Feng_2012_CNS.Neurosci.Ther_18_974

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.