title: Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes.
abstract: Excess of saturated free fatty acids, such as palmitic acid (PA), in hepatocytes has been implicated in nonalcoholic fatty liver disease. α-Lipoic acid (LA) is an antioxidant that protects against oxidative stress conditions. We have investigated the effects of LA in the early activation of oxidative and endoplasmic reticulum stress, lipid accumulation, and Nrf2-mediated antioxidant defenses in hepatocytes treated with PA or in rats fed a high-fat diet. In primary human hepatocytes, a lipotoxic concentration of PA triggered endoplasmic reticulum stress, induced the apoptotic transcription factor CHOP, and increased the percentage of apoptotic cells. Cotreatment with LA prevented these effects. Similar results were found in mouse hepatocytes in which LA attenuated PA-mediated activation of caspase 3 and reduced lipid accumulation by decreasing PA uptake and increasing fatty acid oxidation and lipophagy, thereby preventing lipoapoptosis. Moreover, LA augmented the proliferation capacity of hepatocytes after PA challenge. Antioxidant effects of LA ameliorated reactive oxygen species production and endoplasmic reticulum stress and protected against mitochondrial apoptosis in hepatocytes treated with PA. Cotreatment with PA and LA induced an early nuclear translocation of Nrf2 and activated antioxidant enzymes, whereas reduction of Nrf2 by siRNA abolished the benefit of LA on PA-induced lipoapoptosis. Importantly, posttreatment with LA reversed the established damage induced by PA in hepatocytes, as well as preventing obesity-induced oxidative stress and lipoapoptosis in rat liver. In conclusion, our work has revealed that in hepatocytes, Nrf2 is an essential early player in the rescue of oxidative stress by LA leading to protection against PA-mediated lipoapoptosis.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain; Instituto de Investigación Sanitaria La Paz, 28029 Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pilar Valdecantos
authors.affiliation: Department of Nutrition, Food Science, and Physiology University of Navarra, 31008 Pamplona, Spain.
authors.forename: Pedro Luis
authors.initials: PL
authors.lastname: Prieto-Hontoria
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28029 Madrid, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pardo
authors.affiliation: Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Módol
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain; Instituto de Investigación Sanitaria La Paz, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28029 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Santamaría
authors.affiliation: Department of Biochemistry and Molecular Biology, Institut de Biomedicina, Universitat de Barcelona, E-08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain.
authors.forename: Minéia
authors.initials: M
authors.lastname: Weber
authors.affiliation: Department of Biochemistry and Molecular Biology, Institut de Biomedicina, Universitat de Barcelona, E-08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Herrero
authors.affiliation: Department of Biochemistry and Molecular Biology, Institut de Biomedicina, Universitat de Barcelona, E-08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Serra
authors.affiliation: Departamento de Cirugía General y Digestiva, Hospital Universitario Virgen del Rocío-Virgen Macarena/IBiS/CSIC/University of Sevilla, 41013 Sevilla, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, 28029 Madrid, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Muntané
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain; Instituto de Investigación Sanitaria La Paz, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28029 Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuadrado
authors.affiliation: Department of Nutrition, Food Science, and Physiology University of Navarra, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Moreno-Aliaga
authors.affiliation: Department of Nutrition, Food Science, and Physiology University of Navarra, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Alfredo Martínez
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain; Instituto de Investigación Sanitaria La Paz, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28029 Madrid, Spain. Electronic address: avalverde@iib.uam.es.
authors.forename: Ángela M
authors.initials: ÁM
authors.lastname: Valverde
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D061745:Antioxidant Response Elements; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000494:pharmacology; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D019308:Palmitic Acid; D008063:Thioctic Acid
keywords: Antioxidant; Endoplasmic reticulum stress; Free radicals; Lipoapoptosis; Lipoic acid; Lipophagy; Nonalcoholic fatty liver disease; Nrf2; Palmitic acid; Reactive oxygen species