Fluoxetine suppresses AMP-activated protein kinase signaling pathway to promote hepatic lipid accumulation in primary mouse hepatocytes.
Fluoxetine suppresses AMP-activated protein kinase signaling pathway to promote hepatic lipid accumulation in primary mouse hepatocytes.
复制标题
氟西汀抑制 AMP 激活的蛋白激酶信号通路，促进原代小鼠肝细胞中的肝脂质积累。
DOI：
10.1016/j.biocel.2014.07.019
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Xiong J, Yang H, Wu L, Shang W, Shan E, Liu W, Hu G, Xi T, Ya
中科院分区：
文献类型：
--
作者：
Xiong J, Yang H, Wu L, Shang W, Shan E, Liu W, Hu G, Xi T, Ya
在先前的研究中，我们证明了氟西汀（FLX）调节脂肪生成和脂肪分解基因，以促进肝脏脂质蓄积。在此基础上，本研究以原代小鼠肝细胞为研究对象，着重于细胞内信号转导的研究。脂肪生成和脂解相关基因的表达与特定的激活剂和抑制剂的应用进行了评估。分析各信号通路的激活状态和肝细胞中的脂质积聚。我们提供的证据表明，AMP激活蛋白激酶（AMPK）激活剂AICAR（5-氨基咪唑-4-甲酰胺-1-β-d-呋喃核糖苷）显著抑制FLX引起的代表性脂肪生成相关基因乙酰辅酶A羧化酶（ACC）和脂肪酸合成酶（FAS）的表达增加，同时增加了脂肪分解相关基因羧酸酯酶的抑制表达。同时，FLX以与AMPK抑制剂化合物C相同的方式调节上述基因。AICAR抑制FLX诱导的SREBP 1c蛋白水解激活，导致细胞核SREBP 1c水平降低。进一步的研究表明，FLX显着抑制AMPK的磷酸化和随后的ACC的磷酸化，抑制肝激酶B1（LKB 1）的磷酸化和核输出。作为功能分析，AICAR反复消除了FLX诱导的肝细胞中的脂质蓄积。总之，FLX诱导的肝脏脂质蓄积是通过抑制AMPK信号通路介导的。这些发现不仅为理解选择性5-羟色胺再摄取受体介导的血脂异常效应的机制提供了新的见解，而且还提出了一种新的治疗靶点。
In the previous study, we demonstrated that fluoxetine (FLX) regulated lipogenic and lipolytic genes to promote hepatic lipid accumulation. On this basis, underlying mechanisms were investigated by focusing on the intracellular signaling transduction in the present study using primary mouse hepatocytes. The expression of lipogenesis- and lipolysis-related genes was evaluated with the application of specific activators and inhibitors. Activation status of respective signaling pathway and the lipid accumulation in hepatocytes were analyzed. We provided evidence that AMP-activated protein kinase (AMPK) activator AICAR (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside) significantly suppressed the increased expression of representative lipogenesis-related genes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) by FLX, while increased the repressed expression of lipolysis-related genes, carboxylesterases. In the meanwhile, FLX regulated the above genes in the same way as AMPK inhibitor Compound C did. Furthermore, AICAR inhibited the proteolytic activation of SREBP1c induced by FLX, resulting in the decreased level of nuclear SREBP1c. Further studies demonstrated that FLX significantly suppressed the phosphorylation of AMPK and subsequent phosphorylation of ACC, following the inhibited phosphorylation and nuclear export of liver kinase B1 (LKB1). As a functional analysis, FLX-induced lipid accumulation in hepatocytes was repeatedly abolished by AICAR. In conclusion, FLX-induced hepatic lipid accumulation is mediated by the suppression of AMPK signaling pathway. The findings not only provide new insight into the understanding of the mechanisms for selective serotonin reuptake inhibitors-mediated dyslipidemia effects, but also suggest a novel therapeutic target to interfere.
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影响因子：
2.9
作者：
Warden D;Trivedi MH;Wisniewski SR;Kurian B;Zisook S;Kornstein SG;Friedman ES;Miyahara S;Leuchter AF;Fava M;Rush AJ
通讯作者：
Rush AJ
影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
1.6
作者：
Cheng, Dong;Chu, Ching-Hsuen;Tamura, James K.
通讯作者：
Tamura, James K.
DOI：
10.1124/jpet.111.184242
发表时间：
2011-12-01
影响因子：
3.5
作者：
Bumpus, Namandje N.;Johnson, Eric F.
通讯作者：
Johnson, Eric F.
影响因子：
6.5
作者：
Nassir, Fatiha;Adewole, Okunade L.;Abumrad, Nada A.
通讯作者：
Abumrad, Nada A.