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

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Publisher: American Physiological Society
Document Type: Author abstract; Report
Length: 242 words

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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 hepalocyte-specific autophagy deficiency on liver parenchyma, the UPR, and lipid metabolism. Adult hepatocellular-specific autophagy-deticient mice ([Atg7.sup.F/F] [Alb-Cre.sup.+]) were compared with their autophagy-competent littermates ([Atg7.sup.+/+], [Alb-Cre.sup.+]). Livers were analyzed by electron microscopy, histology, real-time qPCR, and Western blotting. [Atg7.sup.F/F] [Alb-Cre.sup.+] 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.sup.+/+] [Alb-Cre.sup.+] mice. The inositol-requiring enzyme-la signal was unaltered. Fasting-induced steatosis was absent in [Atg7.sup.+/+] [Alb-Cre.sup.+] 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. nonalcoholic fatty liver; steatosis; autophagy; endoplasmic reticulum stress; unfolded protein response doi: 10.1152/ajpgi.00418.2015

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Gale Document Number: GALE|A470868284