title: Atypical antipsychotic drugs perturb AMPK-dependent regulation of hepatic lipid metabolism.
abstract: Dysregulation of lipid metabolism is a key feature of metabolic disorder related to side effects of antipsychotic drugs. Here, we investigated the molecular mechanism by which second-generation atypical antipsychotic drugs (AAPDs) affect hepatic lipid metabolism in liver. AAPDs augmented hepatic lipid accumulation by activating expression of sterol regulatory element-binding protein (SREBP) transcription factors, with subsequent induction of downstream target genes involved in lipid and cholesterol synthesis in hepatocytes. We confirmed the direct involvement of SREBPs on AAPD-induced expression of lipogenic and cholesterogenic genes by utilization of adenovirus for dominant negative SREBP (Ad-SREBP-DN). Interestingly, AAPDs significantly decreased phosphorylation of AMPKα and expression of fatty acid oxidation genes. Treatment of constitutive active AMPK restored AAPD-mediated dysregulation of genes involved in both lipid synthesis and fatty acid oxidation. Moreover, AAPDs decreased transcriptional activity of PPARα, a critical transcriptional regulator for controlling hepatic fatty acid oxidation, via an AMPK-dependent manner. Close investigations revealed that mutations at the known p38 MAPK phosphorylation sites (S6/12/21A), but not mutations at the putative AMPKα phosphorylation sites (S167/373/453A), block AAPD-dependent reduction of PPARα transcriptional activity, suggesting that p38 MAPK might be also involved in the regulatory pathway as a downstream effector of AAPDs/AMPK. Taken together, these data suggest that AAPD-stimulated hepatic dysregulation of lipid metabolism could result from the inhibition of AMPK activity, and pharmaceutical means to potentiate AMPK activity would contribute to restore hepatic lipid homeostasis that occurs during AAPD treatment.
authors.affiliation: Dept. of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, South Korea.
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Oh
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Park
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Lee
authors.forename: Injae
authors.initials: I
authors.lastname: Hwang
authors.forename: Jae Bum
authors.initials: JB
authors.lastname: Kim
authors.forename: Tae-Sik
authors.initials: TS
authors.lastname: Park
authors.forename: Heon-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D051779:Sterol Regulatory Element Binding Proteins; D000263:Adenylate Kinase