPARα in TRI-induced hepatic steatosis and toxicity. Male wild-type (mPPARα), Pparα-null, and humanized PPARα (hPPARα) mice on an Sv/129 background were exposed via inhalation to 0, 1,000, and 2,000 ppm TRI for 8 hr/day for 7 days. We assessed TRI-induced steatosis or hepatic damage through biochemical and histopathological measurements. Plasma alanine aminotransferase and aspartate aminotransferase activities increased in all mouse lines after exposure to 1,000 and 2,000 ppm TRI. Exposure induced hepatocyte necrosis and inflammatory cells in all mouse lines, but hepatic lipid accumulation was observed only in Pparα-null and hPPARα mice. No differences were observed in TRI-mediated induction of hepatic PPARα target genes except for a few genes that differed between mPPARα and hPPARα mice. However, TRI significantly increased expression of triglyceride (TG)-synthesizing enzymes, diacylglicerol acyltransferases, and PPARγ in Pparα-null and hPPARα mice, which may account for the increased TG in their livers. TRI exposure elevated nuclear factor-kappa B (NFκB) p52 mRNA and protein in all mice regardless of PPARα genotype. NFκB-p52 is a candidate molecular marker for inflammation caused by TRI, and PPARα may be involved in TRI-induced hepatosteatosis. However, human PPARα may afford only weak protection against TRI-mediated effects compared with mouse PPARα.
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影响因子：
11.2
作者：
Cheung, C;Akiyama, TE;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
影响因子：
3.5
作者：
Mensing, T;Welge, P;Wilhelm, M
通讯作者：
Wilhelm, M
影响因子：
4.5
作者：
Laughter, AR;Dunn, CS;Corton, JC
通讯作者：
Corton, JC
影响因子：
3
作者：
Ito, Yuki;Yamanoshita, Osamu;Nakajima, Tarnie
通讯作者：
Nakajima, Tarnie
影响因子：
64.8
作者：
ISSEMANN, I;GREEN, S
通讯作者：
GREEN, S