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Hepatocellular autophagy modulates the unfolded protein response and fasting-induced steatosis in mice

Wilhelmus J Kwanten, Yves-Paul Vandewynckel, Wim Martinet, Benedicte Y De Winter, Peter P Michielsen, Viviane O Van Hoof, Ann Driessen, Jean-Pierre Timmermans, Pierre Bedossa, Hans Van Vlierberghe UGent, et al. (2016) AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY. 311(4). p.G599-G609
abstract
Autophagy and the unfolded protein response (UPR) are key cellular homeostatic mechanisms and are both involved in liver diseases, including nonalcoholic fatty liver disease (NAFLD). Although increasing but conflicting results link these mechanisms to lipid metabolism, their role and potential cross talk herein have been poorly investigated. Therefore, we assessed the effects of hepatocyte- specific autophagy deficiency on liver parenchyma, the UPR, and lipid metabolism. Adult hepatocellular-specific autophagy-deficient mice (Atg7F/FAlb-Cre(+)) were compared with their autophagy-competent littermates (Atg7(+/+) Alb-Cre(+)). Livers were analyzed by electron microscopy, histology, real-time qPCR, and Western blotting. Atg7F/FAlb-Cre(+) mice developed hepatomegaly with significant parenchymal injury, as shown 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 activating transcription factor 6 (ATF6) pathway was abolished, whereas the proapoptotic protein kinase RNA-like ER kinase pathway was increased compared with Atg7(+/+) Alb-Cre(+) mice. The inositol-requiring enzyme-1 alpha 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. Hepatocellular autophagy is essential for parenchymal integrity in mice. Moreover, in the 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
nonalcoholic fatty liver, steatosis, autophagy, endoplasmic reticulum stress, unfolded protein response, FATTY LIVER-DISEASE, ENDOPLASMIC-RETICULUM STRESS, DEFECTIVE HEPATIC AUTOPHAGY, ER STRESS, INSULIN-RESISTANCE, LIPID-METABOLISM, STELLATE CELLS, PATHOPHYSIOLOGY, ACTIVATION, INJURY
journal title
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Am. J. Physiol.-Gastroint. Liver Physiol.
volume
311
issue
4
pages
G599 - G609
Web of Science type
Article
Web of Science id
000387910800003
JCR category
PHYSIOLOGY
JCR impact factor
3.468 (2016)
JCR rank
20/84 (2016)
JCR quartile
1 (2016)
ISSN
0193-1857
DOI
10.1152/ajpgi.00418.2015
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8174528
handle
http://hdl.handle.net/1854/LU-8174528
date created
2016-11-28 12:09:55
date last changed
2017-02-01 14:22:20
@article{8174528,
  abstract     = {Autophagy and the unfolded protein response (UPR) are key cellular homeostatic mechanisms and are both involved in liver diseases, including nonalcoholic fatty liver disease (NAFLD). Although increasing but conflicting results link these mechanisms to lipid metabolism, their role and potential cross talk herein have been poorly investigated. Therefore, we assessed the effects of hepatocyte- specific autophagy deficiency on liver parenchyma, the UPR, and lipid metabolism. Adult hepatocellular-specific autophagy-deficient mice (Atg7F/FAlb-Cre(+)) were compared with their autophagy-competent littermates (Atg7(+/+) Alb-Cre(+)). Livers were analyzed by electron microscopy, histology, real-time qPCR, and Western blotting. Atg7F/FAlb-Cre(+) mice developed hepatomegaly with significant parenchymal injury, as shown 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 activating transcription factor 6 (ATF6) pathway was abolished, whereas the proapoptotic protein kinase RNA-like ER kinase pathway was increased compared with Atg7(+/+) Alb-Cre(+) mice. The inositol-requiring enzyme-1 alpha 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. Hepatocellular autophagy is essential for parenchymal integrity in mice. Moreover, in the 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.},
  author       = {Kwanten, Wilhelmus J and Vandewynckel, Yves-Paul and Martinet, Wim and De Winter, Benedicte Y and Michielsen, Peter P and Van Hoof, Viviane O and Driessen, Ann and Timmermans, Jean-Pierre and Bedossa, Pierre and Van Vlierberghe, Hans and Francque, Sven M},
  issn         = {0193-1857},
  journal      = {AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY},
  keyword      = {nonalcoholic fatty liver,steatosis,autophagy,endoplasmic reticulum stress,unfolded protein response,FATTY LIVER-DISEASE,ENDOPLASMIC-RETICULUM STRESS,DEFECTIVE HEPATIC AUTOPHAGY,ER STRESS,INSULIN-RESISTANCE,LIPID-METABOLISM,STELLATE CELLS,PATHOPHYSIOLOGY,ACTIVATION,INJURY},
  language     = {eng},
  number       = {4},
  pages        = {G599--G609},
  title        = {Hepatocellular autophagy modulates the unfolded protein response and fasting-induced steatosis in mice},
  url          = {http://dx.doi.org/10.1152/ajpgi.00418.2015},
  volume       = {311},
  year         = {2016},
}

Chicago
Kwanten, Wilhelmus J, Yves-Paul Vandewynckel, Wim Martinet, Benedicte Y De Winter, Peter P Michielsen, Viviane O Van Hoof, Ann Driessen, et al. 2016. “Hepatocellular Autophagy Modulates the Unfolded Protein Response and Fasting-induced Steatosis in Mice.” American Journal of Physiology-gastrointestinal and Liver Physiology 311 (4): G599–G609.
APA
Kwanten, W. J., Vandewynckel, Y.-P., Martinet, W., De Winter, B. Y., Michielsen, P. P., Van Hoof, V. O., Driessen, A., et al. (2016). Hepatocellular autophagy modulates the unfolded protein response and fasting-induced steatosis in mice. AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 311(4), G599–G609.
Vancouver
1.
Kwanten WJ, Vandewynckel Y-P, Martinet W, De Winter BY, Michielsen PP, Van Hoof VO, et al. Hepatocellular autophagy modulates the unfolded protein response and fasting-induced steatosis in mice. AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY. 2016;311(4):G599–G609.
MLA
Kwanten, Wilhelmus J, Yves-Paul Vandewynckel, Wim Martinet, et al. “Hepatocellular Autophagy Modulates the Unfolded Protein Response and Fasting-induced Steatosis in Mice.” AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 311.4 (2016): G599–G609. Print.