title: Fructose supplementation impairs rat liver autophagy through mTORC activation without inducing endoplasmic reticulum stress.
abstract: Supplementation with 10% liquid fructose to female rats for 2weeks caused hepatic steatosis through increased lipogenesis and reduced peroxisome proliferator activated receptor (PPAR) α activity and fatty acid catabolism, together with increased expression of the spliced form of X-binding protein-1 (Rebollo et al., 2014). In the present study, we show that some of these effects are preserved after sub-chronic (8weeks) fructose supplementation, specifically increased hepatic expression of lipid synthesis-related genes (stearoyl-CoA desaturase, ×6.7-fold; acetyl-CoA carboxylase, ×1.6-fold; glycerol-3-phosphate acyltransferase, ×1.65-fold), and reduced fatty acid β-oxidation (×0.77-fold), resulting in increased liver triglyceride content (×1.69-fold) and hepatic steatosis. However, hepatic expression of PPARα and its target genes was not modified and, further, livers of 8-week fructose-supplemented rats showed no sign of unfolded protein response activation, except for an increase in p-IRE1 levels. Hepatic mTOR phosphorylation was enhanced (×1.74-fold), causing an increase in the phosphorylation of UNC-51-like kinase 1 (ULK-1) (×2.8-fold), leading to a decrease in the ratio of LC3B-II/LC3B-I protein expression (×0.39-fold) and an increase in the amount of the autophagic substrate p62, indicative of decreased autophagy activity. A harmful cycle may be established in the liver of 8-week fructose-supplemented rats where lipid accumulation may cause defective autophagy, and reduced autophagy may result in decreased free fatty acid formation from triglyceride depots, thus reducing the substrates for β-oxidation and further increasing hepatic steatosis. In summary, the length of supplementation is a key factor in the metabolic disturbances induced by fructose: in short-term studies, PPARα inhibition and ER stress induction are critical events, whereas after sub-chronic supplementation, mTOR activation and autophagy inhibition are crucial.
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Baena
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Sangüesa
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Hutter
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Spain; IBUB Institute of Biomedicine, 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: Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Spain; IBUB Institute of Biomedicine, 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: Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Spain; IBUB Institute of Biomedicine, University of Barcelona, Spain; CIBERobn Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Laguna
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Spain; IBUB Institute of Biomedicine, University of Barcelona, Spain; CIBERobn Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Spain. Electronic address: alegret@ub.edu.
authors.forename: Marta
authors.initials: M
authors.lastname: Alegret
mesh_terms: D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D005632:Fructose; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000235:genetics; D015228:Hypertriglyceridemia / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D050155:Lipogenesis; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D010427:Pentose Phosphate Pathway / Q000235:genetics; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D047493:PPAR alpha; D014280:Triglycerides; D005632:Fructose; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases
keywords: Autophagy; Fructose; Hepatic steatosis; mTORC