Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease.
Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease.
复制标题
DOI：
10.1016/j.jhep.2012.11.042
复制
发表时间：
2013-04
影响因子：
25.7
通讯作者：
Wands, Jack R.
中科院分区：
文献类型：
--
作者：
Derdak, Zoltan;Villegas, Kristine A.;Harb, Ragheb;Wu, Annie M.;Sousa, Aryanna;Wands, Jack R.
P53及其转录靶点miRNA34a参与了脂肪肝的发病机制。我们在一种非酒精性脂肪性肝病小鼠模型上测试了P53抑制剂Pificerin-αp-Nitro(PFT)在减轻脂肪变性、相关的氧化应激和细胞凋亡方面的效果。C75Bl/6J小鼠饲喂高脂饲料(HFD)或对照饲料8周，PFT或DMSO(赋形剂)每周3次。用免疫组织化学、Western-Blot、实时荧光定量聚合酶链式反应和生化方法检测氧化应激和细胞凋亡的标志物以及肝脏脂肪酸代谢的调节因子。给予PFT可抑制HFD诱导的体重增加、ALT升高、脂肪变性、氧化应激和细胞凋亡。PFT抑制HFD诱导的miRNA34a表达上调，增加SIRT1的表达。在高脂饲料喂养的小鼠肝脏中，PFT处理的小鼠肝脏中SIRT1/PGC1PPARα/α轴的激活增加了丙二酰辅酶A脱羧酶(MLYCD)的表达，这是一种负责丙二酰辅酶A(MCoA)降解的酶。此外，PFT还促进了MLYCD的上游激活因子SIRT1/LKB1/AMPK通路。因此，PFT诱导的这两条途径通过增强MLYCD的表达和功能来减少肝脏MCOA的含量。由于MCOA抑制肉碱棕榈酰基转移酶1(CPT1)，服用PFT和HFD的小鼠肝脏MCOA的减少增加了CPT1的活性，有利于脂肪酸的氧化，减少了脂肪变性。此外，我们还证明了PFT抑制了棕榈油酸处理的人HepaRG细胞的脂肪变性并促进了MLYCD的表达。P53抑制剂PFT通过耗尽MCOA和促进脂肪酸的β氧化来减少高脂饲料喂养的小鼠肝脏甘油三酯的积累和脂肪毒性。
p53 and its transcriptional target miRNA34a have been implicated in the pathogenesis of fatty liver. We tested the efficacy of a p53 inhibitor, pifithrin-α p-nitro (PFT) in attenuating steatosis, associated oxidative stress and apoptosis in a murine model of non-alcoholic fatty liver disease (NAFLD). C75Bl/6J mice were fed a high-fat (HFD) or control diet for 8 weeks, PFT or DMSO (vehicle) were administered three times per week. Markers of oxidative stress and apoptosis as well as mediators of hepatic fatty acid metabolism were assessed by immunohistochemistry, Western-blot, real-time PCR and biochemical assays. PFT administration suppressed HFD-induced weight gain, ALT elevation, steatosis, oxidative stress and apoptosis. PFT treatment blunted the HFD-induced upregulation of miRNA34a and increased SIRT1 expression. In the livers of HFD-fed, PFT-treated mice activation of the SIRT1/PGC1α/PPARα axis increased the expression of malonyl-CoA decarboxylase (MLYCD), an enzyme responsible for malonyl-CoA (mCoA) degradation. Additionally, the SIRT1/LKB1/AMPK pathway (upstream activator of MLYCD) was promoted by PFT. Thus, induction of these two pathways by PFT diminished the hepatic mCoA content by enhancing MLYCD expression and function. Since mCoA inhibits carnitine palmitoyltransferase 1 (CPT1), the decrease of hepatic mCoA in the PFT-treated, HFD-fed mice increased CPT1 activity, favored fatty acid oxidation and decreased steatosis. Additionally, we also demonstrated that PFT abrogated steatosis and promoted MLYCD expression in palmitoleic acid- treated human HepaRG cells. The p53 inhibitor PFT diminished hepatic triglyceride accumulation and lipotoxicity in mice fed a HFD by depleting mCoA and favoring the β-oxidation of fatty acids.
登录
查看更多内容
影响因子：
25.7
作者：
Derdak Z;Lang CH;Villegas KA;Tong M;Mark NM;de la Monte SM;Wands JR
通讯作者：
Wands JR
影响因子：
4.1
作者：
Lee, GY;Kim, NH;Kim, YS
通讯作者：
Kim, YS
DOI：
10.1038/labinvest.2010.113
发表时间：
2010-10
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Lan, Fan;Cacicedo, Jose M.;Ido, Yasuo
通讯作者：
Ido, Yasuo
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.