Fluoxetine Induces Hepatic Lipid Accumulation Via Both Promotion of the SREBP1c-Related Lipogenesis and Reduction of Lipolysis in Primary Mouse Hepatocytes
Fluoxetine Induces Hepatic Lipid Accumulation Via Both Promotion of the SREBP1c-Related Lipogenesis and Reduction of Lipolysis in Primary Mouse Hepatocytes
复制标题
氟西汀通过促进原代小鼠肝细胞中 SREBP1c 相关的脂肪生成和减少脂肪分解来诱导肝脏脂质积累
DOI：
10.1111/cns.12014
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发表时间：
2012-12-01
影响因子：
5.5
通讯作者：
Yang, Jian
中科院分区：
文献类型：
--
作者：
Feng, Xue-Min;Xiong, Jing;Yang, Jian
目的在本研究中，我们通过肝脏脂质代谢研究氟西汀（FLX）代谢副作用的外周机制。方法采用两步灌注法制备小鼠原代肝细胞。中性油染色法观察小鼠原代肝细胞脂质积累情况。采用RT-PCR和Western blot检测脂质代谢酶。结果氟西汀显著诱导小鼠原代肝细胞脂质积累。此外，FLX增加了乙酰辅酶a羧化酶1 （ACC1）和脂肪酸合成酶（FAS）的表达，这两种酶是脂肪生成的重要酶。相反，氟西汀显著降低了与脂肪分解相关的羧酸酯酶3 （CES3）和羧酸酯酶1 （CES1）的表达。进一步研究表明，flx激活的SREBP1c是协调调节脂肪生成基因ACC1、FAS等的重要转录因子之一。脂肪生成基因（ACC1）的增加被SB203580抑制，而PDTC则不抑制，可能与p38-MAPK通路有关。结论氟西汀通过促进小鼠原代肝细胞srebp1c相关的脂肪生成和减少脂肪分解来诱导肝脏脂质积累。
Aims In this study, we investigated the peripheral mechanisms underlying the metabolic side effects of fluoxetine (FLX) by focusing on hepatic lipid metabolism. Methods Primary mouse hepatocytes were prepared from male mice by the two-step perfusion method. The lipid accumulation in primary mouse hepatocytes was analyzed via neutral oil staining. And the lipid metabolism enzymes were determined with RT-PCR and Western blot. Results Fluoxetine significantly induced the lipid accumulation in primary mouse hepatocytes. Moreover, FLX increased the acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) expression, which are important enzymes in lipogenesis. Oppositely, Fluoxetine significantly decreased the carboxylesterase 3 (CES3) and carboxylesterase 1 (CES1) expression, which are related to lipolysis. Further study demonstrated FLX-activated SREBP1c, which is one of the most important transcription factors conducting coordinated transcriptional regulation of lipogenesis gene such as ACC1 and FAS. And the increase of lipogenesis gene (ACC1) was abolished by SB203580 but not by pyrrolidine dithiocarbamate (PDTC), suggesting through p38-MAPK pathway. Conclusion Fluoxetine induces hepatic lipid accumulation via both promotion of the SREBP1c-related lipogenesis and reduction of lipolysis in primary mouse hepatocytes.