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.
Highlights
The unfolded protein response (UPR) is an adaptive cellular process characterized by translational arrest of protein synthesis in the endoplasmic reticulum (ER), which when dysregulated can perpetuate ER stress and oxidative and inflammatory signaling, both processes known to be important
One study in human liver samples has found that the progression from non-alcoholic steatosis (NAS) to non-alcoholic steatohepatitis (NASH) was accompanied by increased phosphorylation of jun N-terminal kinase (JNK) and increased ER stress reflected by elevated glucose-regulated protein 78 (GRP78) Messenger RNA (mRNA).[5]
This paper reported an enrichment of upregulated genes of autophagy by performing microarrays, their validation was not shown
Summary
The unfolded protein response (UPR) is an adaptive cellular process characterized by translational arrest of protein synthesis in the endoplasmic reticulum (ER), which when dysregulated can perpetuate ER stress and oxidative and inflammatory signaling, both processes known to be important. Autophagy is blocked during development of NAFLD A Gonzalez-Rodrıguez et al in the pathogenesis of NASH.[5] Cellular stressors initiate a signal-transduction cascade mediated by three transmembrane ER sensors: PKR-like eukaryotic initiation factor 2 kinase (PERK), activating transcription factor 6 (ATF6) and inositol requiring 1a (IRE1a). These cascades are kept inactive as long as sensors are bound to the intraluminal chaperone glucose-regulated protein 78 (GRP78). Once formed, autophagosomes traffic along microtubules to reach lysosomes where they fuse to form autophagolysosomes allowing the degradation of their contents by lysosomal acid hydrolases
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
