title: Liquid fructose downregulates Sirt1 expression and activity and impairs the oxidation of fatty acids in rat and human liver cells.
abstract: Fructose ingestion is associated with the production of hepatic steatosis and hypertriglyceridemia. For fructose to attain these effects in rats, simultaneous induction of fatty acid synthesis and inhibition of fatty acid oxidation is required. We aimed to determine the mechanism involved in the inhibition of fatty acid oxidation by fructose and whether this effect occurs also in human liver cells. Female rats were supplemented or not with liquid fructose (10% w/v) for 7 or 14 days; rat (FaO) and human (HepG2) hepatoma cells, and human hepatocytes were incubated with fructose 25mM for 24h. The expression and activity of the enzymes and transcription factors relating to fatty acid β-oxidation were evaluated. Fructose inhibited the activity of fatty acid β-oxidation only in livers of 14-day fructose-supplemented rats, as well as the expression and activity of peroxisome proliferator activated receptor α (PPARα). Similar results were observed in FaO and HepG2 cells and human hepatocytes. PPARα downregulation was not due to an osmotic effect or to an increase in protein-phosphatase 2A activity caused by fructose. Rather, it was related to increased content in liver of inactive and acetylated peroxisome proliferator activated receptor gamma coactivator 1α, due to a reduction in sirtuin 1 expression and activity. In conclusion, fructose inhibits liver fatty acid oxidation by reducing PPARα expression and activity, both in rat and human liver cells, by a mechanism involving sirtuin 1 down-regulation.
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Rebollo
authors.affiliation: IBUB, Institute of Biomedicina University of Barcelona, Spain; CIBERobn (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición), Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Roglans
authors.affiliation: IBUB, Institute of Biomedicina University of Barcelona, Spain; CIBERobn (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición), Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Baena
authors.affiliation: IBUB, Institute of Biomedicina University of Barcelona, Spain; CIBERobn (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición), Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Sánchez
authors.affiliation: IBUB, Institute of Biomedicina University of Barcelona, Spain; CIBERobn (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición), Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Merlos
authors.affiliation: IBUB, Institute of Biomedicina University of Barcelona, Spain; CIBERobn (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición), Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Alegret
authors.affiliation: IBUB, Institute of Biomedicina University of Barcelona, Spain; CIBERobn (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición), Spain. Electronic address: jclagunae@ub.edu.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Laguna
mesh_terms: D000818:Animals; D005227:Fatty Acids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005632:Fructose / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D056564:Sirtuin 1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D005227:Fatty Acids; D047493:PPAR alpha; D005632:Fructose; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: ChREBP; PPARα; Steatosis; Triglyceride