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

• Published in: Biochimica et biophysica acta 2015-02, Vol.1851 (2), p.107-116
• Main Authors: Baena, Miguel, Sangüesa, Gemma, Hutter, Natalia, Sánchez, Rosa M., Roglans, Núria, Laguna, Juan C., Alegret, Marta
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Disease Models, Animal; Endoplasmic Reticulum Stress; Enzyme Activation; Fatty Acids - metabolism; Fatty Liver - chemically induced; Fatty Liver - enzymology; Fatty Liver - genetics; Fatty Liver - pathology; Female; Fructose; Gene Expression Regulation; Glycolysis - genetics; Hepatic steatosis; Hypertriglyceridemia - chemically induced; Hypertriglyceridemia - enzymology; Hypertriglyceridemia - pathology; Lipogenesis; Liver - enzymology; Liver - pathology; mTORC; Oxidation-Reduction; Pentose Phosphate Pathway - genetics; Phosphorylation; PPAR alpha - metabolism; Rats, Sprague-Dawley; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases - metabolism; Triglycerides - metabolism
• ISSN: 1388-1981; 0006-3002; 1879-2618
• DOI: 10.1016/j.bbalip.2014.11.003

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. •We examine the effects of 8-week 10% liquid fructose supplements (F) in female rats.•F increases synthesis and inhibits fatty acid oxidation, causing hepatic steatosis.•PPARα and target genes are not affected and there is no sign of hepatic ER stress.•Reduced autophagy, driven by mTOR activation, contributes to fatty liver.