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Fluoxetine suppresses AMP-activated protein kinase signaling pathway to promote hepatic lipid accumulation in primary mouse hepatocytes.

The international journal of biochemistry & cell biology (2014-08-08)
Jing Xiong, Huan Yang, Lili Wu, Wei Shang, Enfang Shan, Wei Liu, Gang Hu, Tao Xi, Jian Yang
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
DAPI, for nucleic acid staining
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Dorsomorphin, ≥98% (HPLC)
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AICAR, ≥98% (HPLC), powder
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Pyrimidine, ≥98.0%
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5-Amino-4-imidazolecarboxamide, 95%
Dacarbazine impurity B, European Pharmacopoeia (EP) Reference Standard
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Monoclonal Anti-CD95 antibody produced in mouse, clone LT95, purified immunoglobulin, buffered aqueous solution
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Anti-STK11 antibody produced in mouse, purified immunoglobulin, buffered aqueous solution
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Anti-FAS antibody produced in rabbit, affinity isolated antibody
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Anti-LKB1 antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
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Anti-FAS antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
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Anti-FAS (ab1) antibody produced in chicken, affinity isolated antibody, buffered aqueous solution
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Anti-FAS (ab2) antibody produced in chicken, affinity isolated antibody, buffered aqueous solution
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Anti-STK11 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
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Monoclonal Anti-FAS antibody produced in mouse, clone 2G3, purified immunoglobulin, buffered aqueous solution
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Monoclonal Anti-STK11 antibody produced in mouse, clone 2A7-H2, ascites fluid
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Monoclonal Anti-LKB1 antibody produced in mouse, ~1 mg/mL, clone Ley37D/G6, purified immunoglobulin, buffered aqueous solution