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Free Radic Biol Med. 2015 Jul;84:263-278. doi: 10.1016/j.freeradbiomed.2015.03.019. Epub 2015 Apr 1.

Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes.

Author information

1
Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain; Instituto de Investigación Sanitaria La Paz, 28029 Madrid, Spain.
2
Department of Nutrition, Food Science, and Physiology University of Navarra, 31008 Pamplona, Spain.
3
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.
4
Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain.
5
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.
6
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.
7
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.
8
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.
9
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.
10
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.

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.

KEYWORDS:

Antioxidant; Endoplasmic reticulum stress; Free radicals; Lipoapoptosis; Lipoic acid; Lipophagy; Nonalcoholic fatty liver disease; Nrf2; Palmitic acid; Reactive oxygen species

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