title: Epidermal fatty acid-binding protein protects nerve growth factor-differentiated PC12 cells from lipotoxic injury.
abstract: Epidermal fatty acid-binding protein (E-FABP/FABP5/DA11) binds and transport long-chain fatty acids in the cytoplasm and may play a protecting role during neuronal injury. We examined whether E-FABP protects nerve growth factor-differentiated PC12 cells (NGFDPC12 cells) from lipotoxic injury observed after palmitic acid (C16:0; PAM) overload. NGFDPC12 cells cultures treated with PAM/bovine serum albumin at 0.3 mM/0.15 mM show PAM-induced lipotoxicity (PAM-LTx) and apoptosis. The apoptosis was preceded by a cellular accumulation of reactive oxygen species (ROS) and higher levels of E-FABP. Antioxidants MCI-186 and N-acetyl cysteine prevented E-FABP's induction in expression by PAM-LTx, while tert-butyl hydroperoxide increased ROS and E-FABP expression. Non-metabolized methyl ester of PAM, methyl palmitic acid (mPAM), failed to increase cellular ROS, E-FABP gene expression, or trigger apoptosis. Treatment of NGFDPC12 cultures with siE-FABP showed reduced E-FABP levels correlating with higher accumulation of ROS and cell death after exposure to PAM. In contrast, increasing E-FABP cellular levels by pre-loading the cells with recombinant E-FABP diminished the PAM-induced ROS and cell death. Finally, agonists for PPARβ (GW0742) or PPARγ (GW1929) increased E-FABP expression and enhanced the resistance of NGFDPC12 cells to PAM-LTx. We conclude that E-FABP protects NGFDPC12 cells from lipotoxic injury through mechanisms that involve reduction of ROS. Epidermal fatty acid-binding protein (E-FABP) may protect nerve cells from the damaging exposure to high levels of free fatty acids (FA). We show that E-FABP can neutralize the effects of reactive oxygen species (ROS) generated by the high levels of FA in the cell and protect PC12 cells from lipotoxic injuries common in Type 2 diabetes neuropathy. Potentially, E-FABP gene up-regulation may be mediated through the NFkB pathway and future studies are needed to further evaluate this proposition.
authors.affiliation: Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Jo-Wen
authors.initials: JW
authors.lastname: Liu
authors.forename: Manuel
authors.initials: M
authors.lastname: Montero
authors.forename: Liming
authors.initials: L
authors.lastname: Bu
authors.forename: Marino
authors.initials: M
authors.lastname: De Leon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000502:physiology*; D008055:Lipids / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D016716:PC12 Cells; D019308:Palmitic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection
chemical_list: D005136:Eye Proteins; C107356:Fabp5 protein, rat; D050556:Fatty Acid-Binding Proteins; D008055:Lipids; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D019308:Palmitic Acid; D020932:Nerve Growth Factor
keywords: FABP; PPAR; antioxidants; lipotoxicity; reactive oxygen species