title: The flavonoid monoHER promotes the adaption to oxidative stress during the onset of NAFLD.
abstract: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease. An evidence-based pharmacological treatment for NAFLD is still lacking, but flavonoids have shown therapeutic potential. The present study was designed to investigate the effect of the flavonoid monoHER on the onset of NAFLD in Ldlr(-/-) mice on a high-fat and high-cholesterol diet. The focus was put on the effect on oxidative stress as well as the adaptive response. Wild type mice served as a control and the effect of monoHER was compared to that of a placebo. In the Ldlr(-/-) group, monoHER provided only a mild protection against oxidative stress. In the placebo Ldlr(-/-) group an adaptive response elicited by the NRF2 antioxidant defense system was observed, evidenced by a higher HO-1 and Gpx3 gene expression, as well as an increased redox status, evidenced by the higher GSH/GSSG ratio. In the monoHER treated Ldlr(-/-) group both the adaptive response as well as the increase in redox status tended to be higher, although this did not reach significance on a group level. Unexpectedly, a strong within animal relationship was found that links a high adaptive response to a low redox status in the monoHER Ldlr(-/-) group. This correlation was absent in the placebo and wild type group. The concept that emerges is that a thiol-reactive oxidation product of monoHER, formed during oxidative stress, selectively induces the NRF2 pathway and enforces the endogenous antioxidant shield, to provide protection against NAFLD.
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: kristien.lemmens@maastrichtuniversity.nl.
authors.forename: Kristien J A
authors.initials: KJ
authors.lastname: Lemmens
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Bregje
authors.initials: B
authors.lastname: van de Wier
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center and NUTRIM School, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Ger H
authors.initials: GH
authors.lastname: Koek
authors.affiliation: Department of Anatomy and Embryology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Eleonore
authors.initials: E
authors.lastname: Köhler
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Drittij
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Wim J F
authors.initials: WJ
authors.lastname: van der Vijgh
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: g.haenen@maastrichtuniversity.nl.
authors.forename: Guido R M M
authors.initials: GR
authors.lastname: Haenen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005979:Glutathione Peroxidase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006896:Hydroxyethylrutoside / Q000031:analogs & derivatives* / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: C522803:7-monohydroxyethylrutoside; D000975:Antioxidants; D005419:Flavonoids; D006896:Hydroxyethylrutoside; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D011973:Receptors, LDL; C116888:Gpx3 protein, mouse; D005979:Glutathione Peroxidase; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Ldlr(−/−) mice; MonoHER; NAFLD; NRF2; Oxidative stress