Publication
Title
Hepatocellular autophagy modulates the unfolded protein response and fasting-induced steatosis in mice
Author
Abstract
BACKGROUND & AIMS Autophagy and the unfolded protein response (UPR) are key cellular homeostatic mechanisms and are both involved in liver diseases, including non-alcoholic fatty liver disease (NAFLD). Although increasing but conflicting results link these mechanisms to lipid metabolism, their role and potential crosstalk herein has been poorly investigated. Therefore, we assessed the effects of hepatocyte-specific autophagy-deficiency on liver parenchyma, the UPR and lipid metabolism. METHODS Adult hepatocellular-specific autophagy-deficient mice (Atg7F/FAlb-Cre+) were compared with their autophagy-competent littermates (Atg7+/+Alb-Cre+). Livers were analysed by electron microscopy, histology, real-time qPCR and Western blotting. RESULTS Atg7F/FAlb-Cre+ mice developed hepatomegaly with significant parenchymal injury as evidenced by inflammatory infiltrates, hepatocellular apoptosis, pericellular fibrosis and a pronounced ductular reaction. Surprisingly, the UPR exhibited a pathway-selective pattern upon autophagy-deficiency. The activity of the adaptive ATF6 pathway was abolished, whereas the pro-apoptotic PERK pathway was increased compared to Atg7+/+Alb-Cre+ mice. The IRE1α signal was unaltered. Fasting-induced steatosis was absent in Atg7F/FAlb-Cre+ mice. Remarkably, some isolated islands of fat-containing and autophagy-competent cells were observed in these livers. CONCLUSIONS Hepatocellular autophagy is essential for parenchymal integrity in mice. Moreover, in case of autophagy-deficiency, the three different UPR branches are pathway-selectively modulated. Attenuation of the ATF6 pathway might explain the observed impairment of fasting-induced steatosis. Finally, autophagy and lipid droplets are directly linked to each other.
Language
English
Source (journal)
American journal of physiology: gastrointestinal and liver physiology / American Physiological Society. - Bethesda, MD
Publication
Bethesda, MD : 2016
ISSN
0193-1857
Volume/pages
311:4(2016), p. G599-G609
ISI
000387910800003
Full text (Publisher's DOI)
Full text (open access)
The author-created version that incorporates referee comments and is the accepted for publication version Available from 22.09.2017
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 22.09.2016
Last edited 23.07.2017
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