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Biochim Biophys Acta. 2015 Feb;1851(2):107-16. doi: 10.1016/j.bbalip.2014.11.003. Epub 2014 Nov 9.

Fructose supplementation impairs rat liver autophagy through mTORC activation without inducing endoplasmic reticulum stress.

Author information

1
Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Spain.
2
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.
3
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.

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.

KEYWORDS:

Autophagy; Fructose; Hepatic steatosis; mTORC

PMID:
25463011
DOI:
10.1016/j.bbalip.2014.11.003
[Indexed for MEDLINE]

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