title: FOXO1 and LXRα downregulate the apolipoprotein A-I gene expression during hydrogen peroxide-induced oxidative stress in HepG2 cells.
abstract: Reactive oxygen species damage various cell components including DNA, proteins, and lipids, and these impairments could be a reason for severe human diseases including atherosclerosis. Forkhead box O1 (FOXO1), an important metabolic transcription factor, upregulates antioxidant and proapoptotic genes during oxidative stress. Apolipoprotein A-I (ApoA-I) forms high density lipoprotein (HDL) particles that are responsible for cholesterol transfer from peripheral tissues to liver for removal in bile in vertebrates. The main sources for plasma ApoA-I in mammals are liver and jejunum. Hepatic apoA-I transcription depends on a multitude of metabolic transcription factors. We demonstrate that ApoA-I synthesis and secretion are decreased during H2O2-induced oxidative stress in human hepatoma cell line HepG2. Here, we first show that FOXO1 binds to site B of apoA-I hepatic enhancer and downregulates apoA-I gene activity in HepG2 cells. Moreover, FOXO1 and LXRα transcription factors participate in H2O2-triggered downregulation of apoA-I gene together with Src, JNK, p38, and AMPK kinase cascades. Mutations of sites B or C as well as the administration of siRNAs against FOXO1 or LXRα to HepG2 cells abolished the hydrogen peroxide-mediated suppression of apoA-I gene.
authors.affiliation: Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, Acad. Pavlov St., 12, St. Petersburg, 197376, Russia. shavva@iem.sp.ru.|Department of Embryology, St. Petersburg State University, St. Petersburg, Russia. shavva@iem.sp.ru.
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Shavva
authors.affiliation: Department of Biochemistry, St. Petersburg State University, St. Petersburg, Russia.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Bogomolova
authors.affiliation: Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, Acad. Pavlov St., 12, St. Petersburg, 197376, Russia.|Department of Biochemistry, St. Petersburg State University, St. Petersburg, Russia.
authors.forename: Artemy A
authors.initials: AA
authors.lastname: Nikitin
authors.affiliation: Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, Acad. Pavlov St., 12, St. Petersburg, 197376, Russia.
authors.forename: Ella B
authors.initials: EB
authors.lastname: Dizhe
authors.affiliation: Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, Acad. Pavlov St., 12, St. Petersburg, 197376, Russia.
authors.forename: Galina N
authors.initials: GN
authors.lastname: Oleinikova
authors.affiliation: Department of Embryology, St. Petersburg State University, St. Petersburg, Russia.
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Lapikov
authors.affiliation: Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, Acad. Pavlov St., 12, St. Petersburg, 197376, Russia.|Department of Fundamental Medicine and Medical Technologies, St. Petersburg State University, St. Petersburg, Russia.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Tanyanskiy
authors.affiliation: Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, Acad. Pavlov St., 12, St. Petersburg, 197376, Russia.|Department of Embryology, St. Petersburg State University, St. Petersburg, Russia.
authors.forename: Andrej P
authors.initials: AP
authors.lastname: Perevozchikov
authors.affiliation: Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, Acad. Pavlov St., 12, St. Petersburg, 197376, Russia. serge@iem.sp.ru.|Department of Embryology, St. Petersburg State University, St. Petersburg, Russia. serge@iem.sp.ru.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Orlov
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D000071161:Forkhead Box Protein O1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071518:Liver X Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D000071518:Liver X Receptors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide; D019061:src-Family Kinases; C526181:PRKAA2 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human
keywords: Apolipoprotein A-I; FOXO1; Hydrogen peroxide; LXRα; Oxidative stress