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

Am J Physiol Gastrointest Liver Physiol. 2016 Oct 1;311(4):G599-G609. doi: 10.1152/ajpgi.00418.2015. Epub 2016 Aug 11.


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.

Keywords: autophagy; endoplasmic reticulum stress; nonalcoholic fatty liver; steatosis; unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / metabolism
  • Animals
  • Autophagy / physiology*
  • Fasting / metabolism*
  • Fatty Liver / metabolism*
  • Hepatocytes / metabolism*
  • Lipid Metabolism / physiology
  • Liver / metabolism*
  • Mice
  • Mice, Transgenic
  • Unfolded Protein Response / physiology*


  • Activating Transcription Factor 6
  • Atf6 protein, mouse