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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.
Keywords
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

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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.
@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},
}

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