The liver is a central metabolic organ. Activating transcription factor 6 (ATF6) acts as an ER stress responsive gene and is reported to attenuate hepatic steatosis. Over expressing a dominant-negative form of ATF6 exacerbates glucose intolerance and insulin resistance. In the present study, we used the conditional knockout technique to specifically knockout ATF6 in the mouse liver. We used qPCR to detect the mRNA levels of related genes. Western blot analysis was used to evaluate protein levels. Flow cytometry assay showed the apoptosis status. Glucose tolerance tests and insulin tolerance tests were used to determine glucose and insulin sensitivity. The results showed that liver specific knockout of ATF6 exacerbated HFD-induced hepatic steatosis and glucose tolerance. Abolished ATF6 exacerbated gluconeogenic metabolism by MTOR mediated down regulation of autophage. In conclusion, these findings suggest that therapeutic strategies by supplementing ATF6 may be beneficial for the treatment of glucose intolerance as well as insulin resistance in the high fat induced liver metabolic damage condition. (C) 2018 Elsevier Inc. All rights reserved.