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Cell Death Dis. 2014 Apr 17;5:e1179. doi: 10.1038/cddis.2014.162.

Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD.

Author information

1
1] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Barcelona, Spain [2] Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC/UAM), Madrid, Spain.
2
1] Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA [2] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), ISCIII, Barcelona, Spain.
3
Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC/UAM), Madrid, Spain.
4
Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
5
1] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), ISCIII, Barcelona, Spain [2] Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
6
Gastroenterology Unit, Hospital del Tajo, Aranjuez, Madrid, Spain.
7
National Institute for Infectious Diseases IRCCS 'L Spallanzani', Rome, Italy.
8
1] National Institute for Infectious Diseases IRCCS 'L Spallanzani', Rome, Italy [2] Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
9
1] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), ISCIII, Barcelona, Spain [2] Oncology Surgery, Cell Therapy and Transplant Organs, Institute of Biomedicine of Seville (IBiS)/Virgen del Rocio Universitary Hospital/CSIC/University of Seville, Seville, Spain.
10
1] Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC/UAM), Madrid, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), ISCIII, Barcelona, Spain.

Abstract

The pathogenic mechanisms underlying the progression of non-alcoholic fatty liver disease (NAFLD) are not fully understood. In this study, we aimed to assess the relationship between endoplasmic reticulum (ER) stress and autophagy in human and mouse hepatocytes during NAFLD. ER stress and autophagy markers were analyzed in livers from patients with biopsy-proven non-alcoholic steatosis (NAS) or non-alcoholic steatohepatitis (NASH) compared with livers from subjects with histologically normal liver, in livers from mice fed with chow diet (CHD) compared with mice fed with high fat diet (HFD) or methionine-choline-deficient (MCD) diet and in primary and Huh7 human hepatocytes loaded with palmitic acid (PA). In NASH patients, significant increases in hepatic messenger RNA levels of markers of ER stress (activating transcription factor 4 (ATF4), glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP)) and autophagy (BCN1) were found compared with NAS patients. Likewise, protein levels of GRP78, CHOP and p62/SQSTM1 (p62) autophagic substrate were significantly elevated in NASH compared with NAS patients. In livers from mice fed with HFD or MCD, ER stress-mediated signaling was parallel to the blockade of the autophagic flux assessed by increases in p62, microtubule-associated protein 2 light chain 3 (LC3-II)/LC3-I ratio and accumulation of autophagosomes compared with CHD fed mice. In Huh7 hepatic cells, treatment with PA for 8 h triggered activation of both unfolding protein response and the autophagic flux. Conversely, prolonged treatment with PA (24 h) induced ER stress and cell death together with a blockade of the autophagic flux. Under these conditions, cotreatment with rapamycin or CHOP silencing ameliorated these effects and decreased apoptosis. Our results demonstrated that the autophagic flux is impaired in the liver from both NAFLD patients and murine models of NAFLD, as well as in lipid-overloaded human hepatocytes, and it could be due to elevated ER stress leading to apoptosis. Consequently, therapies aimed to restore the autophagic flux might attenuate or prevent the progression of NAFLD.

PMID:
24743734
PMCID:
PMC4001315
DOI:
10.1038/cddis.2014.162
[Indexed for MEDLINE]
Free PMC Article

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