title: Fluoxetine suppresses AMP-activated protein kinase signaling pathway to promote hepatic lipid accumulation in primary mouse hepatocytes.
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.
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shang
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Enfang
authors.initials: E
authors.lastname: Shan
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.affiliation: Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xi
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: jianyang@njmu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D005473:Fluoxetine / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050155:Lipogenesis / Q000187:drug effects*; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012265:Ribonucleotides / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D005473:Fluoxetine; D007004:Hypoglycemic Agents; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D012265:Ribonucleotides; D017367:Selective Serotonin Reuptake Inhibitors; D051780:Sterol Regulatory Element Binding Protein 1; C497388:Srebf1 protein, mouse; C491654:Stk11 protein, mouse; C031143:AICA ribonucleotide
keywords: AMPK; Carboxylesterases; Fluoxetine; Hepatic lipid accumulation; SREBP