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Inhibition of autophagic flux is associated with increased endoplasmic reticulum stress during the development of non-alcoholic fatty liver disease

AuthorsGonzález-Rodríguez, Águeda; Mayoral, Rafael ; Agra, Noelia ; Pardo, Virginia; García-Monzón, Carmelo; Martín-Sanz, Paloma ; Valverde, Ángela M.
Issue Date2013
Citation49th EASD Annual Meeting (2013)
Abstract[Background and aims]: Non-alcoholic fatty liver disease (NAFLD) is an inflammatory chronic disease which is the main hepatic complication of obesity and metabolic syndrome. In fact, epidemiologic and clinical studies have shown a close association between NAFLD and insulin resistance. We have previously reported that hepatic levels of insulin signalling mediators and phosphorylation of Akt and Foxo1 are down-regulated in patients with steatohepatitis (NASH), but not in patients with steatosis (NAS). Furthermore, hepatocyte apoptosis and active caspase 3 were only present in NASH patients. In this study, we have evaluated the relationship between ER stress and the autophagic flux during the onset of NAFLD in human and murine models of hepatic steatosis and NASH. [Materials and methods]: This study comprised 59 patients with a clinical diagnosis of NAS or NASH who underwent a liver biopsy and 30 patients with histological normal liver (NL). Real-time PCR, Western blot, immunohistochemistry and electronic microscopy were used to assess markers of ER and autophagy. Mice fed with high fat diet (HFD) for 7 months or methionine-choline-deficient (MCD) diet during 4 weeks were used to study ER stress and autophagy in the liver. Human Huh7 hepatocytes loaded with palmitic acid were used as an in vitro model. [Results]: In human liver from patients with NAS and NASH, mRNA levels of ER stress markers were elevated together with increased p62 autophagic substrate and LC3II accumulation. However, LC3 punctuate was less evident in patients with NASH. Mice fed with HFD or MCD diet showed increased phosphorylation of mTOR/S6K1, JNK, PERK, eIF2α together with elevated expression of ER chaperones GRP78 and CHOP. As observed in patients, p62 and LC3II were up-regulated by both diet interventions. In Huh7 hepatic cells, treatment with palmitate for 8 h activated the autophagic flux by decreasing p62 and cell death was not observed; this effect was blocked at 24 h, time at which ER stress markers and cell death were highly elevated and autophagic flux was blocked. Co-treatment with rapamycin and palmitate restored autophagic flux and protected Huh7 cells against lipoapoptosis. [Conclusion]: The impaired autophagic flux associated to NAS and NASH might be the consequence of elevated ER stress in the liver, resulting in apoptosis. Our results strongly suggest that therapies aimed to restore the autophagic flux in patients with severe hepatic steatosis might prevent the progression of the non-alcoholic liver disease.
DescriptionResumen del póster presentado al 49th European Association for the Study of Diabetes Annual Meeting, celebrado en Barcelona (España) del 23 al 27 de septiembre de 2013.-- et al.
Appears in Collections:(IIBM) Comunicaciones congresos
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