title: Hepatocellular autophagy modulates the unfolded protein response and fasting-induced steatosis in mice.
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-1α 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.
authors: Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, Antwerp, Belgium; wilhelmus.kwanten@uantwerpen.be.
authors: Wilhelmus J
authors: 0000-0001-9474-6695
authors: WJ
authors: Kwanten
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Yves-Paul
authors: YP
authors: Vandewynckel
authors: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors: Wim
authors: W
authors: Martinet
authors: Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, Antwerp, Belgium.
authors: Benedicte Y
authors: BY
authors: De Winter
authors: Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, Antwerp, Belgium; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem (Antwerp), Belgium.
authors: Peter P
authors: PP
authors: Michielsen
authors: Department of Clinical Chemistry, Antwerp University Hospital, Edegem (Antwerp), Belgium.
authors: Viviane O
authors: VO
authors: Van Hoof
authors: Department of Pathology, Antwerp University Hospital/University of Antwerp, Edegem (Antwerp), Belgium.
authors: Ann
authors: A
authors: Driessen
authors: Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium.
authors: Jean-Pierre
authors: JP
authors: Timmermans
authors: Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Paris University-Denis Diderot, Clichy, France.
authors: Pierre
authors: P
authors: Bedossa
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Hans
authors: H
authors: Van Vlierberghe
authors: Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, Antwerp, Belgium; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem (Antwerp), Belgium.
authors: Sven M
authors: SM
authors: Francque
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D005215:Fasting / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse
keywords: autophagy; endoplasmic reticulum stress; nonalcoholic fatty liver; steatosis; unfolded protein response