BACKGROUND & AIMS Autophagy and the unfolded protein response (UPR) are key cellular homeostatic mechanisms and are both involved in liver diseases, including non-alcoholic fatty liver disease (NAFLD). Although increasing but conflicting results link these mechanisms to lipid metabolism, their role and potential crosstalk herein has been poorly investigated. Therefore, we assessed the effects of hepatocyte-specific autophagy-deficiency on liver parenchyma, the UPR and lipid metabolism. METHODS Adult hepatocellular-specific autophagy-deficient mice (Atg7^F/FAlb-Cre⁺) were compared with their autophagy-competent littermates (Atg7^+/+Alb-Cre⁺). Livers were analysed by electron microscopy, histology, real-time qPCR and Western blotting. RESULTS Atg7^F/FAlb-Cre⁺ mice developed hepatomegaly with significant parenchymal injury as evidenced 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 ATF6 pathway was abolished, whereas the pro-apoptotic PERK pathway was increased compared to Atg7^+/+Alb-Cre⁺ mice. The IRE1α signal was unaltered. Fasting-induced steatosis was absent in Atg7^F/FAlb-Cre⁺ mice. Remarkably, some isolated islands of fat-containing and autophagy-competent cells were observed in these livers. CONCLUSIONS Hepatocellular autophagy is essential for parenchymal integrity in mice. Moreover, in 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.