title: Stevia-derived compounds attenuate the toxic effects of ectopic lipid accumulation in the liver of obese mice: a transcriptomic and metabolomic study.
abstract: There is a close interaction between Type 2 Diabetes, obesity and liver disease. We have studied the effects of the two most abundant Stevia-derived steviol glycosides, stevioside and rebaudioside A, and their aglycol derivative steviol on liver steatosis and the hepatic effects of lipotoxicity using a mouse model of obesity and insulin resistance. We treated ob/ob and LDLR-double deficient mice with stevioside (10 mg⋅kg(-1)⋅day-1 p.o., n = 8), rebaudioside A (12 mg⋅kg(-1)⋅day-1 p.o., n = 8), or steviol (5 mg⋅kg(-1)⋅day(-1) p.o., n = 8). We determined their effects on liver steatosis and on the metabolic effects of lipotoxicity by histological analysis, and by combined gene-expression and metabolomic analyses. All compounds attenuated hepatic steatosis. This could be explained by improved glucose metabolism, fat catabolism, bile acid metabolism, and lipid storage and transport. We identified PPARs as important regulators and observed differences in effects on insulin resistance, inflammation and oxidative stress between Stevia-derived compounds. We conclude that Stevia-derived compounds reduce hepatic steatosis to a similar extent, despite differences in effects on glucose and lipid metabolism, and inflammation and oxidative stress. Thus our data show that liver toxicity can be reduced through several pathophysiological changes. Further identification of active metabolites and underlying mechanisms are warranted.
authors.affiliation: Atherosclerosis and Metabolism Unit, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Leuven, Belgium. Electronic address: paul.holvoet@med.kuleuven.be.
authors.forename: Paul
authors.initials: P
authors.lastname: Holvoet
authors.affiliation: Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Rull
authors.affiliation: Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Anabel
authors.initials: A
authors.lastname: García-Heredia
authors.affiliation: Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: López-Sanromà
authors.affiliation: Atherosclerosis and Metabolism Unit, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Benjamine
authors.initials: B
authors.lastname: Geeraert
authors.affiliation: Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Joven
authors.affiliation: Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Camps
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D004195:Disease Models, Animal; D045786:Diterpenes, Kaurane / Q000494:pharmacology; D005234:Fatty Liver / Q000188:drug therapy*; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy; D018384:Oxidative Stress / Q000187:drug effects; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D028321:Plant Preparations / Q000494:pharmacology*; D036625:Stevia / Q000737:chemistry*; D059467:Transcriptome
chemical_list: D000596:Amino Acids; D001647:Bile Acids and Salts; D045786:Diterpenes, Kaurane; D005960:Glucosides; D047492:Peroxisome Proliferator-Activated Receptors; D028321:Plant Preparations; C012043:stevioside; C012042:steviol; C025474:rebaudioside A; D005978:Glutathione; D005947:Glucose
keywords: Insulin resistance; Liver steatosis; Liver toxicity; Metabolomics; Obesity; Steviosides