Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease.
Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease.
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DOI：
10.1016/j.jhep.2010.08.007
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发表时间：
2011-01
影响因子：
25.7
通讯作者：
Wands JR
中科院分区：
文献类型：
--
作者：
Derdak Z;Lang CH;Villegas KA;Tong M;Mark NM;de la Monte SM;Wands JR
Long-Evans（LE）大鼠的慢性乙醇消耗与肝脏p53激活以及由于10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）表达增加而导致的胰岛素/PI 3 K/AKT信号转导级联抑制相关。我们推测p53的激活和胰岛素信号的改变可能会影响大鼠对乙醇诱导的肝损伤的易感性。此外，p53不仅激活程序性细胞死亡途径并抑制肝细胞存活信号，而且由于新的代谢功能而促进肝细胞生成以增加全身性胰岛素抵抗。在这里，我们提出的证据表明，在Fischer（F），Sprague-Dawley（SD）和LE大鼠慢性乙醇喂养促进p53激活，肝脂肪变性，氧化应激，p53上调的凋亡调节因子（p53）和PTEN表达，这有助于肝细胞死亡和减少肝脏中的胰岛素信号传导。这种变化在LE中明显，在SD中不太明显，在F大鼠品系中几乎不存在。更重要的是，在乙醇喂养的LE大鼠中存在Tp 53诱导的糖酵解和凋亡调节因子（TIGAR）的激活。该事件导致肝脏果糖-2，6-二磷酸（Fru-2，6-P2）水平降低，乳酸/丙酮酸比值降低，并可能导致正常血糖高胰岛素钳夹期间基础葡萄糖周转增加和残留肝脏葡萄糖产生增加。结论：p53激活与不同品系大鼠对乙醇诱导的肝损伤的易感性相关。p53不仅协调细胞凋亡和抑制细胞存活，而且通过激活TIGAR和降低肝Fru-2，6-P2水平，它还可能促进胰岛素抵抗，因此，有助于与肝脂肪变性相关的代谢异常。
Chronic ethanol consumption in the Long-Evans (LE) rat has been associated with hepatic p53 activation, and inhibition of the insulin/PI3K/AKT signal transduction cascade due to increased expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). We hypothesize that p53 activation and altered insulin signaling may influence the susceptibility of rats to ethanol-induced liver damage. Furthermore, p53 not only activates programmed cell death pathways and suppresses hepatocellular survival signals, but promotes gluconeogenesis to increase systemic insulin resistance due to a novel metabolic function. Here, we present evidence that chronic ethanol feeding in Fischer (F), Sprague-Dawley (SD) and LE rats promotes p53 activation, hepatic steatosis, oxidative stress, p53 up-regulated modulator of apoptosis (PUMA) and PTEN expression, which contribute to hepatocellular death and diminished insulin signaling in the liver. Such changes are pronounced in the LE, less prominent in SD, and virtually absent in the F rat strain. More importantly, there is activation of Tp53-induced glycolysis and apoptosis regulator (TIGAR) in the ethanol-fed LE rat. This event generates low hepatic fructose-2, 6-bisphosphate (Fru-2,6-P2) levels, reduced lactate/pyruvate ratio and may contribute to increased basal glucose turnover and high residual hepatic glucose production during euglycemic hyperinsulinemic clamp. Conclusions: p53 activation correlates with the susceptibility to ethanol-induced liver damage in different rat strains. p53 not only orchestrates apoptosis and suppresses cell survival, but by activating TIGAR and decreasing hepatic Fru-2,6-P2 levels it may also promote insulin resistance and therefore, contribute to the metabolic abnormalities associated with hepatic steatosis.
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DOI：
10.1016/j.bbrc.2008.06.006
发表时间：
2008-08-22
影响因子：
3.1
作者：
Lieber, Charles S.;Leo, Maria Anna;DeCarli, Leonore M.
通讯作者：
DeCarli, Leonore M.
影响因子：
8
作者：
Trinei, M;Giorgio, M;Pelicci, PG
通讯作者：
Pelicci, PG
影响因子：
16
作者：
Shimomura, I;Matsuda, M;Goldstein, JL
通讯作者：
Goldstein, JL
影响因子：
25.7
作者：
Pang, Maoyin;de la Monte, Suzanne M.;Wands, Jack R.
通讯作者：
Wands, Jack R.
DOI：
10.1111/j.1440-1746.2008.05339.x
发表时间：
2008-08-01
影响因子：
4.1
作者：
de la Monte, Suzanne M.;Yeon, Jong-Eun;Wands, Jack R.
通讯作者：
Wands, Jack R.